Comparison of Insulin Monotherapy and Combination Therapy With Insulin and Metformin or Insulin and Troglitazone in Type 2 Diabetes

Abstract

OBJECTIVE—To evaluate the safety and efficacy of treatment with insulin alone, insulin plus metformin, or insulin plus troglitazone in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 88 type 2 diabetic subjects using insulin monotherapy (baseline HbAlc 8.7%) were randomly assigned to insulin alone (n = 31), insulin plus metformin (n = 27), or insulin plus troglitazone (n = 30) for 4 months. The insulin dose was increased only in the insulin group. Metformin was titrated to a maximum dose of 2,000 mg and troglitazone to 600 mg. RESULTS—HbAlc levels decreased in all groups, the lowest level occurring in the insulin plus troglitazone group (insulin alone to 7.0%, insulin plus metformin to 7.1%, and insulin plus troglitazone to 6.4%, P < 0.0001). The dose of insulin increased by 55 units/day in the insulin alone group (P < 0.0001) and decreased by 1.4 units/day in the insulin plus metformin group and 12.8 units/day in the insulin plus troglitazone group (insulin plus metformin versus insulin plus troglitazone, P = 0.004). Body weight increased by 0.5 kg in the insulin plus metformin group, whereas the other two groups gained 4.4 kg (P < 0.0001 vs. baseline). Triglyceride and VLDL triglyceride levels significantly improved only in the insulin plus troglitazone group. Subjects taking metformin experienced significantly more gastrointestinal side effects and less hypoglycemia. CONCLUSIONS—Aggressive insulin therapy significantly improved glycemic control in type 2 diabetic subjects to levels comparable with those achieved by adding metformin to insulin therapy. Troglitazone was the most effective in lowering HbAlc, total daily insulin dose, and triglyceride levels. However, treatment with insulin plus metformin was advantageous in avoiding weight gain and hypoglycemia.

Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin

“…However, metformin is known to positively affect other parameters which influence the development of cardiovascular disease, regardless of any effect on BP (30,31). Our results agree with the literature regarding the effect of metformin on BMI reduction (9,12,13), reduction of daily insulin dose (9,12,13), biguanide-related sideeffects (21,24), and reduction of WC, which is a cornerstone for the diagnosis of metabolic syndrome and may play the role of a co-variate when other parameters are analyzed (18,32).…”

“…The present study showed that the addition of metformin to a scheme of NPH insulin administered twice daily improved glycemic control of type 2 diabetic patients with the metabolic syndrome after 6 months, regardless of BMI reduction, as already shown in other studies (11,12). Although one study showed that metformin can lead to WC reduction (15), the improvement of A1C levels in our sample was independent of WC reduction, indicating that metformin improves sensitivity to the action of insulin by mechanisms already described, such as inhibition of hepatic gluconeogenesis (16).…”

“…More intensive insulin therapy with fast-acting insulins and self-monitoring might have led to better results (17). The mean FBG and A1C values of our patients were similar to those reported in other studies (11)(12)(13), although most studies did not report the percentage of patients who reached the established cut-off points for A1C. Such information would have shed light on the extent of glycemic control reached at other centers, since the mean value is sensitive to extreme values.…”

“…However, there is no consensus about its beneficial effects on these parameters (10). Most studies have analyzed independent samples, comparing patients on insulin with patients on combined insulin-metformin therapy (11)(12)(13) with no conclusive results.…”

Metformin and body weight

“…However, as weight gain is an early event after initiation of insulin, the short-term effects of metformin on body weight may be relevant in the setting of concomitant insulin use. A number of these trials, listed in Table 2, 54-66 demonstrated significant reductions in body weight between patients receiving insulin and metformin compared with insulin and placebo 54,56,59,60,62 although other studies did not. 55,57,58,61,63,64 Two trials demonstrated Figure 1 Effects of randomized treatments on body weight in overweight patients in the UK Prospective Diabetes Study.…”