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- 1. AACE Diabetes Guidelines 2000 ALAD Guia de Dg y Tto DM-2 , 2000 ADA Clinical Practice Recomendations 2001 INSULINO TERAPIA Dr. Freddy Valdivia Fernández-Dávila
- 10. Algoritmo de Tratamiento Terapia No farmacológica Monoterapia Sulfonylureas/Benzoic acid analogue Biguanide Alpha-glucosidase inhibitors Thiazolidinediones Insulin Terapia Combinación Insulina Very symptomatic Severe hyperglycemia Ketosis Latent autoimmune diabetes Pregnancy
- 13. Comparación de Insulinas Humanas Inicio de Duración de Tipos de Insulina Acción Pico Acción Lispro 5 – 15’ 1 -2 hr 4 - 6 hr Humana Regular 30 – 60’ 2 - 4 hr 6 - 10 hr Humana NPH 1 - 2 hr 4 - 6 hr 10 - 16 hr Humana Lenta 1 - 2 hr 4 - 6 hr 10 - 16 hr Ultralenta 2 - 4 hr Unpredictable <24 hr * The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered as general guidelines only.
- 15. Esquemas de Insulinoterapia NPH R - R + NPH B NPH R R R A NPH R R + NPH R E NPH R + NPH R + NPH R + NPH D NPH R R R + NPH C 10-11pm CENA ALMUERZO DESAYUNO
- 16. Regímenes con Insulina Mixta Regular B L S HS B Reg NPH Insulin Effect Meals NPH Reg Insulin Effect B L S HS B Meals Lispro NPH Lispro NPH Lispro
- 17. NPH + Regular NPH at HS + Regular AC NPH at AM and HS + Regular AC B L S HS B Reg Insulin Effect Meals Reg NPH NPH B L S HS B Reg Insulin Effect Meals Reg Reg NPH
- 18. NPH + Lispro NPH at HS + Lispro AC NPH at AM and HS + Lispro AC B L S HS B Lispro Insulin Effect Meals Lispro NPH NPH B L S HS B Lispro Insulin Effect Meals Lispro Lispro NPH
- 19. Ultralenta PM + Regular B L S HS B Insulin Effect Meals Reg Ultralente Reg Reg
- 24. Insulina Glargina Vs. NPH Time (h) after S.C. Injection 0 Glargine insulin NPH insulin 30 0 1 2 3 4 5 6 Glucose Utilization Rate (mg/kg/h ) 20 10 End of observation period Lepore, et al. Diabetes 1999;48 (Suppl 1):A97.
- 28. Tratamiento Intensivo de DM 2 y complicaciones microvasculares (años) Pacientes con eventos microvascular (%) *Microvascular events = renal failure, death from renal failure, retinal photocoagulation or vitreous haemorrhage UK Prospective Diabetes Study Group (1998) 0 2 4 6 8 10 12 14 16 18 20 0 3 6 9 12 15 Intensive treatment (n=2,729) Conventional treatment (n=1,138) ( p =0.0099 )
- 29. ADA Treatment Guidelines Biochemical Index Normal Goal Action Suggested Preprandial glucose <90 mg/dL 80-120 mg/dL <80 or >140 mg/dL Bedtime glucose <120 mg/dL 100-140 mg/dL <100 or >160 mg/dL HbA 1c <6%* <7% >8% *Depending on assay norms
- 30. El Estudio Kumamoto : Efectos de Terapia con Insulina Convencional vs. Intensiva Ohkubo Y, et al. Diabetes Res Clin Pract . 1995;28:103-117.
- 31. UKPDS : Efectos de Terapia Intensiva en la Glicemia UKPDS Group. Lancet . 1998;352:837-853.
- 32. UKPDS 10-Year Cohort Data: Reducciones con Terapia Intensiva vs. Convencional UKPDS Group. Lancet . 1998;352:837-853.
- 36. Meta-Análisis de Terapia con Sulfonilurea/Insulina Johnson JL, et al. Arch Intern Med. 1996;156:259-264.
- 37. Comparación de Regímenes de Insulina en Falla de Terapia Oral Yki-Jarvinen H, et al. N Engl J Med . 1992;327:1426-1433.
