The reliability and credibility of current glycemia guidelines in type 2 diabetes

Notas do Editor

1. Arch Inter Med 171: 577-585,2011Thant you for giving me this opportunity to visit Um alrabien Al mosul and to talk about this important subject.To present on : The Reliability and Credibility of Current Glycemia guidelines in Type 2 Diabetes MellitusMy talk which is entitled : The Reliability and Credibility of Current Glycemia guidelines in Type 2 Diabetes MellitusI am moderating this next section which is entitled future guidelines that you can see from the titles.I am going to discuss the limitations of present guidelines with hope for some directions in terms that those organizations that are attempting to define the guidelinesWe all recognize the need for guidelines as being something important for our primary care colleagues to be able to follow and helping to improve their management of care patients with diabetes and comorbidities .But also I will talk about the importance of clinical judgment and individualization which of course leads to a very complicated System of trying to come with the guidelines. I will would like to introduce our first speaker robertHis current status is he director of diabetes institute of Walterlead health care system professor of medicine at the uniform services universityHis research interests are in technology ofThank you and thank for the invitation to speak and also I appreciate your tremindous efforts to bring this meeting into reality.National Guideline Clearing house
2. للكتاب وللبحث والمحاضراتSulfonylureas Up Mortality Risk in DiabetesBy Charles Bankhead, Staff Writer, MedPage Today Published: June 24, 2012 Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoTake PosttestAction PointsNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Diabetic patients treated with three commonly prescribed sulfonylurea drugs had a 50% higher mortality risk compared with patients treated with metformin.Point out that cost is not a distinguishing factor, as all three drugs are available in inexpensive generic forms.HOUSTON -- Diabetic patients treated with three commonly prescribed sulfonylurea drugs had a 50% higher mortality risk compared with patients treated with metformin, data from a large retrospective cohort study suggested.The relative risk ranged from 59% with glyburide to 68% with glimepiride. In the subgroup of patients with coronary artery disease (CAD), glipizide and glyburide had significant associations with mortality versus metformin but not glimepiride."Metformin, when not contraindicated, should be the first-line agent prescribed to control blood sugar levels in patients with type 2 diabetes," Kevin Pantalone, DO, of Summa Western Reserve Hospital in Cuyahoga Falls, Ohio, said at a press briefing during ENDO 2012."This research is relevant to the general public because there are 25.8 million people with diabetes in the U.S. alone, 8.3% of the population," he added. "The medications under study in our report are some of the most commonly prescribed medications utilized in the treatment of type 2 diabetes."Until recently, sulfonylureas had been considered comparable in safety and effectiveness. Several studies have changed that perception by suggesting that some of the drugs might be safer than others, Pantalone said. Specifically, conflicting results have emerged from studies of the drugs' cardiovascular safety. A theoretical difference in risk exists because the drugs vary with respect to hypoglycemic risk, sulfonylurea receptor selectivity, and effects on myocardial ischemic preconditioning.Cost is not a distinguishing factor, as all three drugs are available in inexpensive generic forms. Metformin offers an alternative to sulfonylureas as first-line oral therapy for diabetes and also is available as a generic.To continue the exploration of sulfonylurea safety, Pantalone and collaborators used an enterprise-wide electronic health record (EHR) system to conduct a retrospective study of diabetic patients who started treatment with one of the sulfonylureas or metformin from Oct. 24, 1998 to Oct. 12, 2006.The search produced records for 23,915 patients. About half (12,774) started treatment with metformin, followed by glipizide (4,325), glyburide (4,279), and glimepiride (2,537). All patients were adults treated in outpatient clinics. Investigators excluded patients using insulin, other injectable diabetes medications, or multiple oral drugs for diabetes.The patients had a median follow-up of 2.2 years and 2,546 patients died, as verified by the EHR or Social Security Death Index.Overall, patients treated with a sulfonylurea had a mortality hazard ratio of 1.50 compared with metformin, including: Glipizide -- HR 1.64, 95% CI 1.39 to 1.94Glyburide -- HR 1.59, 95% CI 1.35 to 1.88Glimepiride -- HR 1.68, 95% CI 1.37 to 2.06Because recent reports suggested sulfonylurea risk varied in patients with CAD, investigators conducted a separate analysis of 2,721 patients with a history of CAD. Pantalone said 419 deaths occurred during follow-up in that subgroup.As compared with metformin, patients who started treatment with glyburide had a 38% increase in the mortality hazard (HR 1.38, 95% CI 1.04 to 1.83), and there was a 41% increased risk in patients started on glipizide (HR 1.41, 95% CI 1.07 to 1.87). Only glimepiride was not associated with an increased mortality hazard versus metformin."Our results suggest that if a sulfonylurea is required to control blood sugar levels, glimepiride may be the preferred sulfonylurea in those with known coronary artery disease," Pantalone said.The story about sulfonylurea safety will continue to evolve as more information becomes available, said Alvin Powers, MD, of Vanderbilt University in Nashville, Tenn., who was not involved in the study."What we really need is a prospective comparison, which is one of the standards now being used by the FDA on the cardiovascular risk of drugs," said Powers, who moderated the press briefing. "We don't know enough about those drugs [sulfonylureas].""I think metformin remains the primary drug," he added. "I think that in studies we've shown that glipizide and glimepiride are probably preferred over glyburide because of the length of the studies. I think that, because glycemic control is important, the second-line drug still can be a sulfonylurea."The study was supported by AstraZeneca.Pantalone had no conflicts of interest.Primary source: ENDO 2012Source reference:Pantalone KM, et al "Increased risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, and glimepiride vs. metformin. A retrospective analysis" ENDO 2012.  
3. To present on : The Reliability and Credibility of Current Glycemia guidelines in Type 2 Diabetes MellitusMy talk which is entitled : The Reliability and Credibility of Current Glycemia guidelines in Type 2 Diabetes MellitusHow far the conflicts of interest might undermine the reliability and credibility of present guidelines for treatment of type 2 diabetes.The need for guidelines as being something important for our primary care colleagues to be able to follow and helping them to improve their management of care patients with diabetes and comorbidities .The importance of clinical judgment and individualization of treatment of type 2 diabetesI am going to discuss the limitations of present guidelines for treatment of type 2 diabetes and how far the conflicts of interest might undermine the reliability and credibility of these guidelines.We all recognize the need for guidelines as being something important for our primary care colleagues to be able to follow and helping to improve their management of care patients with diabetes and comorbidities .But also I will talk about the importance of clinical judgment and individualization of treatment of type 2 diabetesHow far the conflicts of interest might undermine the reliability and credibility of present guidelines for treatment of type 2 diabetes.The need for guidelines as being something important for our primary care colleagues to be able to follow and helping them to improve their management of care patients with diabetes and comorbidities .The importance of clinical judgment and individualization of treatment of type 2 diabetes
4. Others, however, argue that conflict of interest policies—when they exist—are often weak, inconsistent, and inadequately administered and enforced.
