5. Adapted from DeFronzo RA. Med Clin N Am 2004;88:787–835.
Type 2 Diabetes is a Progressive Disease: Early
Intervention is Critical
Prevention Treatment–10 10+ Years
Diagnosis
Macrovascular complications
Microvascular complications
0
IFG/IGT Type 2 diabetes
Blood
glucose
-cell function
Insulin
resistance
IFG: impaired fasting glucose
IGT: impaired glucose tolerance
6. Diabetes: Magnitude of Complications
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults
Diabetic
Neuropathy
Leading cause of non-traumatic
lower extremity amputations
Diabetic
Nephropathy
Leading cause of
end-stage renal disease
Stroke
Cardiovascular
Disease
2- to 4- fold
increase in
cardiovascular
mortality
and stroke
National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes. (website)
http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm
8. Does Pioglitazone Still Have a Place in
Therapy? – YES!
• Early – prevention? – ACT NOW
• Combination with metformin – durability
• Insulin resistance syndrome
• High insulin doses – with caution
• CVD patients? – PROactive/BARI 2D
9. None of the Major Oral Monotherapies Are Able to
Address All 3 Core Defects in Type 2 Diabetes
Oral Monotherapies
α-Glucosidase
Inhibitors
Lowers hepatic
glucose
production
SUs
Glinides
TZDs
Improves insulin
resistance
Improves insulin
secretion
DPP-4
Inhibitors
Metformin
MechanismsofAction
10. TZDs
Muscle
Glucose uptake
and diposal
Liver
Glucose uptake
VLDL cholesterol
Adipose tissue
Glucose uptake and
disposal
Free fatty acid uptake
Alteration of other
adipocyte factors
Improvement
in metabolic
imbalances
DeFronzo R. Diabetes 1988;37:667–687;
Reginato & Lazar,.Trends Endocrinol Metab,1999;10:9–13; Saltiel & Olefsky. Diabetes 1996;45:1661–1669
Metabolic Control in Type 2 Diabetes by TZDs
11. 9.0
8.5
8.0
7.5
7.0
6.5
42 0
Glibenclamide plus metformin (n=250)
Pioglitazone plus metformin (n=250)
* *
†
Time (months)
*p<0.05, †p<0.005
Pioglitazone vs glibenclamide as add-on to
metformin: HbA1c results
MeanchangeinHbA1c(%)
Hanefeld M et al. Curr Med Res Opin 2006:22:1211–1215
12. Achieving Glycaemic Goals with Actos
PROactive*
Actos significantly reduced and sustained mean HbA1c
Adapted from Presentation Metabolic Results by Professor Bernard Charbonnel. Accessed February 12, 2008. http://www.proactive-
results.com/html/PowerPoints.htm .
* PROspective pioglitAzone Clincal Trial In macroVascular Events (PROactive) included patients with type 2
diabetes, aged 35–75 years with HbA1c >6.5% despite existing treatment with diet alone or with oral glucose-
lowering agents with or without insulin.