- 39. Insulin Pump
- 41. Insulin Pen
- 42. Insulina Inhalada Gelfand RA, et al. Presented at ADA 58th Annual Meeting. 1998:Abstract 0235.
- 44. United Kingdom Prospective Diabetes Study (UKPDS)
- 47. UKPDS: Design Metformin treatment Overweight patients (n=342) Conventional management (n=1138) Sulphonylurea treatment (n=1573) Insulin treatment (n=1156) Intensive management (n=2729) Non-overweight and overweight patients (n=3867) Randomisation (n=4209 ) 3 month run-in period Diet management regimen (n=5102) UKPDS Group. Lancet. 1998;352:837–853.
- 51. UKPDS: Therapy progression Years from randomisation Percentage of patients 1 2 3 4 5 6 7 8 9 10 11 12 0 20 40 60 80 100 diet alone 1 2 3 4 5 6 7 8 9 10 11 12 intensive pharmacological therapy diet alone additional non-intensive pharmacological therapy Intensive Policy (aim for <6 mmol/l) Conventional Policy (accept <15 mmol/l) 0 20 40 60 80 100 UKPDS Group. Lancet. 1998;352:837–853.
- 52. UKPDS: Effects of management on HbA 1c 9 Years from randomisation 0 6 7 8 0 3 6 9 12 15 HbA 1c (%) Conventional Intensive 6.2% upper limit of normal range UKPDS Group. Lancet. 1998;352:837–853.
- 53. UKPDS: Effects of management on fasting plasma glucose 0 3 6 9 12 15 Years from randomisation Conventional Intensive 7.8 8.9 10.0 11.1 6.7 Median FPG (mmol/l) UKPDS Group. Lancet. 1998;352:837–853. 0 5.6
- 54. UKPDS: Effects of management on body weight 0 3 6 9 12 15 -2.5 0.0 2.5 5.0 7.5 Change in body weight (kg) Conventional Intensive Years from randomisation UKPDS Group. Lancet. 1998;352:837–853.
- 55. UKPDS: Effects of management on myocardial infarction 0 10 20 30 0 3 6 9 12 15 Percentage of patients with event Years from randomisation Intensive Conventional p=0.052 UKPDS Group. Lancet. 1998;352:837–853.
- 56. UKPDS: Effects of management on microvascular endpoints 0 3 6 9 12 15 Percentage of patients with event Years from randomisation Intensive p<0.01 Intensive Conventional UKPDS Group. 1998;352 Lancet. :837–853. 0 10 20 30
- 57. UKPDS: Effects of management on hypoglycaemia 0 10 20 30 40 50 0 3 6 9 12 15 Percentage of patients Years from randomisation 0 1 2 3 4 5 0 3 6 9 12 15 Any episode Major episodes Intensive Conventional Intensive Conventional UKPDS Group. Lancet. 1998;352:837–853.
- 59. Any Diabetes Related Endpoint Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 21% decrease per 1% decrement in HbA1c p<0.0001
- 60. Diabetes Related Deaths 21% decrease per 1% decrement in HbA1c p<0.0001 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 61. All Cause Mortality 14% decrease per 1% decrement in HbA1c p<0.0001 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 62. Fatal and Non-Fatal Myocardial Infarction 14% decrease per 1% decrement in HbA1c p<0.0001 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 63. Fatal and Non-Fatal Stroke 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 12% decrease per 1% decrement in HbA1c p=0.035 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 64. Microvascular Endpoints 0 . 5 1 1 0 1 5 0 5 6 7 8 9 1 0 1 1 37% decrease per 1% decrement in HbA1c p<0.0001 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 65. Cataract Extraction 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 19% decrease per 1% decrement in HbA1c p<0.0001 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 66. Amputation or Death from Peripheral Vascular Disease 0 . 1 1 1 0 2 0 0 5 6 7 8 9 1 0 1 1 43% decrease per 1% decrement in HbA1c p<0.0001 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 67. Heart Failure 0 . 5 1 5 0 5 6 7 8 9 1 0 1 1 16% decrease per 1% decrement in HbA1c p=0.016 Updated mean HbA 1c Hazard ratio UKPDS 35. BMJ 2000; 321: 405-12
- 68. UKPDS 35. BMJ 2000; 321: 405-12 Myocardial Infarction and Microvascular Disease Myocardial infarction Microvascular disease Updated mean HbA 1c (%) Incidence per 1000 patient-years
- 70. Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure : UKPDS 110 120 130 140 150 160 170 Incidence per 1000 Person Years (%) Adler AI et al. BMJ 2000;321:412-419. Updated Mean Systolic Blood Pressure (mmHg) Adjusted for age, sex, and ethnic group Myocardial Infarction Microvascular Endpoints
- 71. Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A 1c : UKPDS 5 6 7 8 9 10 11 Incidence per 1000 Person Years (%) Stratton IM et al. BMJ 2000;321:405-412. Updated Mean Hemoglobin A 1c Concentration (%) Adjusted for age, sex, and ethnic group Myocardial Infarction Microvascular Endpoints
