A Cochrane review included 37 studies with 40 treatment comparisons involving a total of 3 227 subjects. Overall methodological quality of the studies was low. Insulin monotherapy (once-daily long-acting or intermediate-acting, twice-daily premixed insulin, and multiple injections) was compared to insulin in combination with sulphonylureas (17 comparisons), metformin (11 comparisons), pioglitazone (4 comparisons), alpha-glucosidase inhibitors (like acarbose), dipeptidyl peptidase-4 inhibitors (3 comparisons). No studies assessed diabetes-related morbidity, all-cause mortality or health-related quality of life.
Insulin-oral glucose-lowering agents combination therapy had statistically significant benefits on glycaemic control (HbA1c) over insulin monotherapy (table ). In most trials the participants with combination therapy needed less insulin, whereas insulin requirements increased or remained stable in participants with insulin monotherapy. In most trials the insulin-sulphonylurea combination resulted in a higher number of mild episodes of hypoglycaemia, compared to insulin alone group (range: 2.2 to 6.1 versus 2.0 to 2.6 episodes per participant). Pioglitazone combination therapy also resulted in more mild to moderate hypoglycaemic episodes compared with insulin alone (range 15 to 90 episodes versus 9 to 75 episodes, respectively). The trials that reported hypoglycaemic episodes in the other combinations found comparable numbers of mild to moderate hypoglycaemic events. Use of metformin combination therapy was the only therapy which was associated with weight loss (see table ).
| Outcome | Insulin monotherapy | Insulin plus oral sulphonylureas (95% CI) | No of participants (studies) Quality of evidence |
|---|---|---|---|
| Weight gain (kg) Follow-up: 2 to 12 mo | Mean weight gain -0.8 kg to 2.1 kg | Mean weight gain 0.4 kg to 1.9 kg | 220 (7) Low |
| HbA1c, change from baseline Follow-up: 2 to 12 mo | Mean change -1.5% to 3% | Mean change 1% lower (1.6% lower to 0.5% lower) | 316 (9) Low |
| Outcome | Insulin monotherapy | Insulin plus oral metformin (95% CI) | No of participants (studies) Quality of evidence |
| Weight gain (kg) Follow-up: 3 to 12 mo | Mean weight gain 0 kg to 4.4 kg | Mean weight gain 2.1 kg lower (3.2 kg lower to 1.1 kg lower) | 615 (7) Low |
| HbA1c, change from baseline Follow-up: 3.5 to 6 mo | Mean change -1.6% to 0.5% | Mean change 0.9% lower (1.2% lower to 0.5% lower) | 698 (9) Low |
| Outcome | Insulin monotherapy | Insulin plus alpha-glucosidase inhibitors (95% CI) | No of participants (studies) Quality of evidence |
| Weight gain (kg) Follow-up: 6 to 12 mo | Mean weight gain +0.7 kg to +3.6 kg | Mean weight gain 0.5 kg lower (1.2 kg lower to 0.3 kg higher) | 241 (2) Low |
| HbA1c, change from baseline Follow-up: 3 to 6 mo | Mean change -1.1% to 0.04% | Mean change 0.4% lower (0.5% lower to 0.2% lower) | 448 (3) Low |
| Outcome | Insulin monotherapy | Insulin plus DPP4-inhibitor (95% CI) | No of participants (studies) Quality of evidence |
| Weight gain (kg) Follow-up: 6s to 12 mo | Mean weight gain 0.6 kg to 1.1 kg | Mean weight gain -0.7 kg to 1.3 kg | 362 (2) Low |
| HbA1c, change from baseline Follow-up: 6 to 12 mo | Mean change -0.2% to -0.3% | Mean change 0.4% lower (0.5% lower to 0.4% lower) | 265 (2) Low |
| Outcome | Insulin monotherapy | nsulin plus pioglitazone (95% CI) | No of participants (studies) Quality of evidence |
| Weight gain (kg) Follow-up: 4 to 6 mo | Mean weight gain 0.2 kg to 1.7 kg | Mean weight gain 3.8 kg higher (3.0 kg higher to 4.6 kg higher) | 288 (2) Low |
| HbA1c, change from baseline Follow-up: 3 to 6 months | Mean change -0.6% to 0% | Mean change -0.5% to -1.0% | 785 (3) Low |
Comment: The quality of evidence is downgraded by risk of performance bias.