UKPDS 33^A1

Multicenter RCT comparing sulfonylureas, insulin, and dietary intervention in 3,867 participants with newly diagnosed type 2 diabetes mellitus; mean age = 54 years

Treatment reduced the risk of microvascular end points by 25%; reduced mortality occurred with improved blood pressure and lipid control but not glycemic control

Blood pressure and lipid control significantly reduce cardiovascular mortality rates in patients with diabetes

Tight blood glucose control reduces retinal microvascular complications but not other outcomes

UKPDS 34^A2

Randomized embedded trial comparing metformin vs. dietary intervention in 753 participants with newly diagnosed type 2 diabetes; BMI at randomization > 120% of ideal

36% reduction in all-cause mortality with metformin, and 42% reduction in diabetes-related death vs. conventional therapy

Metformin should be the medication of choice in patients with type 2 diabetes, especially in those with obesity

UKPDS 80^A3

Posttrial monitoring of 3,277 participants (78% of original UKPDS cohort); 1,010 from sulfonylurea/insulin intensive therapy group; 379 from conventional therapy group; 136 from metformin intensive therapy group

Annual visits for five years in UKPDS clinics with collection of outcome measures and two questionnaires

Clinical examinations once every three years

Collection of questionnaires only in years 6 to 10

Relative risk reductions persisted at 10 years:

Sulfonylurea/insulin group: any diabetes-related end point (9%); microvascular disease (24%); myocardial infarction (15%); death from any cause (13%)

Metformin group: any diabetes-related end point (21%); myocardial infarction (33%); death from any cause (27%)

Despite early loss of differences in glycemic control between groups, risk reductions for microvascular complications persisted and risk reductions for myocardial infarction and death from any cause emerged during 10 years of follow-up

Diabetes Prevention Program^A4

Multicenter RCT comparing metformin, placebo, and intensive lifestyle intervention, which included 150 minutes of weekly exercise and a goal of 7% weight loss

3,234 participants at least 25 years of age with BMI ≥ 24 kg per m²; fasting glucose level = 95 to 125 mg per dL (5.3 to 6.9 mmol per L); two-hour postglucose load = 140 to 199 mg per dL (7.8 to 11.0 mmol per L)

Average weight loss:

Placebo: 0.1 kg (0.2 lb)

Metformin: 2.1 kg (4.6 lb)

Lifestyle: 5.6 kg (12.3 lb)

Incidence of diabetes:

11 per 100 person-years for placebo; 7.8 per 100 person-years for metformin; and 4.8 per 100 person-years for lifestyle changes

Number needed to treat to prevent one new case of diabetes in three years:

Metformin: 13.9

Lifestyle: 6.9

ACCORD^A5

Multicenter RCT comparing intensive therapy with target A1C < 6% vs. standard therapy with target A1C of 7% to 9%

10,251 participants; mean age = 62.2 years; median duration of diabetes = 10 years with CVD or at least two risk factors for CVD; median A1C = 8.1%

Trial stopped early because of increased mortality in the intensive therapy group; median A1C in intensive therapy group = 6.4%, in usual therapy group = 7.5%

Patients with diabetes and established CVD or numerous CVD risk factors and with longer duration of diabetes have higher mortality risk using target A1C < 6% (one extra death for every 95 patients treated for 3.5 years)

ADVANCE^A6

Multicenter, factorial RCT comparing intensive therapy with target A1C ≤ 6.5% vs. standard therapy with target A1C based on local guidelines

11,140 participants; mean age = 66 years; median duration of diabetes = 8 years, with history of major macro- or microvascular disease

Intensive therapy significantly reduced incidence of combined major macro- and microvascular events; significantly reduced microvascular events primarily from significant reduction of nephropathy

Intensive therapy had no significant effect on the incidence of macrovascular events, death from any cardiovascular causes, or death from any cause

Intensive therapy had no significant effect on cardiovascular events or mortality

VADT^A7

Randomized, open-label trial; intensive therapy group treatment goal of absolute reduction of 1.5 percentage points in A1C level

1,791 participants; mean age = 60.4 years; mean duration of diabetes = 11.5 years; mean A1C = 9.4%; 40% had a history of cardiovascular events

Intensive therapy had no significant effect on occurrence of cardiovascular events, death from any cause, or microvascular events

Intensive therapy had no significant effect on cardiovascular events or mortality