5. Candidate List of Categories of Financial Relationships with Industry to Be DisclosedView in own windowResearch grants and contractsConsulting agreementsParticipation in speakers bureausHonorariaIntellectual property, including patents, royalties, licensing feesStock, options, warrants, and other ownership (excepting general mutual funds)Position with a companyCompany governing boardsTechnical advisory committees, scientific advisory boards, and marketing panelsCompany employee or officer, full or part timeAuthorship of publications prepared by othersExpert witness for a plaintiff or a defendantOther payments or financial relationshipsFrom: 3, Policies on Conflict of Interest: Overview and EvidenceConflict of Interest in Medical Research, Education, and Practice.Institute of Medicine (US) Committee on Conflict of Interest in Medical Research, Education, and Practice; Lo B, Field MJ, editors.Washington (DC): National Academies Press (US); 2009.Copyright © 2009, National Academy of Sciences.NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
6. “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” A Journal of the American Medical Association review published by Wazana and colleagues in 2000“Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”  said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.  “If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”  According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today. “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today. “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-CampoyAccording to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel LexchinAccording to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine. But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. StosselAccording to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily ShaferFor more information:Blum J. JAMA. 2009;302:2230-2234.Campbell E. N Engl J Med. 2007;356:1742-1750.Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest. Accessed April 15, 2011.Mendelson T. Arch Intern Med. 2011:177:577-585.Rochon P. Open Med. 2010;4:e69-e91.Roseman M. JAMA. 2011;305:1008-1017.Wazana A. JAMA. 2000;283:373-380.Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  
7. • Lifestyle interventions to improve glucose, blood pressure and lipidlevels, and to promote weight loss or at least to avoid weight gainremain the underlying strategy throughout the management of diabeteseven when additional medications are needed.• Metabolic variables, such as HbA 1c , post - prandial blood glucoseconcentrations, serum triglyceride and low density lipoproteincholesterol levels, can be used to suggest the most appropriate intakesof carbohydrate - containing foods.• Vegetables, legumes, fruits and wholegrain cereal - based foods shouldbe part of the diet because they are rich in dietary fiber, low inglycemic index or load and provide a range of micronutrients.• In those treated with insulin or oral hypoglycemic agents, the timingand dosage of medication should match the quantity and nature ofcarbohydrate to avoid hyperglycemia or hypoglycemia. Blood glucoseself - monitoring may help to make appropriate choices.
8. • Lifestyle interventions to improve glucose, blood pressure and lipidlevels, and to promote weight loss or at least to avoid weight gainremain the underlying strategy throughout the management of diabeteseven when additional medications are needed.• Metabolic variables, such as HbA 1c , post - prandial blood glucoseconcentrations, serum triglyceride and low density lipoproteincholesterol levels, can be used to suggest the most appropriate intakesof carbohydrate - containing foods.• Vegetables, legumes, fruits and wholegrain cereal - based foods shouldbe part of the diet because they are rich in dietary fiber, low inglycemic index or load and provide a range of micronutrients.• In those treated with insulin or oral hypoglycemic agents, the timingand dosage of medication should match the quantity and nature ofcarbohydrate to avoid hyperglycemia or hypoglycemia. Blood glucoseself - monitoring may help to make appropriate choices.
9. • Regular exercise increases insulin sensitivity in both individuals withand without diabetes.• In individuals without diabetes, plasma insulin levels decrease duringlow to moderate intensity exercise to compensate for increases ininsulin sensitivity. Glucose production and glucose disposal increase inparallel in order to maintain blood glucose homeostasis.• In individuals with type 1 diabetes (T1DM), low to moderate intensityexercise can result in hypoglycemia, as insulin levels cannot beregulated physiologically.• During and after high intensity exercise, glucose production can exceedglucose disposal, causing hyperglycemia in individuals both with andwithout diabetes. In T1DM, hyperglycemia can be more marked andprolonged, as insulin cannot increase in response.• It is recommended that individuals with T1DM adjust their insulin doseand carbohydrate consumption prior to, during and/or after exercise toaccommodate the type, intensity and duration of exercise performed.
10. • Regular exercise increases insulin sensitivity in both individuals withand without diabetes.• In individuals without diabetes, plasma insulin levels decrease duringlow to moderate intensity exercise to compensate for increases ininsulin sensitivity. Glucose production and glucose disposal increase inparallel in order to maintain blood glucose homeostasis.• In individuals with type 1 diabetes (T1DM), low to moderate intensityexercise can result in hypoglycemia, as insulin levels cannot beregulated physiologically.• During and after high intensity exercise, glucose production can exceedglucose disposal, causing hyperglycemia in individuals both with andwithout diabetes. In T1DM, hyperglycemia can be more marked andprolonged, as insulin cannot increase in response.• It is recommended that individuals with T1DM adjust their insulin doseand carbohydrate consumption prior to, during and/or after exercise toaccommodate the type, intensity and duration of exercise performed.• While regular exercise has not conclusively been found to improveglycemic control in T1DM, it is associated with decreased long - termmorbidity and mortality in this population.• Structured supervised diet and exercise interventions can reduce therisk of developing type 2 diabetes mellitus (T2DM) by about 60% inindividuals with impaired glucose tolerance.• Regular exercise improves glycemic control significantly in T2DM.• Individuals with T1DM and T2DM with moderate or high aerobic fitnesshave long - term mortality that is 50 – 60% lower than individuals withdiabetes and low cardiorespiratoryfitness.• Resistance training is a safe and effective means of improving glycemiccontrol in individuals with T2DM of all ages. To maximize the impact oflifestyle measures on glycemic control, combined aerobic and resistanceexercise is more effective than either type of exercise alone.
