Table 1.
Large-scale clinical trials comparing intensive glucose-lowering therapy with standard therapy.
| Study | Population | Design | Hypoglycaemia | CVD | All-cause mortality |
|---|---|---|---|---|---|
| DCCT/EDIC 9,10 | Patients with T1D aged 13–39 years (N = 1441) | Conventional treatment with 1–2 daily insulin injections
versus intensive treatment with ⩾3 daily
injections or insulin pump Mean follow up of 6.5 years |
Threefold increase in severe hypoglycaemia in the intensive treatment group (p < 0.001) | No difference after the initial 6.5 years of
follow-up. 57% reduction in in MACE (p = 0.02) after median follow up of 17 years |
No difference between groups |
| UKPDS3 11,12 | Patients with newly diagnosed T2D (N = 4209) | Intensive treatment (metformin and SU/insulin)
versus conventional therapy (primarily
diet) Median follow up of 10 years |
Two-fold increase in severe hypoglycaemia in the intensive treatment group (p < 0.0001) | No difference after the initial 10-years of follow
up Significant reductions in both SU/insulin and metformin group after 10 years of post-trial follow up MI SU/insulin: RR 0.85 (p = 0.01) Metformin: RR 0.67 (p = 0.005) Stroke SU/insulin: RR 0.91 (p = 0.39) Metformin: RR 0.80 (p = 0.35) |
No difference for Insulin/SU group 36% reduction in the obese metformin group (p = 0.01) 13% (p = 0.007) and 17% (p = 0.002) reduction after 10 years of post-trial follow up |
| ACCORD 4 | Patients with T2D and established CVD (35%) or high CV risk (N = 10,251) | Intensive glycaemic control (HbA1c<6.0%)
versus standard therapy (HbA1c
7.0–7.9%) All glucose-lowering therapies allowed. Discontinued after a mean follow up of 3.5 years |
Percentage of patients experiencing at least one episode of
severe hypoglycaemia 16.2 versus 5.1% (p < 0.001), respectively |
MACE HR 0.90 (p = 0.16) CV mortality HR 1.35 (p = 0.02) Nonfatal MI HR 0.76 (p = 0.004) Nonfatal stroke HR 1.06 (p = 0.74) CV mortality remained significantly increased after a mean 7.7 years of follow up HR 1.20 (p = 0.02) |
HR 1.22 (p = 0.04) All-cause mortality normalized after a mean of 7.7 years of follow up HR 1.01 (p = 0.91) |
| ADVANCE 13,14 | Patients with T2D and microvascular or macrovascular complication or ⩾ 1 risk factors (N = 11,140) | Intensive treatment (HbA1c<6.5%)
versus standard treatment. Median follow up of 5 years |
Significant increase in severe hypoglycaemia in the intensive
treatment group HR 1.86 (p < 0.001) |
MACE HR 0.94 (p = 0.37) CV mortality HR 0.88 (p = NS) Nonfatal MI HR 1.02 (p = NS) Nonfatal stroke HR 0.98 (p = NS) No effect observed after 5.4 years of post-trial follow up |
HR 0.93 (p = 0.28) No effect observed after 5.4 years of post-trial follow up |
| VADT 15,16 | Patients with T2D treated with insulin or maximal-dose oral agent (N = 1791) | Intensive treatment (HbA1c<6.0%)
versus standard therapy. Median follow up of 5.6 years |
Significant increase in hypoglycaemia in the intensive treatment group (p < 0.001) | No difference in the primary composite CV endpoint HR 0.88 (p = 0.14) Significant reduction in the primary composite CV endpoint after 9.8 years of follow up HR 0.83 (p = 0.04) |
HR 1.07 (p = 0.62) No reduction after 9.8 years of follow up HR 1.05 (p = 0.54) |
| ORIGIN 17 | Patients with IFG, IGT or T2D and CV risk factors (N = 12,537) | Early treatment with insulin glargine (target FPG 5.3 mmol/l)
versus standard care. Median follow up of 6.2 years |
Threefold increase in severe hypoglycaemia (p < 0.001) | MACE HR 1.03 (p = 0.63) CV death HR 1.00 (p = 0.98) |
HR 0.98 (p = 0.70) |
CV, cardiovascular; CVD, cardiovascular disease; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; HR, hazard ratio; IFG, impaired fasting glucose; IGT impaired glucose tolerance; MACE, major adverse cardiovascular event (composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke); MI, myocardial infarction; NS, nonsignificant; RR, relative risk; SU, sulphonylurea; T1D, type 1 diabetes; T2D, type 2 diabetes.