UKPDS 33

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Turner R, et al. "Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes". The Lancet. 1998. 352(9131):837-53.
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Contents

Clinical Question

Among adults with newly diagnosed T2DM, what is the effect of intensive glycemic control with a sulfonylurea or insulin therapy on glycemic control and the complications of diabetes compared to diet alone?

Bottom Line

Intensive glycemic control (fasting glucose <108mg/dl) that reduces HbA1c by 11% over 10 years (median 7.0%) is associated with a 25% reduction in microvascular complications. However, there was no effect on macrovascular disease or mortality among patients with T2DM.

Major Points

Prior to UKPDS, the University Group Diabetes Program (UGDP), the only large-scale RCT to investigate the role of glycemic control on macrovascular outcomes in T2DM, demonstrated no macrovascular benefit with sulfonylureas. However, it revealed an unexpected increase in cardiovascular mortality with the sulfonylrea tolbutamine.

This prompted the larger United Kingdom Prospective Diabetes Study (UKPDS), which further compared the efficacy of different treatment regimens on glycemic control as well as microvascular and macrovascular complications. After a median follow-up of 10 years, UKPDS demonstrated that intensive therapy maintaining an 11% lower HbA1c (median 7.0% vs. 7.9%) substantially reduced microvascular endpoints by 25%, largely due to decreased retinopathy requiring photocoagulation. The number needed to treat to prevent one patient developing any of the diabetes-related endpoints, including mortality, over 10 years was 20. There was a nonsignificant trend towards decreased MIs, but there was no effect on diabetes-related mortality or all-cause mortality. The disadvantages of intensive therapy were weight gain and hypoglycemia, particularly in patients treated with insulin.

While this study investigated different regimens of intensive therapy, all regimens were equivalent in their ability to reduce the incidence of microvascular endpoints. This suggests that it is not any one therapy but rather improving glycemic control that is important.

Design

  • Multicenter, open-label, randomized, controlled trial
  • N=3,867
    • Intensive therapy (n=2,729)
    • Conventional therapy (n=1,138)
  • Setting: 23 UKPDS centers
  • Enrollment 1977-1991
  • Median follow-up: 10 years
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Newly diagnosed T2DM Age 25-65 years
  • Fasting glucose >108 mg/dl on two mornings measured 1-3 weeks apart

Exclusion Criteria

  • Ketonuria >54 mg/dl
  • Creatinine >2 mg/dl
  • MI within previous year
  • Current angina
  • Current CHF
  • >1 major vascular event
  • Retinopathy requiring laser treatment
  • Malignant HTN
  • Uncorrected endocrine disorder
  • Occupation precluding insulin therapy (eg, heavy machinery worker)
  • Severe concurrent life-limiting illness

Baseline Characteristics

  • Mean age: 53 years
  • Male: 61%
  • Ethnicity: 81% Caucasian, 10% Indian Asian, 8% Afro-Caribbean
  • Weight: 77.5 kg
  • BMI: 27.5 kg/m2
  • SBP: 135 mmHg
  • DBP: 82 mmHg
  • Smoking: 34% never, 35% ex-, 31% current
  • Alcohol: 25% none, 56% social, 18% regular, 1% dependent
  • Exercise: 20% sedentary, 35% moderately active, 40% active, 5% fit
  • Fasting glucose: 144 mg/dL (93% ≥126 mg/dL, 86% ≥ 140 mg/dL)
  • HbA1c: 7.1%
  • Total cholesterol: 209 mg/dL
  • LDL: 135 mg/dL
  • HDL: 41 mg/dL
  • Triglycerides: 208 mg/dL
  • Retinopathy: 36%
  • Proteinuria: 1.9%
  • Plasma creatinine: 1.06 mg/dL
  • Biothesiometer >25 volts: 11.5%

Baseline Medications

  • >1 aspirin daily: 1.6%
  • Diuretic: 13%
  • Digoxin: 1.1%
  • Antihypertensive: 12%
  • Lipid-lowering: 0.3%
  • HRT or OC: 0.8%

Interventions

3-month dietary run-in period prior to randomization:

  • Monthly clinic visits with physician and dietician advised patients to follow diets (low in saturated fat, moderately high in fiber, carboyhdrates comprising 50% of calories)
  • After run-in period, mean fasting glucose measured on 3 days over 2 weeks

Randomization stratified by IBW:

  • Non-overweight patients (N=3,867) randomized to intensive therapy with sulfonylurea (40%) or insulin (30%) vs. conventional

therapy (30%)

  • Overweight patients (N=343), defined as >120% IBW, randomized to intensive therapy with metformin vs. conventional therapy

Intensive therapy with sulfonylurea (chlorpropamide 100-500 mg, glibenclamide 2.5-20 mg, or glipizide 2.5-40 mg daily):

  • Goal fasting glucose <108 mg/dl

Intensive therapy with insulin:

  • Goal fasting glucose 72-126 mg/dl
  • Long-acting: ultralente or isophane insulin once daily
  • Short-acting: regular insulin, added if long-acting insulin >14 units or pre-meal/bed-time glucose >126 mg/dl

Conventional therapy with diet alone:

  • Goal fasting glucose <270 mg/dl without symptoms (polydipsia, polyuria)
  • Each group had clinic visits every 3 months to assess glycemic control:
  • If not at goal, additional agents (including sulfonylurea, metformin, insulin) added

Outcomes

Comparisons are intensive vs. conventional therapy. Units expressed as absolute events per 1000 patient years, unless otherwise stated.