11. “These conflicts undermine the reliability and credibility of the guidelines,”One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” “Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”  said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.  “If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”  According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today. “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today. “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-CampoyAccording to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel LexchinAccording to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine. But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. StosselAccording to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily ShaferFor more information:Blum J. JAMA. 2009;302:2230-2234.Campbell E. N Engl J Med. 2007;356:1742-1750.Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest. Accessed April 15, 2011.Mendelson T. Arch Intern Med. 2011:177:577-585.Rochon P. Open Med. 2010;4:e69-e91.Roseman M. JAMA. 2011;305:1008-1017.Wazana A. JAMA. 2000;283:373-380.Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  
12. “Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”  said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.  “If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”  According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today. “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today. “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-CampoyAccording to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel LexchinAccording to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine. But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. StosselAccording to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily ShaferFor more information:Blum J. JAMA. 2009;302:2230-2234.Campbell E. N Engl J Med. 2007;356:1742-1750.Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest. Accessed April 15, 2011.Mendelson T. Arch Intern Med. 2011:177:577-585.Rochon P. Open Med. 2010;4:e69-e91.Roseman M. JAMA. 2011;305:1008-1017.Wazana A. JAMA. 2000;283:373-380.Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  
13. A Journal of the American Medical Association review published by Wazana and colleagues in 2000“Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” “Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”  said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.  “If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”  According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today. “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today. “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-CampoyAccording to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel LexchinAccording to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine. But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. StosselAccording to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily ShaferFor more information:Blum J. JAMA. 2009;302:2230-2234.Campbell E. N Engl J Med. 2007;356:1742-1750.Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest. Accessed April 15, 2011.Mendelson T. Arch Intern Med. 2011:177:577-585.Rochon P. Open Med. 2010;4:e69-e91.Roseman M. JAMA. 2011;305:1008-1017.Wazana A. JAMA. 2000;283:373-380.Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  
14. To provide more specific and comprehensive guidance to academic institutions on conflict of interest policies, the Association of American Medical Colleges (AAMC, 2001, 2002, 2008c), the Association of American Universities (AAU, 2001), AAMC and AAU jointly (AAMC-AAU, 2008), and the Council on Government Relations (COGR, 2002) have issued several reports with recommendations. Policies on Conflict of Interest: Overview and EvidenceCurrent conflict of interest policies and practices have evolved over more than four decades of increasing relationships with industry in medical education, research, and practice. The increase has been accompanied by intensifying discussions about how the risks and the expected benefits of these relationships should be evaluated and balanced.
15. To provide more specific and comprehensive guidance to academic institutions on conflict of interest policies, the Association of American Medical Colleges (AAMC, 2001, 2002, 2008c), the Association of American Universities (AAU, 2001), AAMC and AAU jointly (AAMC-AAU, 2008), and the Council on Government Relations (COGR, 2002) have issued several reports with recommendations. Policies on Conflict of Interest: Overview and EvidenceCurrent conflict of interest policies and practices have evolved over more than four decades of increasing relationships with industry in medical education, research, and practice. The increase has been accompanied by intensifying discussions about how the risks and the expected benefits of these relationships should be evaluated and balanced. The influence of the pharmaceutical industry on medical research has been a major cause for concern. In 2009 a study found that "a number of academic institutions" do not have clear guidelines for relationships between Institutional Review Boards and industry.[4][4]Policies regarding IRB members' industry relationships often lacking.
16. In preparing for this talk I first searched in the National Guideline Clearinghouse website and look at what algorithms and guidelines for the management of type 2 diabetes have appeared in the last three years. I am going to limit my discussion to these five algorithms and guidelines . Diabetes Care,Diabetologia. 19April 2012 [Epub ahead of print]And I am going to show them in a quick way. The first thing in preparing for this talk was is to search in the National Guideline Clearinghouse website and look at what algorithms and guidelines for the management of type 2 diabetes have appeared in the last three years. There are other guidelines out thereهناك that have been registered or in the process being registered, but these the ones that are actually out thereهناك. I am going to limit my discussion to these five. The first one I am going to talk are ACCE and ADA/EASD guidelines and I am going to talk about the NICE which is British and the SIGN which is Scottish guidelines and then the VA/DoD. His current statusDisclosuresNo relevantfinacial relationships with any commercial interestsAlgorithm (in guidelines) A flow chart of the clinical decision pathway described in the guideline, where decision points are represented by boxes, linked with arrows. NICE (National Institute For Health and Clinical Excellence )- 2009 I am going to talk about each one in detail what these actually look like when you go the paper that describe them.These 5 guidelines have been published in 2009 and 2010 versions. So they are reasonably up to date with all the new classes , that we use for management of diabetes.Statement by anAACE (American Association of Clinical Endocrinologists)ADA/EASDCaliforniaCanadian Diabetes AssociationInstitute for clinical systems improvementNICE (National Institute For Health and Clinical Excellence )- 2009SIGN (Scottish Intercollegiate Guidelines Network ) - 2010MichiganWisconsinVA (Veterans Health Affairs)American Association of Clinical Endocrinologists /American College of EndocrinologyConsensus Panel on Type 2 Diabetes Mellitus:An Algorithm for Glycemic ControlVA/ DoD(Veterans Health Affairs / Department of Defense)
17. So I decided to do the same thing for some of the guideline I am going to be discussing. So these the conflicts of AACE.There were 12 authors.If you look at the bottom75% of them has Research grants88% had Honoraria/Speakers bureau income16% only few of them has Stock/Other Ownership88% had Consultant/ Advisory board income.So it is very similar to the cardiology colleagues.What is not in any of these guidelines is the amount of money that is involved in all these activities.Many of you may know ProPublica website that you can go on and plugging your favorite doctor and find out how much of money he or she has received from various pharmaceutical companies in the last year.
18. Here is the amount of money they were received by these authors in the last year.The mean is $89,691The median = $ 44,044The range is from $ 44,00 to over $ 200,000So one of the things in terms of transparency of our conflicts is we are publishing what the guidelines but the amount of those conflicts or potential conflicts are rarely published and I think they do inform us about what could or may or may not be influencing what the guideline says. And I am not impugning any body’s reputation here but I thing transparency is really key.
19. In this slide You Can see that for each of these guideline for diabetes there are large number of potential conflicts of interest.Excluding VA/DoD in which there are no conflicts at all. You can see that the conflicts of interest of all groups that are putting out guidelines and algorithms for diabetes have a high level of potential of conflicts of interest and this is no difference than our cardiology colleagues and arguably any other specialty.
20. Now When we do guidelines we use hierarchy of evidence and this is the general Hierarchy that every body knows about and it assumed that meta-analysis are the highest level of evidence and are assumed to be in no respect immune from various conflicts. Well it turns out that may not actually be the case.
