Changes in outcomes from trial entry to 18 months*
| Metformin+insulin (n=206) | Placebo+insulin (n=206) | Metformin vs placebo | p Value | |
|---|---|---|---|---|
| Carotid ultrasound measures | ||||
| Mean carotid IMT (mm)† | −0.001 (−0.011 to 0.010) | −0.014 (−0.024 to −0.003) | 0.012 (−0.003 to 0.026) | 0.1105 |
| Maximal carotid IMT (mm) | −0.003 (−0.015 to 0.010) | −0.014 (−0.026 to −0.002) | 0.011 (−0.006 to 0.029) | 0.1943 |
| Body composition | ||||
| Weight (kg) | 1.6 (1.1 to 2.1) | 4.2 (3.6 to 4.7) | −2.6 (−3.3 to −1.8) | <0.001 |
| Body mass index (kg/m2) | 0.45 (0.28 to 0.63) | 1.36 (1.19 to 1.54) | −0.91 (−1.16 to −0.66) | <0.001 |
| Waist-hip ratio | 0.01 (0.00 to 0.02) | 0.00 (−0.01 to 0.01) | 0.01 (−0.01 to 0.02) | 0.2834 |
| Glycaemic control | ||||
| HbA1c (%) | −0.78 (−0.92 to −0.64) | −0.36 (−0.50 to −0.22) | −0.42 (−0.62 to −0.23) | <0.001 |
| HbA1c (mmol/mol) | −8.5 (−10.1 to −7.0) | −3.9 (−5.5 to −2.4) | −4.6 (−6.8 to −2.5) | <0.001 |
| HbA1c at 18 months (%) | 7.97 (7.78 to 8.16) | 8.27 (8.08 to 8.47) | −0.31 (−0.52 to −0.09) | 0.0063 |
| HbA1c at 18 months (mmol/mol) | 64 (62 to 66) | 67 (65 to 69) | −3.4 (−5.7 to −1.0) | 0.0063 |
| Participants with HbA1c≤7.0% at end of trial, N (%) | 53 (26) | 28 (14) | 0.0038 | |
| Fasting p-glucose (mmol/L) | −2.14 (−2.64 to −1.64) | −1.67 (−2.18 to −1.16) | −0.47 (−1.18 to 0.25) | 0.2008 |
| Fasting p-insulin (relative change from baseline) | 0.67 (0.58 to 0.77) | 0.63 (0.54 to 0.73) | 107% (87% to 131%) | 0.5312 |
| Fasting C-peptide (relative change from baseline) | 0.73 (0.67 to 0.80) | 0.69 (0.63 to 0.75) | 106% (94% to 120%) | 0.3477 |
| Insulin dose at end of trial (IU/day/kg) | 1.04 (0.94 to 1.15) | 1.36 (1.23 to 1.51) | 76% (68% to 86%) | <0.001 |
| Insulin dose at end of-trial (IU/day) | 102 (91 to 115) | 138 (123 to 155) | 74% (65% to 84%) | <0.001 |
| Insulin dose (relative change from baseline) | 2.13 (2.00 to 2.26) | 2.82 (2.64 to 3.01) | 75% (69% to 83%) | <0.001 |
| Blood pressure and lipids | ||||
| Systolic blood pressure (mm Hg) | −5.7 (−8.0 to −3.4) | −5.4 (−7.7 to −3.0) | −0.3 (−3.6 to 2.9) | 0.8434 |
| Diastolic blood pressure (mm Hg) | −3.5 (−4.8 to −2.3) | −3.0 (−4.2 to −1.7) | −0.6 (−2.3 to 1.2) | 0.5383 |
| Heart rate (bpm) | −0.3 (−1.7 to 1.1) | −3.0 (−4.4 to −1.5) | 2.7 (0.6 to 4.7) | 0.0100 |
| Total cholesterol (mmol/L) | 0.07 (−0.04 to 0.18) | 0.20 (0.09 to 0.32) | −0.13 (−0.29 to 0.03) | 0.1089 |
| LDL cholesterol (mmol/L) | 0.04 (−0.06 to 0.13) | 0.21 (0.12 to 0.31) | −0.18 (−0.31 to −0.04) | 0.0101 |
| VLDL cholesterol (relative change from baseline) | 1.02 (0.96 to 1.08) | 0.97 (0.92 to 1.03) | 104% (96% to 113%) | 0.3042 |
| HDL cholesterol (mmol/L) | 0.01 (−0.02 to 0.04) | 0.00 (−0.03 to 0.02) | 0.02 (−0.03 to 0.06) | 0.4577 |
| Triglycerides (relative change from baseline) | 1.01 (0.95 to 1.07) | 0.98 (0.93 to 1.04) | 103% (95% to 112%) | 0.4735 |
The variables p-insulin, C-peptide, insulin dose, VLDL cholesterol and triglycerides did not meet the criteria of a normal distribution and were accordingly log transformed. Therefore, these variables are presented with relative change from baseline instead of absolute change.
To adjust for multiplicity, the significance level can be adjusted to 0.05/(K+1)/2 (where K represents the number of prespecified secondary outcomes) equalling in this case an α=0.0045.
HbA1c, haemoglobin A1c; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.
*Intention to treat, mixed model analyses with random effect person adjusted for stratification variables, results are presented as mean (95% CI).
†Between group differences are analysed using multiple imputation of missing values.