- 72. UKPDS 10-Year Follow-up Results : Glycemic Control, Weight, and Plasma Insulin UKPDS Group. Lancet 1998;352:837-853. Years from Randomization Years from Randomization Conventional Conventional Intensive Intensive Conventional Intensive Intensive Conventional Fasting plasma glucose Median (mmol/L) Hemoglobin A 1c Weight Plasma insulin 11 10 9 8 7 6 0 Median (%) 9 8 7 6 0 7.5 5 2.5 0 -2.5 Baseline = 75 kg Mean Change (kg) 40 30 20 10 0 -10 -20 Median Change (pmol/L) Baseline = 89 pmol/L 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12
- 73. UKPDS: Endpoints by Glucose Treatment Group Rate/1000 Patient-Years Any diabetes-related* MI Stroke PVD** Microvascular UKPDS Group. Lancet 1998;352:837-853. Rate/1000 Patient-Years P Cause 40.9 14.7 5.6 1.1 8.6 *Combined microvascular and macrovascular events **Amputation or death from PVD % Risk Reduction 46.0 17.4 5.0 1.6 11.4 0.029 0.052 0.52 0.15 0.009 12 16 – – 25 Conventional Intensive
- 75. UKPDS Results: Intensive Blood Pressure Control Any diabetes-related endpoint Deaths related to diabetes Myocardial infarction Stroke Microvascular disease Intensive Blood Pressure Control 24 32 21 44 37 0.0046 0.019 NS 0.013 0.092 Adapted from UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. Reduction (%) P Value
- 76. Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS Any diabetes-related endpoint Myocardial infarction Stroke Microvascular disease 12 16 11 25 Reduction % = Increase in risk Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-853; UK Prospective Diabetes Study Group. BMJ 1998;317:703-713. P Value Reduction % P Value Intensive Blood Glucose Control (n=2729) Intensive Blood Pressure Control (n=758) 0.029 0.052 NS 0.0099 24 21 44 37 0.0046 NS 0.013 0.092
- 80. UKPDS metformin study in overweight patients: Risk reduction Any diabetes-related end-point 32 7 Diabetes-related deaths 42 20 Myocardial infarction 39 21 Microvascular disease 29 16 Risk reduction* (%) UKPDS Group. Lancet. 1998;352:854–865. Metformin intensive Sulphonylurea/ insulin intensive * Compared with conventional therapy
- 81. UKPDS sulphonyurea inadequacy: HbA 1c 9 Years from randomisation 0 6 7 8 0 3 2 4 5 1 HbA 1c (%) Conventional Intensive (insulin alone) 6.2% upper limit of normal range UKPDS Group. Diabetes Care. 2002;25:330–336. 6 5 Intensive (sulphonylurea ± insulin)
- 83. Hirsch, I. B. N Engl J Med 2005;352:174-183 Alteraciones de aa en Insulina Lispro, Insulina Aspart e Insulina Glargina
- 84. Perfil Farmacocinético de Insulina Humana y Análogos de Insulina
Notas do Editor
- The primary goal of the UKPDS was to establish whether an intensive blood glucose control policy with a sulphonylurea, insulin, or metformin reduces the risk of microvascular (eg, retinopathy, nephropathy, neuropathy) or macrovascular complications (eg, myocardial infarction, coronary heart disease, stroke) and mortality in Type 2 diabetes. A secondary goal of the study was to determine whether any particular intensive therapy — first- or second-generation sulphonylurea, insulin, or metformin — has any specific disadvantages or advantages in improving the prognosis for Type 2 diabetes. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- The UKPDS was a multicentre, prospective, randomised, intervention trial conducted from 1977 to 1997. Between 1977 and 1991, general practitioners from 23 participating UKPDS hospitals were asked to refer all patients aged 25 to 65 years, non-overweight and overweight (defined as >120% ideal body weight), with newly diagnosed Type 2 diabetes for inclusion in the UKPDS. A total of 5102 patients with fasting plasma glucose (FPG) >6 mmol/l (>108 mg/dl) were recruited: 59% men, 41% women; 82% white, 10% Asian, and 8% Afro-Caribbean. At recruitment, the median FPG was 11.5 mmol/l (207 mg/dl) and the median HbA 1c was 9.1%. Although data collection took place over 20 years, the mean duration of patient participation was 11 years. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Following recruitment, all eligible patients participated in a 3-month dietary run-in period during which they were advised to follow a diet high in carbohydrates and fibre and low in saturated fats. Calorie restriction was advised in overweight patients (defined as >120% ideal body weight). 1 After 3 months, 4209 asymptomatic patients with fasting plasma glucose (FPG) of 6–15 mmol/l (108–270 mg/dl) entered the trial. Patients were stratified by ideal body weight. Of the 2187 patients (52%) with body weight >120% ideal body weight, 342 were randomly assigned to intensive treatment with metformin. This part of the UKPDS became known as the Metformin Study, and the results were reported separately from the rest of the Glucose Control Study. 