21. Why do we talk about systematic reviews so much?There are more than 30,000 medical and health journals. They publish far more information than anyone can read, and it is not all of equal quality and value. So how can anyone know what to read and keep up any more? Even if you only consider controlled trials, the challenge is enormous: more than 60 are published every day. This is why we need systematic reviews to sort out the wheat from the chaff for us. Researchers look for all the trials they can find. They analyse them to see what treatments might really work. But even keeping up with these is getting harder. There are four new systematic reviews every day, too. Our team will keep a watch on them and choose interesting and important ones to help you keep on top of the flood of health information.
22. Well it turns out that may not actually be the case. So in a paper by Roseman in JAMA this year 2011 , he and his colleagues look at the conflicts of interest that were in Meta-analysis . They looked 29 high impact journals that had Meta-analysis and they looked 29 of these . Just look to see how many of Meta-analysis reported the funding sources of the RCT that they were doing the Meta-analysis on.and turns out the vast majority don’t report them at all.
23. So then they went and they looked at 509 RCT in these 29 Meta-analysis and looked at them to see if they reported funding sources and of them 318 reported and 191 did not. And of those industry funded yes was 69% and no 31%. And we know generally that those that are industry funded tend to report positive results and those who are not industry funded tend to report negative results.
24. And then further they looked at the authors of those RCTs and whether not they had in their RCTs reported their financial disclosures and the vast majority did not and those who did, 91 of the 132 had at least one conflicts of interest.So I think this is cautionary note so that even we look at Meta-analysis and we use them for developing our clinical practice guidelines, there is the potential, may be more than the potential for using that data that may actually have some bias from these conflicts of interest. “There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.”
25. Now If we were developing a guideline, in this case diabetes , we have to establish what are glycemic goal is. Of course, this is been subject of some controversy.
26. Most of you are familiar with thermometer , showing A1c on the left and corresponding blood glucose on the right. And just for the referenceThis is a paper from Hoeger describing the enhanced data and from that data it shows that the control in A1c actually is getting better, this was through 2004, but 43% of people still have A1Cs over 7%, but if you actually look at subgroups, those who are AA 56% of them are not well controlled, 63% Hispanic and you further drill down into various age ranges, these percentages get even higher in age ranges of 40 to 65.Now what are the goals of the guidelines I am going to discuss, the A1c goals, we will go into more detail in just a bit. The ACCE and NICE set a goal of 6.5% , the ADA/EASD combined guideline, SIGN and DoD/VA have chosen 7%. And interestingly and I am going to discuss it little later, the NICE guideline actually establishes a higher goal at some point later in the algorithm and that goal is 7.5%. So you can see there is considerable variation from 6.5 to 7.5% and the reason of this and some of the new answers I am going to discuss in a bit.*Referenced to a nondiabetic range of 4.0–6.0% using a DCCT-based assay. †Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.
27. Scottish Intercollegiate Guidelines Network (SIGN) – 2010: REVIEW AND SET GLYCAEMIC TARGET: HBA1C <7% (53 mmol/mol) OR INDIVIDUALISED AS AGREEDSlide 2. A1C Targets Suggested by Different Organizations I'm going to outline where we are with incretin therapies and cover the gamut of what we know today. When we talk about glucose control, Dr. Horton essentially hit the nail on the head. We can talk about glycosylated hemoglobin (A1C), and we can talk about the current guidelines for both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinology (AACE) - and it is important enough to get the A1C down to goal - but what's even more important is how sustained that effect will be. Throughout the lecture tonight I'm going to try to show you the data on not only achieving glucose control, but how well these agents and, more importantly, combinations of agents get the job done.Setting a target HbA1c● When setting a target HbA1c:– involve the person in decisions about their individual HbA1c target level, which may be abovethat of 6.5% set for people with type 2 diabetes in general– encourage the person to maintain their individual target unless the resulting side effects(including hypoglycaemia) or their efforts to achieve this impair their quality of life– offer therapy (lifestyle and medication) to help achieve and maintain the HbA1c target level– inform a person with a higher HbA1c that any reduction in HbA1c towards the agreedtarget is advantageous to future health– avoid pursuing highly intensive management to levels of less than 6.5%.
28. Now why we get to 7% which always has been the goal with the ADA for instant says the spouse. Most of you in this room is familiar with results of DCCT study and particularly the microvascular risk reduction and all the microvascular outcomes, and once you get down below 7% you could achieve over 90% of the benefit.
29. ميراث أثرDCCT/EDIC.NEJM 353:2643-2653, 2005That is microvscular disease but then there was the extension of that study the EDIC study, which showed in terms of macrovascular effects that there was a legacy of that intensive treatment in terms of both cardiovascular outcomes and mortality. The problem with using this as a reason to establish 7% as a goal is that this was actually an observational study. The original DCCT study was a randomized study , but the EDIC is a follow up observation study.
30. The parallel study for type 2 diabetes, was a follow up of UKPDS study .But on the left are the outcomes after the completion of the randomized controlled trial, the follow up of patients on the left who run sulfonylurea and insulin and on the right on metformin. And you can see that virtually all the outcomes there is an improvement in long term outcomes both microvascular and macrovasular as a results of these two types of managements. However, this also is an observation study. And again in theHierarchy of our evidence rates lower or should rate lower than the randomized control trial.On the leftFigure 3. Hazard Ratios for Four Prespecified Aggregate Clinical Outcomes.Hazard ratios for patients in the United Kingdom Prospective Diabetes Study who had any diabetes-related end point (Panels A and B), myocardial infarction (Panels C and D), or microvascular disease (Panels E and F) or who died from any cause (Panels G and H) are shown for the sulfonylurea–insulin group versus the conventional-therapy group and for the metformin group versus the conventional-therapy group. The overall values at the end of the study,1 in 1997, are shown (red squares), along with the annual values during the 10-year post-trial monitoring period (blue diamonds). Hazard ratios below unity indicate a favorable outcome from sulfonylurea or metformin therapy. Numbers of first events in an aggregate outcome that accumulated in each group are shown at 2-year intervals. The vertical bars represent 95% confidence intervals.10-Year Follow-up of Intensive Glucose Control in Type 2 DiabetesRury R. Holman, F.R.C.P., Sanjoy K. Paul, Ph.D., M. Angelyn Bethel, M.D., David R. Matthews, F.R.C.P., and H. Andrew W. Neil, F.R.C.P.N Engl J Med 2008; 359:1577-1589October 9, 2008AbstractArticleReferencesCiting Articles (631) BackgroundDuring the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.Full Text of Background...MethodsOf 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.Full Text of Methods...ResultsBetween-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea–insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).Full Text of Results...ConclusionsDespite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)
31. Now If we were developing a guideline, in this case diabetes , we have to establish what are glycemic goal is. Of course, this is been subject of some controversy.