Me
an
Hb
A1
c
(%)
Over a 3-year period
Ti
me
(m
ont
hs)
*P<
0.0
1
place
bo
Act
os
13. Months
Baseline 6 12 18 24 30 36 Final visit
6.5
6.7
6.9
7.1
7.3
7.5
7.7
7.9
8.1
Insulin + Pioglitazone
Insulin + placebo
HbA1c (%)
* *
**
†
Pioglitazone Plus Insulin:
HbA1c Results from PROactive
Charbonnel B et al. J Clin Endocrinol Metab 2010;95:2163–2171
*p<0.0001 & †p=0.0149 vs insulin + placebo
18. PROspective PioglitAzone Clinical Trial In
Macrovascular Events
May 2001 – April 2002
5238 patients, type 2 diabetes
Age 35-75
HbA1c > 6.5%
Any background therapy (except for solely insulin)
Evidence of macrovascular disease
Pioglitazone vs. placebo
Dormandy J et al. 2005;366:1279–1289 Lance
19. ProActive
Primary endpoint – composite:
− All cause mortality
− MI, stroke, ACS, arterial intervention (coronary, peripheral),
major amputation
Secondary endpoint:
− Time to death, MI or stroke
− CV death
− Each of the above primary endpoints
22. Effect of Pioglitazone on Recurrent Stroke
in Patients with Previous Stroke
N at Risk:
Time (months)
984 926 877 132
Kaplan-MeierEventRate
0.04
0.08
0
0.12
0 12 24 36
Placebo
(51 / 498)
Pioglitazone
(27 / 486)
0.0080.53
p valueHR
- 47%
Wilcox R et al. STROKE 2007; 38: 865-873
PIO vs
Placebo
23. 36
0.10
0.08
0.06
0.04
0.02
399
0 12 24
Kaplan-MeierEventRate
0.72
0
# at risk:2455
Placebo
(88 / 1215)
2337 2245
Pioglitazone
(65 / 1230)
Effect of Pioglitazone on Recurrent MI
in Patients with Previous MI
Erdmann E. et al. JACC 2007; 49: 1772-1780
- 28%
0.0450.72
p valueHR
PIO vs
Placebo
Time (months)
24. Side Effects of Oral Antihyperglycemic
Medications
Hypo-
glycaemia
Oedema Lactic
acidosis
GI Weight
gain
Contraindications
SU
• •
Moderate to severe liver
dysfunction, adjust dose in severe
kidney dysfunction. Avoid use of
glyburide in elderly patients or
patients with kidney dysfunction
Non-SU
• •
Severe liver or kidney dysfunction.
Avoid concomitant use of repaglinide
with gemfibrozil
Biguanide
• •
Moderate to severe liver or cardiac
dysfunction, mild renal dysfunction
TZDs
• •
Severe liver dysfunction, NYHA
class II-IV CHF
AGI
•
Irritable bowel syndrome, severe
kidney or liver dysfunction
Insulin
• • •
CDA 2003 Guidelines
25. Warn patient about increased hunger
Consultation with dietician
Weekly weight (scale)
Call physician if > 2-4 kg weight gain
Weight Gain with TZD’s
26. 5-10% of TZD-treated patients develop edema; < 1% of these
individuals develop CHF
CHF is secondary to diastolic dysfunction and fluid overload
If edema does not resolve, TZD should be discontinued
Fluid Retention
27. Results of Overall and Bladder Malignancy Analysis by TZD
Use and Original Double-blind Therapy
Erdmann E, et al. Presented at: 72nd Scientific Sessions of the American Diabetes Association. Philadelphia, PA. June 8-12, 2012. Abstract 935-P.
CI=confidence interval.
Original Treatment
During Double-blind
Period
Pioglitazone (n=1820) Placebo (n=1779)
Follow-up
Treatment
No TZD (n=1449)
Pioglitazone
(n=246)
Other TZD
(n=144)
No TZD
(n=1497)
Pioglitazone
(n=179)
Other TZD
(n=127)
Any malignancy 135 (9.3%) 18 (7.3%) 12 (8.3%) 135 (9.0%) 15 (8.4%) 8 (6.3%)
Bladder malignancy 10 (0.7%) 0 0 13 (0.9%) 3 (1.7%) 2 (1.6%)
In patients ever/never exposed to pioglitazone the # of bladder cancer events
was 25/20, HR 0.98 (CI: 0.6, 1.8)
PROactive 6-year Observational Follow-up
28.
29. Protection of Multiple Organs by Pioglitazone
47% of SecondaryStroke in
Patients with previous Stroke
(PROactive)
28% of Re-Infarction in
Patients with previous MI
(PROactive)
37% of Acute Coronary
Syndrome after previous MI
(PROactive)
of MI, Stroke & Death in
Patients with CKD
(PROactive)
Stop of Progression of
Coronary Atherosclerosis
(PERISCOPE)
Microalbuminuria
(QUARTET)
51% Mortality in Patients
on Hemodialysis (USA)
Reduction of CIMT
(Carotid artery Intima-
Media Thickness)
CHICAGO
Reduction of Inflammation
& Necrosis in NASH
(Nonalcoholic Steatohepatitis)
31. How Can We Minimize the Side Effects
of TZD?