2 The remaining 3867 patients (non-overweight and overweight) were randomly assigned to conventional treatment with diet (30%, n=1138) or intensive treatment (70%, n=2729) with one of two sulphonylureas (n=1573) or insulin (n=1156). The nonbalanced randomisation was chosen so that there would be sufficient patients in the sulphonylurea group to allow comparison between those receiving the first-generation sulphonylurea chlorpropamide and those receiving the second-generation sulphonylurea glyburide. References 1 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853. 2 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet . 1998; 352:854–865.
- Diet was the primary treatment in the conventional management regimen and patients received professional dietary advice every 3 months.The treatment goal of conventional management was for patients to attain near normal body weight, maintain fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl) and premeal glucose 4–7 mmol/l (72–126 mg/dl), and remain free of hyperglycaemic symptoms. If marked hyperglycaemia or hyperglycaemic symptoms developed, patients were secondarily randomised to receive nonintensive sulphonylurea or insulin therapy, with the additional option of metformin for overweight patients (defined as >120% ideal body weight). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- The intensive management regimen consisted of sulphonylurea or insulin. Patients treated with sulphonylurea received either 500 mg/day chlorpropamide or 20 mg/day glibenclamide. Patients treated with insulin received a daily injection of an intermediate- or long-acting ultralente insulin. All patients attended clinic at least 3 times monthly and received dietary advice from a dietician. The treatment goal was for patients to achieve fasting plasma glucose (FPG) <6 mmol/l (108 mg/dl) and remain free of hyperglycaemic symptoms. Patients managed with insulin had an additional treatment goal to achieve a premeal glucose concentration of 4–7 mmol/l (72–126 mg/dl). If marked hyperglycaemia or hyperglycaemic symptoms developed in patients receiving the maximum dose of a sulphonylurea, metformin was added to the management regimen. If marked hyperglycaemia recurred, oral agents were discontinued and patients were switched to insulin therapy. If marked hyperglycaemia or hyperglycaemic symptoms developed in patients initially randomised to receive insulin therapy, patients were switched to a more complex insulin regimen. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- The UKPDS prospectively established 21 clinical endpoints representing both fatal and nonfatal clinical events. Major fatal diabetes-related endpoints included sudden death, death from hypoglycaemia or hyperglycaemia, fatal myocardial infarction, and death from peripheral vascular disease. Major nonfatal diabetes-related clinical endpoints included nonfatal myocardial infarction, angina, heart failure, stroke, amputation, renal failure, retinal photocoagulation, vitreous haemorrhage, blindness in one eye, and cataract extraction. Fatal non-diabetes-related endpoints included death from accidents or cancer. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Patients randomised to a conventional management regimen (diet) progressively required pharmacological therapy. Within 1 year of randomisation, approximately 10% of patients received pharmacological management (nonintensive sulphonylurea or insulin) and by 12 years, only approximately 20% patients were able to maintain fasting plasma glucose (FPG) <15 mmol/l (<270 mg/dl). In the intensive management group with sulphonylurea or insulin, 86% patients randomised to receive sulphonylurea continued to do so after 6 years, but 19% were also receiving metformin and 11% were also receiving insulin. Of patients initially randomised to insulin, 77% were still receiving a single daily injection at bedtime after 6 years; however 24% of these patients had been switched to a more complex insulin regimen. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- In the conventional management group (diet), HbA 1c increased steadily over the study period. In the first year of management, the intensive management group with sulphonylurea or insulin had a decrease in median HbA 1c to the upper limit of the normal range. Following approximately 6 years of randomisation, the HbA 1c in the intensive management group had progressively increased to a pre-study value of 7%. An intensive management regimen achieved significantly lower HbA 1c values throughout the study, with a median difference of 0.9% over 10 years (7.0% in the intensive management group compared with 7.9% in the conventional management group, p<0.0001). Intensive management did not maintain optimal glycaemic control, a reflection of the progressive nature of Type 2 diabetes. However, in the case of the UKPDS, the term ‘intensive management can be misleading as it was no more intensive than usual clinical management in many centres at the time the study results were reported. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- In the first year of treatment, fasting plasma glucose (FPG) decreased in the intensive management group (sulphonylurea or insulin). After approximately 9 years, FPG in the intensive management group had increased progressively to the pretreatment value of 8.1 mmol/l (146 mg/dl). Throughout the study, intensive management resulted in significantly lower FPG concentrations compared with conventional management (diet); however intensive management did not maintain glycaemic control, reflecting the progressive nature of Type 2 diabetes. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- At baseline, mean body weight of patients was 77.5 kg (170 Ib). Intensive management with sulphonylurea or insulin resulted in a significant increase in body weight compared with conventional management (diet). Maximum differences in weight change were observed 10 years after randomisation; patients in the intensive management group were, on average, 3.1 kg (6.8 Ib) heavier than patients in the conventional group (p<0.0001). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Intensive management with sulphonylurea or insulin reduced the risk of myocardial infarction (including fatal and nonfatal myocardial infarction and sudden death) by 16% compared with conventional management with diet (p=0.052). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Microvascular endpoints in UKPDS were renal failure, death from renal failure, vitreous haemorrhage, and retinopathy requiring photocoagulation therapy. Relative risk was defined as the relative risk of intensive management (sulphonylurea or insulin) resulting in a single microvascular endpoint. The relative risk of renal failure was 0.73, death from renal failure 1.83, vitreous haemorrhage 0.77, and retinal photocoagulation 0.71. Intensive management significantly reduced the risk of microvascular endpoints by 25% compared with conventional management with diet (p=0.0099). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- A major hypoglycaemic episode was defined as requiring third-party assistance or medical intervention. Hypoglycaemic episodes were significantly higher in the intensive management group (sulphonylurea or insulin) compared with the conventional management group (diet) (p<0.0001). Comparison of the three intensive management regimens revealed that major hypoglycaemic episodes were more common in patients managed with insulin. The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Diabetes-related endpoints included sudden death, death from hypoglycaemia or hyperglycaemia, myocardial infarction, death from peripheral vascular disease, angina, heart failure, stroke, amputation, renal failure, death from renal failure, retinal photocoagulation, vitreous haemorrhage, blindness in one eye, and cataract extraction. Over the 15-year study period, the risk of developing any diabetes-related endpoint was reduced by 12% and myocardial infarction reduced by 16% with intensive management (sulphonylurea or insulin). The most significant decrease was a 25% reduction in microvascular endpoints. Intensive management was also associated with a reduction in the risk of retinopathy progression at 12 years (21%), of cataract extraction (24%) and of microalbuminuria (33%). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Incidence Rates of MI and Microvascular Endpoints by Mean Systolic Blood Pressure: UKPDS In the UK Prospective Diabetes Study (UKPDS), systolic blood pressure was equally related to both myocardial infarction and microvascular endpoints. Reference: Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR, on behalf of the UK Prospective Diabetes Study Group. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412-419.