32. Now that of course brings us to more current studies and I have summarized in this one slide, the ACCORD, the ADVANCE and VA diabetes trial which have done on a large number of patients, typical type 2 patients, mean A1Cs starting in the 7.5% to 9.4 % range, they achieved improvement in control and in intensive arms ……. And here the drugs that were used in the various studies as will know in the ACCORD study the actually show not only there is no benefit, there is actually higher mortality and that there was no difference in the cardiovascular outcomes in the ADVANCE andVA/DoD trials.So the goal for A1Cs , one interpretation exists is that our current therapies may not be able to safely achieved or achieve any benefit in the macrovascular arena when we target 7%.VA diabetesADVANCE
33. ( in hypertesion 10-70% to thiazide diuretics and in hyperlipidemia 35-75% to HMG CoAReductase inhibitors 6.5% of new hospital admissions to internal medicine wards are directly related to ADRs!(1,225 admissions out of 18,820 during six months)4% of bed occupancy - directly due to ADRsAnnual UK cost: EUR 706 million (direct hospitalization costs - actual costs much higher!)Women: 59% of ADRs (while only 52% of admissions)Pirmohamed et al (July 2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 329:15-19.
34. Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [20]
35. In fact the VA/DoD guideline , actually gives and I think this is the first and the only one, some recommendations for specific A1C recommendations in which the comorbidities and life expectancy is taken into account. So , for those who are greater than 10 years of life expectancy and have no or very mild complications the goal is 7% or less and on the other extreme if you have less than 5 years of life expectancy and advanced complications the goal will be as higher as 8-9%. And so I think that while this is a consensus opinion, the consensus that is now building I think in our field that one size does not fit all and we can not be rigid about these and turn the reimbursing people based on how well the patient is controlled may be totally inappropriate.
36. So now I am going to get to the existing algorithms
37. The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus. Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated hemoglobin;MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4aFor patients with diabetes mellitus and HbA1c <6.5%, pharmacologic treatment may be considered.bDPP-4 ifPPG andFPG or GLP-1ifPPG.cTZD if metabolic syndrome and/or nonalcoholic fatty liver disease.dHbA1c ifPPG.eIf HbA1c goal not achieved safely.fLow-dose secretagogue recommended.gGlinide ifPPG or SU ifFPG.hDecreasesecretagogue by 50% when added to GLP-1 or DPP-4.ia) Discontinue insulin secretagogue with multidose insulin; b) can use pramlintide with prandial insulin.jIf HbA1c >8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution.kGLP-1 not approved for initial combination pharmacologic treatment.lIf HbA1c >8.5%, in patients on dual therapy, insulin should be considered.
38. The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus. Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated hemoglobin;MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4aFor patients with diabetes mellitus and HbA1c <6.5%, pharmacologic treatment may be considered.bDPP-4 ifPPG andFPG or GLP-1ifPPG.cTZD if metabolic syndrome and/or nonalcoholic fatty liver disease.dHbA1c ifPPG.eIf HbA1c goal not achieved safely.fLow-dose secretagogue recommended.gGlinide ifPPG or SU ifFPG.hDecreasesecretagogue by 50% when added to GLP-1 or DPP-4.ia) Discontinue insulin secretagogue with multidose insulin; b) can use pramlintide with prandial insulin.jIf HbA1c >8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution.kGLP-1 not approved for initial combination pharmacologic treatment.lIf HbA1c >8.5%, in patients on dual therapy, insulin should be considered.
39. Here are the effects of monotherapy of all the various classes, you can see the A1c reduction is quite similar in all these classes and you can see that the cost per month varies greatly obviously from very low cost Sulphonylura,Biguanide to very high cost of Bromocriptine, Exenatide,Sitagliptin,Saxagliptin,and so for, for the same A1C reduction.
40. and you can see that the cost per month varies greatly obviously from very low cost Sulphonylura,Biguanide to very high cost of Bromocriptine, Exenatide,Sitagliptin,Saxagliptin,and so for, for the same A1C reduction.
41. The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus. Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated hemoglobin;MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4aFor patients with diabetes mellitus and HbA1c <6.5%, pharmacologic treatment may be considered.bDPP-4 ifPPG andFPG or GLP-1ifPPG.cTZD if metabolic syndrome and/or nonalcoholic fatty liver disease.dHbA1c ifPPG.eIf HbA1c goal not achieved safely.fLow-dose secretagogue recommended.gGlinide ifPPG or SU ifFPG.hDecreasesecretagogue by 50% when added to GLP-1 or DPP-4.ia) Discontinue insulin secretagogue with multidose insulin; b) can use pramlintide with prandial insulin.jIf HbA1c >8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution.kGLP-1 not approved for initial combination pharmacologic treatment.lIf HbA1c >8.5%, in patients on dual therapy, insulin should be considered.