• Use lower doses
• Avoid using in combination with insulin in high-risk
patients
• Avoid use in patients with high risk for fractures
• Decrease salt and calorie intake
• Avoid calcium channel blockers
• Discontinue if patients have weight gain and edema
• Develop new PPAR-agonists that have fewer side
effects
32. Prevention of Diabetes With
Pioglitazone in ACT NOW
• Exams: the metabolic characteristics that attend the development of type 2 diabetes
(T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT
NOW Study and had complete end-of-study metabolic measurements.
• Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and
were observed for a median of 2.4 years.
• Indices of insulin sensitivity, insulin secretion and β-cell function were calculated from
plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance
tests at baseline and study end.
• Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects, 48% of PGZ-
treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-
treated subjects (P< 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM)
was associated with improvements in insulin sensitivity and β-cell function.
Ralph A. DeFronzo, Devjit Tripathy, Dawn C. Schwenke, MaryAnn Banerji, George A. Bray, Thomas A. Buchanan, Stephen C. Clement, Amalia Gastaldelli,
Robert R. Henry, Abbas E. Kitabchi, Sunder Mudaliar, Robert E. Ratner, Frankie B. Stentz, Nicolas Musi, Peter D. Reaven Diabetes.
2013;62(11):3920-3926
33. Conclusion: Pioglitazone Benefit-Risk Remains Positive
• The combination of the mechanism of action, efficacy, and durability
with low incidence of hypoglycemia distinguish pioglitazone from other
currently available anti-diabetic medications
• Only antidiabetes drug with cardiovascular safety documented by a
prospective outcomes study
• Risks are well characterised in more than 20 million patient-years of
experience in the past 10 years globally
• The risk of bladder cancer should be balanced by the benefits of
pioglitazone in the context of the overall morbidity of patients with
T2DM
• Pioglitazone continues to be an important therapeutic option for the
successful management of patients with T2DM
34. •Name of the medicinal product: Actos 15,30,45 mg tablets
•Therapeutic indications: Pioglitazone is indicated as second or third line treatment of type 2 diabetes
mellitus as described: as monotherapy, as dual oral therapy in combination with metformin or sulphonylurea
or as triple oral therapy in combination with metformin and sulphonylurea, Pioglitazone is also indicated for
combination with insulin.
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess
adequacy of response to treatment. In patients who fail to show an adequate response, pioglitazone should be
discontinued
•Posology and method of administration: Pioglitazone treatment may be initiated at 15 mg or 30 mg once
daily. The dose may be increased in increments up to 45 mg once daily.
•Special population: Elderly- No dose adjustment is necessary, Physicians should start treatment with the
lowest available dose. Renal impairment- No dose adjustment is necessary in patients with impaired renal
function, No information is available from dialysed patients therefore pioglitazone should not be used in such
patients. Hepatic impairment- Pioglitazone should not be used in patients with hepatic impairment. Paediatric
population-The safety and efficacy of Actos in children and adolescents under 18 years of age have not been
established.
•Method of administration: Pioglitazone tablets are taken orally once daily with or without food.
•Contraindications : Pioglitazone is contraindicated in patients with: hypersensitivity to the active substance
or to any of the excipients, cardiac failure or history of cardiac failure (NYHA stages I to IV), hepatic
impairment, diabetic ketoacidosis, current bladder cancer or a history of bladder cancer, uninvestigated
macroscopic haematuria.
•ABREVIATED SUMMARY OF
PRODUCT CHARACTERISTICS
35. •Special warnings and precautions for use:
Fluid retention and cardiac failure -Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart
failure. physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed
for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve.
Elderly- Combination use with insulin should be considered with caution in the elderly because of increased risk of
serious heart failure.
Bladder Cancer- Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment. Any
macroscopic haematuria should be investigated before starting pioglitazone therapy.
Monitoring of liver function- It is recommended, therefore, that patients treated with pioglitazone undergo periodic
monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all
patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT >
2.5 X upper limit of normal) or with any other evidence of liver disease.
Weight gain- weight should be closely monitored.
Haematology - There was a small reduction in mean haemoglobin and haematocrit during therapy with pioglitazone,
consistent with haemodilution.