- Incidence Rates of MI and Microvascular Endpoints by Mean Hemoglobin A 1c : UKPDS In the UKPDS, in contrast with the equal association of systolic blood pressure with both microvascular and macrovascular endpoints, for hemoglobin A 1c a stronger relation was found with microvascular complications. Compared with a hemoglobin A 1c value of 5.5%, a value of 11% increased risk for microvascular complications tenfold, whereas risk for myocardial infarction was increased only twofold. These differences were highly statistically significant. Reference: Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412.
- UKPDS 10-Year Follow-up Results: Glycemic Control, Weight, and Plasma Insulin The results of UKPDS demonstrated that initially, intensive therapy with exogenous insulin or a sulphonylurea reduced hemoglobin A 1c , but after 4-5 years, hemoglobin A 1c increased at a rate similar to that in patients treated with conventional therapy. This finding demonstrates that there is progressive loss of glycemic control, which in other papers has been linked to progressive loss of beta cell function. If an intervention is withdrawn, then glycemic control gets worse, suggesting that it is not a loss of efficacy of a specific agent, but progressive loss due to the disease. The UKPDS results provide a rationale for the use of combination therapy when hemoglobin A 1C and fasting glucose rise. This study also found that intensive control was associated with increased weight gain and increased risk for hypoglycemic episodes, which may be related to a diminution of the potential benefits of intensive glycemic control. Reference: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
- UKPDS: Endpoints by Glucose Treatment Group Among the primary endpoints in UKPDS, there was a 12% reduction in risk for any diabetes-related event, which was significant at p=0.029. The reduction in risk for myocardial infarction was relatively modest at 16%, which was not quite statistically significant at p=0.052. The large 25% reduction in microvascular disease is consistent with the updated hemoglobin A 1C data from UKPDS included in the Epidemiology module of this slide set (slide 17). Reference: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
- UKPDS: Impact of Glucose-Lowering Agents on MI and Stroke In UKPDS patients randomized to intensive therapy with a sulphonylurea or exogenous insulin, there was a 16% reduction in myocardial infarction and an 11% increase in stroke, though the numbers for the latter are very small. Overweight patients were randomized to a metformin group in addition to the two intensive therapy groups or the conventional therapy group; the metformin group had a very impressive 39% reduction in myocardial infarction, and a 41% reduction in stroke. In a supplementary study of overweight and nonoverweight patients randomized to sulphonylurea therapy with or without metformin, patients treated with both metformin and a sulphonylurea had a statistically significant 96% increase in risk of diabetes-related death compared with patients treated with a sulphonylurea alone. Most diabetologists believe that this combination metformin-sulphonylurea group was aberrant. A combined analysis of the main UKPDS and the supplementary study found a significant 19% reduction in risk for diabetes-related endpoints with metformin. References: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865.
- UKPDS Results: Intensive Blood Pressure Control Approximately 1,100 subjects out of the 4,000 subjects in the UKPDS were randomized either to intensive blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor or a beta-blocker or to less-intensive blood pressure control. At 9-year follow-up, systolic blood pressure was a mean 10 mm Hg lower and diastolic blood pressure was a mean 5 mm Hg lower with intensive control compared with less-intensive control. In contrast to the results of glycemic control, intensive blood pressure control in the UKPDS was associated with significant reductions in macrovascular disease, specifically stroke, as well as a nonsignificant 21% decline in myocardial infarction, which was larger than in the comparison of glycemic interventions. Intensive blood pressure control also reduced microvascular disease endpoints by 37%. Some investigators have interpreted these results as suggesting that blood pressure reduction is more important than glycemic control in diabetic patients. However, this is not quite a correct interpretation, because there were many fewer people in the blood pressure study than in the glycemic control study. In addition, in unpublished data, those individuals who were randomized to both intensive blood pressure control and intensive glycemic control had the best results of all. Reference: UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713.
- Comparison of Glucose Lowering and Blood Pressure Lowering in UKPDS The results of intensive glucose control and intensive blood pressure control in the UKPDS are combined to facilitate the comparison of the relative benefits of glucose-lowering and blood pressure-lowering on clinical endpoints in that study. References: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713.