42. eFigure 6. Results of Mixed Treatment Comparison Meta-analysis Presented as Forest PlotsThe squares represent the pooled effect size for each class of oral antidiabetic drug. Error barsrepresent 95% credible intervals (CrIs). The number of trials included in each mixed-treatmentcomparison analysis is as follows: A=26 trials, B=13 trials, C=15 trials, and D=24 trials.Abbreviations: AGI=alpha-glucosidase inhibitor; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; SU=sulfonylurea; TZD=thiazolidinedionesFinancial Disclosures: Drs Phung and Coleman reported previously receiving research support from Takeda Pharmaceuticals North America, a manufacturer of antidiabetic drugs. Dr Scholle and Ms Talwar reported no disclosures.Funding/Support: This work was supported financially by the Hartford Hospital Research Foundation, Hartford, Connecticut.JAMA. 2010;303(14):1410-1418. doi: 10.1001/jama.2010.405 Effect of Noninsulin Antidiabetic Drugs Added to Metformin Therapy on Glycemic Control, Weight Gain, and Hypoglycemia in Type 2 Diabetes Olivia J. Phung, PharmD; Jennifer M. Scholle, PharmD; MehakTalwar, BS; Craig I. Coleman, PharmD[+] Author AffiliationsAuthor Affiliations: University of Connecticut School of Pharmacy, Storrs, and Drug Information Center, Hartford Hospital, Hartford, Connecticut. Corresponding Author: Craig I. Coleman, PharmD, University of Connecticut School of Pharmacy, 80 Seymour St, Hart- ford, CT 06102-5037 (ccolema@harthosp.org). More author informationNext SectionAbstractContextMetformin is the recommended initial drug therapy for patients with type 2 diabetes mellitus (DM). However, the optimal second-line drug when metforminmonotherapy fails is unclear. Objective To determine the comparative efficacy, risk of weight gain, and hypoyglycemia associated with noninsulin antidiabetic drugs in patients with type 2 DM not controlled by metformin alone. Data Sources A literature search via MEDLINE (beginning in January 1950) and Cochrane CENTRAL through January 2010 and a manual search of references for additional relevant studies. Study Selection Randomized controlled trials (RCTs) with at least 3 months’ duration, evaluating noninsulin antidiabetic drugs added to metformin in patients experiencing an inadequate response to maximized and stable (≥4 weeks at ≥1500 mg or maximally tolerated dose) metformin therapy. Data Extraction Inclusion/exclusion criteria; duration of patient follow-up; drug, dose, and schedule used; use of concurrent lifestyle modification; and baseline characteristics (age, sex, anthropometrics, glycated hemoglobin A1c [HbA1c], duration of DM, and metformin dose). End points collected included mean change in HbA1c, proportion of patients achieving HbA1c goal of less than 7%, change in weight, and incidence of hypoglycemia. Mixed-treatment comparison meta-analysis was used to calculate the weighted mean difference for changes from baseline in HbA1c and body weight and relative risk (RR) of HbA1c goal attainment and hypoglycemia, with associated 95% credible intervals. Data Synthesis Overall, 27 RCTs (n = 11 198) were included. Mean (range) trial duration was 32 (12-52) weeks. The different classes of drugs were associated with similar HbA1c reductions (range, 0.64%-0.97%) compared with placebo. Although use of thiazolidinediones, sulfonylureas, and glinides were associated with weight gain (range, 1.77-2.08 kg), glucagon-like peptide-1 analogs, α-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were associated with weight loss or no weight change. Sulfonylureas and glinides were associated with higher rates of hypoglycemia than with placebo (RR range, 4.57-7.50). Conclusion When added to maximal metformin therapy, all noninsulin antidiabetic drugs were associated with similar HbA1c reductions but differed in their associations with weight gain and risk of hypoglycemia.
43. The American Association of Clinical Endocrinologists/American College of Endocrinology algorithm for treatment of patients with type 2 diabetes mellitus. Abbreviations: AGI, alpha-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, glycosylated hemoglobin;MET, metformin; PPG, postprandial glucose; SU, sulfonylurea; TZD, thiazolidinedione. Adapted with permission from Rodbard HW, et al.4aFor patients with diabetes mellitus and HbA1c <6.5%, pharmacologic treatment may be considered.bDPP-4 ifPPG andFPG or GLP-1ifPPG.cTZD if metabolic syndrome and/or nonalcoholic fatty liver disease.dHbA1c ifPPG.eIf HbA1c goal not achieved safely.fLow-dose secretagogue recommended.gGlinide ifPPG or SU ifFPG.hDecreasesecretagogue by 50% when added to GLP-1 or DPP-4.ia) Discontinue insulin secretagogue with multidose insulin; b) can use pramlintide with prandial insulin.jIf HbA1c >8.5%, combination pharmacologic treatment with agents that cause hypoglycemia should be used with caution.kGLP-1 not approved for initial combination pharmacologic treatment.lIf HbA1c >8.5%, in patients on dual therapy, insulin should be considered.
44. Now what about the ADA\\EASD algorithm and circle here consensus , so this is a consensus algorithm.And it starts at the time of diagnosis with lifestyle and metformin and then uses 7% as stratification point and it talks about first tier drugs which are insulin and sulfonylurea and then second tier drugs which are less well validated GLP-1 agonistand pioglitazone and if those do not work then you go to intensive insulin.
45. Moving from the top to the bottom of the figure, potential sequences of anti-hyperglycaemic therapy. In most patients, begin with lifestyle changes; metforminmonotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications).
46. If the A1c target is not achieved after ~3 months, consider one of the 5 treatment options combined with metformin (dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist or basal insulin. Note that the order in the chart is determined by historical introduction androute of administration and is not meant to denote any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision-making with the patient may help in the selection of therapeutic options.Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandialhypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted, and proceed accordingly.Consider starting with 2-drug combinations in patients with very high HbA1c (e.g. ≥9%).
47. Further progression to 3-drug combinations are reasonable if 2-drug combinations do not achieve target. If metformin contraindicated or not tolerated, while published trials are generally lacking, it is reasonable to consider 3-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g. ≥9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (see Fig. 3)
48. Ultimately, more intensive insulin regimens may be required (see Figure 3.)Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥10.0-12.0%). Consider beginning with insulin if patient presents with severe hyperglycemia (≥300-350 mg/dl [≥16.7-19.4 mmol/l]; HbA1c ≥10.0-12.0%) with or without catabolic features (weight loss, ketosis, etc).
49. So it is much simpler algorithm , but there is some problem.Explicitصريحندرةpaucity
50. March 2010Some recommendations were updated and replaced by ‘Neuropathic pain: thepharmacological management of neuropathic pain in adults in non-specialist settings’(NICE clinical guideline 96). More information on the management of neuropathic painis available from www.nice.org.uk/guidance/CG96September 2010The European Medicines Agency (EMA), the European Union (EU) body responsible for monitoring the safety of medicines, recommended the suspension of the marketing authorisation for rosiglitazone (Avandia, Avandamet and Avaglim) from GlaxoSmithKline.The EMA concluded that the benefits of rosiglitazone no longer outweigh its risks and the marketing authorisation should be suspended across the EU.The EMA has advised that patients who are currently taking rosiglitazone-containing medicines should make an appointment with their doctor at a convenient time to discuss suitable alternative treatments. Patients are advised not to stop their treatment without speaking to their doctor. NICE does not recommend the use of drugs without marketing authorisation. Therefore, as a result of the EMA’s decision, NICE has temporarily withdrawn its recommendations on the use of rosiglitazone in this guideline. Recommendations for theuse of a thiazolidinedione apply to pioglitazone only.July 2011The Medicine and Health products Regulatory Agency has issued new advice on risk of bladder cancer with the anti-diabetic drug pioglitazone. Please refer to the advice at the website …….