Hypoglycaemia - As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral
therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a
reduction in the dose of the sulphonylurea or insulin may be necessary.
Eye disorders - It is unclear whether or not there is a direct association between pioglitazone and macular oedema but
prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity.
Others - An increased incidence in bone fractures in women, The risk of fractures should be considered in the long term
care of women treated with pioglitazone.
As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may
result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of
pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued
Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g.
gemfibrozil) or inducers (e.g. rifampicin).
Actos tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
•.
36. • Interaction with other medicinal products : Interaction studies have shown that pioglitazone has no relevant effect on either the
pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. administration of pioglitazone with
sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea.
• Fertility, pregnancy and lactation: Pregnancy- There are no adequate human data to determine the safety of pioglitazone during
pregnancy, pioglitazone should not be used in pregnancy.
Breastfeeding- pioglitazone should not be administered to breast-feeding women.
Fertility- In animal fertility studies there was no effect on copulation, impregnation or fertility index.
• Effects on ability to drive and use machines: Actos has no or negligible effect on the ability to drive and use machines.
•Undesirable effects as monotherapy:
very common(≥ 1/10)
common (≥ 1/100 to < 1/10) - upper respiratory tract infection, hypo-aesthesia, visual disturbance, fracture bone, weight increased
uncommon (≥ 1/1,000 to < 1/100) – sinusitis, insomnia, bladder cancer
rare (≥ 1/10,000 to< 1/1,000)
very rare (< 1/10,000)
not known - Hypersensitivity and allergic reactions, macular oedema, Alanine aminotransferase increased
• Overdose - In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The
maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.
Symptomatic and general supportive measures should be taken in case of overdose.
•Pharmacological properties - Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to
act via activation of specific nuclear receptors leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in
animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in
the case of insulin resistance.
Absorption - Following oral administration, pioglitazone is rapidly absorbed, and peak plasma concentrations of unchanged
pioglitazone are usually achieved 2 hours after administration. Pioglitazone and all active metabolites are extensively bound to
plasma protein (> 99%).
Biotransformation - Pioglitazone undergoes extensive hepatic metabolism This is predominantly via cytochrome P450 2C8.
Elimination - Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a
lesser amount in urine (45%).
Patients with renal impairment- Total plasma concentration of pioglitazone is unchanged, but with an increased volume of
distribution. Intrinsic clearance is therefore reduced, coupled with a higher unbound fraction of pioglitazone
There is a temporal relationship between insulin resistance, insulin secretion and the development of diabetes.
In the early stages of pathogenesis, as insulin resistance rises, there is a compensatory increase in insulin secretion and the individual remains normoglycaemic.1
In the long term, if the β-cells begin to fail, insulin secretion falls, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) develop, and hyperglycaemia reaches levels defined as type 2 diabetes mellitus.1 However, diabetes may not be diagnosed until many years later.
Development of diabetes is associated with the development of serious complications that begin before type 2 diabetes is diagnosed.2 The risk of complications increases as the disease progresses.3
There are two potential approaches to delaying the progression of the disease and its associated complications: firstly, prevention interventions at the stage of IGT/IFG, and secondly, treatment interventions to delay disease progression following diagnosis.
DeFronzo RA. Med Clin N Am 2004;88:787–835.
Hu FB, et al. Diabetes Care 2002;25:1129–1134.
Stratton IM, et al. BMJ 2000;32:405–412.
Diabetic microvascular complications are most commonly manifested in the eyes, kidneys, and nerves.
Diabetic retinopathy and diabetic macular edema: Diabetes is the leading cause of new cases of blindness in adults between the ages of 20 and 74 years.1 After 15 years of diabetes, 2% of patients become blind and 10% develop severe visual disability.4
Diabetic nephropathy: In end-stage renal disease, diabetes accounts for about 35% to 40% of new cases.1 People with diabetes make up the fastest-growing group of renal dialysis and transplant recipients.3
Diabetic neuropathy and amputations: Diabetes is the leading cause of nontraumatic lower-extremity amputations, accounting for 50% of amputations in the United States. About 60% to 70% of people with diabetes have some degree of diabetic nerve damage.4
There is also a high frequency of atherosclerosis (macrovascular disease) leading to increased risk of stroke and/or heart attack.