- Effect of Blood Pressure Control in the UKPDS: Tight vs. Less Tight Control In the UKPDS, a subgroup of patients with type 2 diabetes mellitus was randomized to either “tight” blood pressure control, in which blood pressure was lowered to a mean of 144/82 mm Hg, or to “loose” control, in which blood pressure was lowered to a mean of 154/87 mm Hg. Patients were also randomized to captopril or atenolol, with diuretics added to achieve target blood pressure levels, and were followed up for 9 years. Tight blood pressure control led to a significant reduction in diabetes-related endpoints, including diabetes-related deaths and complications related to microvascular disease. Heart failure and stroke were remarkably reduced. There was a trend toward a reduction of myocardial infarction, with a risk reduction of 21%, but it did not achieve statistical significance. Reference: UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-713.
- The presence of diabetes complications are associated with poorer quality of life. People who had macrovascular complications reported significantly worse health, problems with mobility and usual activities, and reduced vigor. People who had microvascular complications reported more tension and total mood disturbance. There was no significant difference in quality of life between an intensive management regimen (sulphonylurea or insulin) and convention management regimen (diet). Reference UK Prospective Diabetes Study (UKPDS) Group. Quality of life in type 2 diabetic patients is affected by complications not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). Diabetes Care . 1999; 22:1125–1136.
- Results of the UKPDS demonstrated that glycaemic control deteriorated over time with sulphonylurea and insulin management. However, an intensive management regimen over a 10-year period reduced HbA 1c by 0.9% compared with a conventional management regimen (diet). There was no statistically significant reduction in macrovascular events with intensive management with a sulphonylurea or insulin, although the 16% risk reduction in myocardial infarction (including non-fatal and fatal myocardial infarction and sudden death) was borderline significant (p=0.052). Pharmacological management was associated with a significant increase in body weight over 10 years; patients in the intensive management group were, on average 3.1 kg (6.8 Ib) heavier than patients in the conventional group (p<0.0001). Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Based on data from 15 years of the Metformin Study, intensive treatment of overweight patients (defined as >120% ideal body weight) with metformin resulted in significant risk reductions in several clinical endpoints. Compared with the conventional management group (diet), the reduction in risk for any diabetes-related endpoint was 32% with metformin (p=0.00023), 42% for diabetes-related death (p=0.017), and 39% for myocardial infarction (p=0.01). Metformin was also associated with a 29% lower risk of microvascular disease and a 41% lower risk of stroke, although this was not statistically significant. In this group of overweight patients, therefore, macrovascular complications were decreased significantly in the metformin group compared with conventional management groups. Reference UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet . 1998; 352:854–865.
- Median HbA 1c in the sulphonylurea ± insulin intensive management group was significantly lower than in the intensive management group with insulin alone (6.6% vs. 7.1% respectively, p=0.0066). Significantly more people in the sulphonylurea ± insulin intensive management group had an HbA 1c <7.0% (47% vs. 35% respectively, p=0.011). Reference UK Prospective Diabetes Study (UKPDS) Group. Efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the UK Prospective Diabetes Study (UKPDS 57). Diabetes Care . 2002; 22:330–336.
- The results of the UKPDS allow certain conclusions to be drawn regarding the management of people with Type 2 diabetes. Intensive glycaemic control in Type 2 diabetes is mandatory in order to decrease the incidence of microvascular disease. The results of the UKPDS also demonstrate that prevention of macrovascular disease in people with Type 2 diabetes requires treatment of cardiovascular risk factors in addition to hyperglycaemia. The benefits of intensive management with sulphonylurea or insulin outweigh the risk of hypoglycaemia. The UKPDS Blood Pressure Control Study demonstrated that tight blood pressure control with an ACE inhibitor or beta-blocker in people with Type 2 diabetes significantly reduces diabetes-related mortality, heart failure and stroke. The term ‘intensive’ was adopted to distinguish one arm of a clinical trial from the other arm (conventional management with diet). However, the intensive management arm of the UKPDS was no more intensive than usual clinical management in many centres by the time the study results were reported. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin treatment compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet . 1998; 352:837–853.
- Figure 1. Amino Acid Alterations in Insulin Lispro, Insulin Aspart, and Insulin Glargine.
- Figure 2. Approximate Pharmacokinetic Profiles of Human Insulin and Insulin Analogues. The relative duration of action of the various forms of insulin is shown. The duration will vary widely both between and within persons.