51. March 2010Some recommendations were updated and replaced by ‘Neuropathic pain: thepharmacological management of neuropathic pain in adults in non-specialist settings’(NICE clinical guideline 96). More information on the management of neuropathic painis available from www.nice.org.uk/guidance/CG96September 2010The European Medicines Agency (EMA), the European Union (EU) body responsible for monitoring the safety of medicines, recommended the suspension of the marketing authorisation for rosiglitazone (Avandia, Avandamet and Avaglim) from GlaxoSmithKline.The EMA concluded that the benefits of rosiglitazone no longer outweigh its risks and the marketing authorisation should be suspended across the EU.The EMA has advised that patients who are currently taking rosiglitazone-containing medicines should make an appointment with their doctor at a convenient time to discuss suitable alternative treatments. Patients are advised not to stop their treatment without speaking to their doctor. NICE does not recommend the use of drugs without marketing authorisation. Therefore, as a result of the EMA’s decision, NICE has temporarily withdrawn its recommendations on the use of rosiglitazone in this guideline. Recommendations for theuse of a thiazolidinedione apply to pioglitazone only.July 2011The Medicine and Health products Regulatory Agency has issued new advice on risk of bladder cancer with the anti-diabetic drug pioglitazone. Please refer to the advice at the website …….
52. March 2010Some recommendations were updated and replaced by ‘Neuropathic pain: thepharmacological management of neuropathic pain in adults in non-specialist settings’(NICE clinical guideline 96). More information on the management of neuropathic painis available from www.nice.org.uk/guidance/CG96September 2010The European Medicines Agency (EMA), the European Union (EU) body responsible for monitoring the safety of medicines, recommended the suspension of the marketing authorisation for rosiglitazone (Avandia, Avandamet and Avaglim) from GlaxoSmithKline.The EMA concluded that the benefits of rosiglitazone no longer outweigh its risks and the marketing authorisation should be suspended across the EU.The EMA has advised that patients who are currently taking rosiglitazone-containing medicines should make an appointment with their doctor at a convenient time to discuss suitable alternative treatments. Patients are advised not to stop their treatment without speaking to their doctor. NICE does not recommend the use of drugs without marketing authorisation. Therefore, as a result of the EMA’s decision, NICE has temporarily withdrawn its recommendations on the use of rosiglitazone in this guideline. Recommendations for theuse of a thiazolidinedione apply to pioglitazone only.July 2011The Medicine and Health products Regulatory Agency has issued new advice on risk of bladder cancer with the anti-diabetic drug pioglitazone. Please refer to the advice at the website …….
53. The Scottish Intercollegiate Guidelines Network (SIGN) is in some respect what I think is the simplest and clearest and most elegant in many ways. Their goals is less than 7% and it should be individualized as agreed and they start with metformin in black box as their first line therapy , then they go to sulfonyurea and then third line options going down the line here and without going into the specific they do include most of the classes for possible use as second line agent.All currently avail­able oral glucose-lowering agents are more or less simi­lar in their glucose-lowering potency.Usual approachAlternative approach. Special considerationsContinue medication if EITHER individualised target achieved OR HbA1c falls >0.5% (5.5 mmol/mol) in 3-6 monthsPrescribers should refer to the British National Formulary (www.bnf.org) and the Scottish Medicines Consortium (www.scottishmedicines.org.uk) for updated guidance on licensed indications, full contraindications and monitoring requirements.
54. And finally the VA/DoD establishes A1C goals start with diet and exercise before adding drug and first drug is metformin and alternatively sulfonylurea or insulin and then adds alternative agents,including DPP-4 inhibitor or GLP-1 agonist and then goes to dual therapy with a combination of metformin and sulfonylure or metformin and insulin or metformin and insulin, it does consider some of these others.
55. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2 DPP-4 inhibitors Cochrane review conclusions abstract :COCHRANE Author ' conclusions DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these new agents. More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. Also, long-term data are needed investigating patient-oriented parameters like health related quality of life, diabetic complications and all cause mortality.Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitusPlain Language SummaryDipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitusDipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin are promising new medicines for the treatment of type 2 diabetes mellitus. They are supposed to improve metabolic control (as measured by lowering blood glucose) without causing severe hypoglycaemia (low blood sugar levels leading to unconsciousness and other symptoms). Altogether 12.864 people took part in 25 studies investigating the new compounds sitagliptin and vildagliptin. Most studies lasted 24 weeks, the longest trials evaluated 52 weeks of treatment. So far, no study reported on patient-oriented parameters like mortality, diabetic complications, costs of treatment and health-related quality of life. When compared to placebo treatment sitagliptin and vildagliptin improved metabolic control. Comparison with other already established blood-glucose lowering drugs did not reveal advantages of DPP-4 treatment. Weight gain was not observed after sitagliptin and vildagliptin therapy. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. However, all-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. Unfortunately, all published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements. Since the new DPP-4 inhibitors may influence immune function additional long-term data on the safety of these drugs are necessary. Also, cardiovascular outcomes like heart attacks and strokes should not be increased with any antidiabetic therapy but data so far are lacking. Until new information arrives, DPP-4 inhibitors should only be used under controlled conditions and in individual patients.This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 10, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).This record should be cited as: Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2Editorial Group: Metabolic and Endocrine Disorders GroupThis version first published online: April 16. 2008Last assessed as up-to-date: January 31. 2008 AbstractBackgroundIn type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. ObjectivesTo assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus.Search strategyStudies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library.Selection criteriaStudies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks.Data collection and analysisTwo authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis.Main resultsTwenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurementsAuthors' conclusionsDPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these new agents. More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. Also, long-term data are needed investigating patient-oriented parameters like health-related quality of life, diabetic complications and all-cause mortality. 