Cardiovascular disease: People with diabetes are 2 to 4 times more likely to die from heart disease than people without diabetes. Cardiovascular disease is responsible for 50% of diabetes-related deaths.2
Stroke: A person with diabetes is 2 to 4 times more likely to suffer a stroke than a person without diabetes.1
1. National Diabetes Information Clearinghouse. Diabetes Statistics–Complications of Diabetes. http://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm Accessed May 1, 2001.
Does Pioglitazone Still Have a Place in Therapy? – YES!
Studies of the thiazolidinedione pioglitazone suggest that the agent is beneficial in therapy, although potential adverse effects warrant caution.
Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes
Given the multiple pathophysiologic abnormalities in type 2 diabetes, combination therapy with 2 or 3 drugs with distinct mechanisms of action is a logical approach to managing the disease.1
As can be seen from the table above, a combination of metformin with a DPP-4 inhibitor may help target 3 contributing pathophysiologies of type 2 diabetes1-4
Using smaller doses of 2 drugs in combination may also result in fewer adverse events than titrating a single drug to maximal doses1,3
A combination of metformin and a DPP-4 inhibitor may not compromise weight gain or hypoglycaemic risk to help get to glucose control,2,3 and would not cause oedema, anaemia, or congestive heart failure
Combination therapy may provide4
More glycaemic control than individual monotherapies
More comprehensive action of key pathophysiologies of type 2 diabetes than monotherapy
An appropriately chosen combination therapy may help more patients get to their HbA1c goal without increasing adverse events1,3
PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive)
Randomized, double-blind, add-on PBO-controlled outcome study
Type 2 diabetes (35-75 years old) with a history of macrovascular disease
Managed with diet and/or OHAs ± Insulin
Randomized to receive pioglitazone (45 mg/day) vs. placebo in addition to existing therapy
Primary end point is the time from randomization to occurrence of a new macrovascular event or death
Mean follow-up: 34.5 months
Primary outcome:
All-cause mortality, nonfatal AMI, nonfatal CVA, coronary revascularization, acute coronary syndrome, leg amputation, leg revascularization
Secondary outcome:
All-cause mortality, nonfatal AMI, nonfatal CVA
Surrogate outcome studies with TZDs provide indirect evidence for CV event reduction.
CV risk factor reductions observed with TZD treatment may also reduce CV morbidity and mortality.
Harold Bays, Lawrence Mandarino, and Ralph A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., Feb 2004; 89: 463 - 478.
PROactive: Pioglitazone Reduces “Hard” Coronary Heart Disease Endpoints
In a prespecified secondary endpoint study from the PROactive trial that examined time to fatal or nonfatal myocardial infarction (MI), patients who were treated with pioglitazone had a 28% reduction in MI compared with patients treated with placebo. In a post hoc exploratory analysis of time to occurrence of acute coronary syndromes, the pioglitazone group also showed benefit, with a 37% reduction in risk. These data would indicate that pioglitazone is not associated with an excess risk for MI, although the drug did increase the risk for congestive heart failure (CHF) in this trial. The increase in CHF risk is not surprising, since these patients had cardiovascular disease; many of them were also on insulin therapy and received pioglitazone at the highest dosage range.
Reference:
Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, on behalf of the PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007;49:1772-1780.
http://www.ncbi.nlm.nih.gov/pubmed/17466227
How Can We Minimize the Side Effects of PPAR-γ Agonists?
The side effects of peroxisome proliferator–activated receptor–γ (PPAR-γ) agonists can be minimized by using low doses, avoiding use in patients at high risk for adverse effects, avoiding use with calcium channel blockers, and monitoring patients for weight gain and edema.
How Can We Minimize the Side Effects of PPAR-γ Agonists?
The side effects of peroxisome proliferator–activated receptor–γ (PPAR-γ) agonists can be minimized by using low doses, avoiding use in patients at high risk for adverse effects, avoiding use with calcium channel blockers, and monitoring patients for weight gain and edema.