Primary Outcomes

Any diabetes-related endpoint
Diabetes-related death (see below), non-fatal MI, angina, CHF, non-fatal stroke, renal failure, amputation, vitreous hemorrhage, retinal photocoagulation, blindness, cataract extraction
40.9 vs. 46.0 (RR 0.88; 95% CI 0.79-0.99; P=0.029)
Diabetes-related death
Death from MI, stroke, PAD, renal disease, hyper- or hypo-glycemia, sudden death
10.4 vs. 11.5 (RR 0.90; 95% CI 0.73-1.11; P=0.34)
All-cause mortality
17.9 vs. 18.9 (RR 0.94; 95% CI 0.80-1.10; P=0.44)
MI and sudden death
14.7 vs. 17.4 (RR 0.84; 95% CI 0.71-1.00; P=0.052)
Stroke
5.6 vs. 5.0 (RR 1.11; 95% CI 0.81-1.51; P=0.52)
Microvascular complications
Retinopathy requiring photocoagulation, vitreous hemorrhage, renal failure
8.6 vs. 11.4 (RR 0.75; 95% CI 0.60-0.93; P=0.0099)
Amputation or death from PAD
1.1 vs. 1.6 (RR 0.65; 95% CI 0.36-1.16; P=0.15)

Secondary Outcomes

Fatal MI
7.5 vs. 8.0 (RR 0.94; 95% CI 0.68-1.30; P=0.63)
Non-fatal MI
7.5 vs. 95 (RR 0.79; 95% CI 0.58-1.09; P=0.067)
Sudden death
0.9 vs. 1.6 (RR 0.54; 95% CI 0.24-1.21; P=0.047)
CHF
3.0 vs. 3.3 (RR 0.91; 95% CI 0.54-1.52; P=0.63)
Angina
6.8 vs. 6.7 (RR 1.02; 95% CI 0.71-1.46; P=0.91)
Fatal stroke
1.6 vs. 1.3 (RR 1.17; 95% CI 0.54-2.54; P=0.60)
Non-fatal stroke
4.3 vs. 4.0 (RR 1.07; 95% CI 0.68-1.69; P=0.72)
Retinal photocoagulation
7.9 vs. 11.0 (RR 0.71; 95% CI 0.53-0.96; P=0.0031)
Vitreous hemorrhage
0.7 vs. 0.9 (RR 0.77; 95% CI 0.28-2.11; P=0.51)
Blind in one eye
2.9 vs. 3.5 (RR 0.84; 95% CI 0.51-1.40; P=0.39)
Cataract extraction
5.6 vs. 7.4 (RR 0.76; 95% CI 0.53-1.08; P=0.046)
Renal failure
0.6 vs. 0.8 (RR 0.73; 95% CI 0.25-2.14; P=0.45)
Death from renal failure
0.3 vs. 0.2 (RR 1.63; 95% CI 0.21-12.49; P=0.53)
Death from PAD
0.1 vs. 0.3 (RR 0.26; 95% CI 0.03-2.77; P=0.12)
Amputation
1.0 vs. 1.6 (RR 0.61; 95% CI 0.28-1.33; P=0.099)
Median HbA1c
7.0% vs. 7.9% (RR 0.89; P<0.0001)

Adverse Events

Comparisons are chlorpropamide vs. glibenclamide vs. insulin vs. conventional.

Any hypoglycemic episodes
16.0% vs. 21% vs. 28% vs. 1.0% (intention-to-treat)
11.0% vs. 17.7% vs. 36.5% vs. 1.2% (actual therapy)
Major hyperglycemic episodes
1.0% vs. 1.4% vs. 1.8% vs. 0.7% (intention-to-treat)
0.4% vs. 0.6% vs. 2.3% vs. 0.1% (actual therapy)
Weight gain compared to conventional
2.6 vs. 1.7 vs. 4.0 kg vs. conventional (P<0.0001)

Funding

Supported by the UK Medical Research Council, British Diabetic Association, UK Department of Health, US National Eye Institute and US National Institute of Diabetes, Digestive and Kidney Disease, British Heart Foundation, Wellcome Trust, Charles Wolfson Charitable Trust, Clothworkers’ Foundation, Health Promotion Research Trust, Alan and Babette Sainsbury Trust, Oxford University Medical Research Fund Committee, Novo-Nordisk, Bayer, Bristol-Myers Squibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba, Boehringer Mannheim, Becton Dickinson, Owen Mumford, Securicor, Kodak, Cortecs Diagnostics, Glaxo Wellcome, Smith Kline Beecham, Pfizer, Zeneca, Pharmacia and Upjohn, and Roche.