56. BMC EndocrDisord. 2010; 10: 7. Published online 2010 April 22. doi: 10.1186/1472-6823-10-7PMCID: PMC3161395Copyright©2010 Williams-Herman et al; licensee BioMed Central Ltd.Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetesDebora Williams-Herman, 1 1Merck Research Laboratories, Rahway, NJ USASamuel S Engel,1 Elizabeth Round,1 Jeremy Johnson,1 Gregory T Golm,1 Hua Guo,1 Bret J Musser,1 Michael J Davies,1 Keith D Kaufman,1 and Barry J Goldstein11Merck Research Laboratories, Rahway, NJ USACorresponding author.Debora Williams-Herman: debora_williamsherman@merck.com ; Samuel S Engel: samuel_engel@merck.com ; Elizabeth Round: elizabeth_round@merck.com ; Jeremy Johnson: jeremy_johnson@merck.com ; Gregory T Golm: gregory_golm@merck.com ; HuaGuo: hua_guo2@merck.com ; Bret J Musser: bret_musser@merck.com ; Michael J Davies: michael.davies2@merck.com ; Keith D Kaufman: keith_kaufman@merck.com ; Barry J Goldstein: barry_goldstein@merck.comReceived February 10, 2010; Accepted April 22, 2010.Competing interestsAll authors are employed by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., the manufacturer of sitagliptin and may have company stock or stock options.ConclusionsIn this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
57. Declaration of interest:Funding for this research was provided to i3 Drug safety by Amylin Pharmaceuticals, , Inc., which has a global agreement with Eli Lilly and Company to collaborate on the development and commercialization of exentide. D.D.D., J. D.S. and K.A.C. are employees of i3 Drug Safety.Curr Med Res Opin. 2009 Apr;25(4):1019-27.Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.Dore DD, Seeger JD, Arnold Chan K.Sourcei3 Drug Safety, 950 Winter Street, Waltham, MA 02451, USA. david.dore@i3drugsafety.comAbstractOBJECTIVE: To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide).RESEARCH DESIGN AND METHODS: The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded.MAIN OUTCOME MEASURE: Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0).RESULTS: There were 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6-1.7) and sitagliptin (RR 1.0; 95% CI 0.5-2.0) relative to the comparison cohorts.CONCLUSIONS: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.
58. Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or SitagliptinA retrospective observational pharmacy claims analysisRajesh Garg, MD1, William Chen, PHD, MPH2 and Merri Pendergrass, MD, PHD2,3Published online before print August 3, 2010, doi: 10.2337/dc10-0482 Garg R, et al. Diabetes Care November 2010 vol. 33 no. 11 2349-2354 + Author Affiliations1Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 2Medco Health Solutions, Franklin Lakes, New Jersey; 3University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Merri Pendergrass, merri_pendergrass@medco.com. Next SectionAbstractOBJECTIVE Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis. RESEARCH DESIGN AND METHODS A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use. RESULTS Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7–2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6–1.5]) and sitagliptin versus diabetic control group (1.0 [0.7–1.3]). CONCLUSIONS Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk. Despite these limitations, these data provide valuable information for practicing clinicians weighing potential reported benefits versus risks, including the FDA warning of increased pancreatitis. Although this retrospective analysis cannot rule out with certainty that an association between exenatide, sitagliptin, and acute pancreatitis exists, it appears that exenatide and sitagliptin may not be associated with a large increased risk of acute pancreatitis.
59. (نفخ الأبواق لإفتتاح حفل أو لإستقبال شخص)the use of these drugs has not been formally recommended by all expert panels. The occasional acute episode of pancreatitis in some individuals treated with GLP-1-based therapy along with the suggestion from animal studies [1, 11] suggest that asymptomatic chronic pancreatitis may not be an uncommon consequence of GLP-1 based therapy. )innocent bystanderor friendly fireButler PC, et al. Diabetologia (2010) 53:1–6.Glucagon-like peptide-1 therapy and the exocrine pancreas:innocent bystander or friendly fire?P. C. Butler & A. V. Matveyenko & S. Dry & A. Bhushan &R. ElashoffDiabetologia (2010) 53:1–6DOI 10.1007/s00125-009-1591-5Fig. 1. From: Glucagon-like peptide-1 therapy and the exocrine pancreas: innocent bystander or friendly fire?. The occasional acute episode of pancreatitis in some individuals treated with GLP-1-based therapy along with the suggestion from animal studies [1, 11] suggest that asymptomatic chronic pancreatitis may not be an uncommon consequence of GLP-1 based therapy. P. C. Butler, et al. Diabetologia. 2010 January;53(1):1-6.IntroductionIn the present edition of Diabetologia, Nachnani andcolleagues report that rats treated with the glucagon-likepeptide-1 (GLP-1) mimetic, exendin-4, for 75 days developed low-grade pancreatitis [1]. The obvious question is whether low-grade pancreatitis is also present in humans treated with synthetic exendin-4 (exenatide) or other GLP-1-based therapies? The paper by Nachnani et al. is a timely addition to an area of growing interest and controversy in which, atpresent, there are more questions than answers.( For the slide : The occasional acute episode of pancreatitis in some individuals treated with GLP-1-based therapy along with the suggestion from animal studies [1, 11] suggest that asymptomatic chronic pancreatitis may not be an uncommon consequence of GLP-1 based therapy. )Nachnani JS, Bulchandani DG, Nookala A et al (2009) Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia. doi:10.1007/s00125-009-1515-4.11. Matveyenko AV, Dry S, Cox HI et al (2009) Beneficialendocrine but adverse exocrine effects of Sitagliptin in theHIP rat model of type 2 diabetes, interactions with metformin.Diabetes 58:1604–1615Medications associated with AP** Trivedi CD, et al.ClinGastroenterol. 2005 Sep;39(8):709-16.Class I medications (medications implicated in greater than 20 reported cases of acute pancreatitis with at least one documented case following reexposure): didanosine, asparaginase, azathioprine, valproic acid, pentavalentantimonials, pentamidine, mercaptopurine, mesalamine, estrogen preparations, opiates, tetracycline, cytarabine, steroids, trimethoprim/sulfamethoxazole, sulfasalazine, furosemide, and sulindac. Class II medications (medications implicated in more than 10 cases of acute pancreatitis): rifampin, lamivudine, octreotide, carbamazepine, acetaminophen, phenformin, interferon alfa-2b, enalapril, hydrochlorothiazide, cisplatin, erythromycin, and cyclopenthiazide. Class III medications (all medications reported to be associated with pancreatitis).
60. (What I can conclude from all this)Diabetes guideline are powerful documents which are challenging to develop and need near-continual updating given the pace of new developments (and this is a challenge to all organizations)Transparency is a critical element in guideline development(I think as time passes and it is going forward , Iwe are going to see more transparency in this)(importantly) Conflicts (Duality) of interest are nearly ubiquitous among experts in this field ( and it is very difficult to develop a guideline among expert people who do not actually have conflicts of interest, and that is just the state of the way things are)The pendulum is swinging toward the individualization of A1c goalsAlgorithms for diabetes care are mostly consensus documents since few head-to-head, long-term trials exist to inform us about best practices(and the final point is that)Clinical judgment ( actually is important and ) sometimestrumps “evidence- based guideline”(So the word guideline should be taken literally حرفيا it is just a guideline )