Improved Glycemic Control Without Weight Gain Using Triple Therapy in Type 2 Diabetes

Abstract

OBJECTIVE -To evaluate the safety and effectiveness of triple therapy using insulin, metformin, and a thiazolidinedione following a course of dual therapy using insulin and metformin or insulin and a thiazolidinedione in type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty-eight type 2 diabetic subjects using insulin monotherapy (baseline HbA lc level 8.5%) who had been randomly assigned to insulin (INS) and metformin (MET) (INS ϩ MET, n ϭ 14) or INS and the thiazolidinedione troglitazone (TGZ) (INS ϩ TGZ, n ϭ 14) (dual therapy) for 4 months were given INS, MET, and TGZ (triple therapy: INS ϩ MET, add TGZ; or INS ϩ TGZ, add MET) for another 4 months. The INS dose was not increased. CONCLUSIONS -Triple therapy using INS, MET, and TGZ resulted in lower HbA lc levels and total daily insulin dose than during dual therapy. The use of triple therapy resulted in 100% of subjects achieving an HbA lc Ͻ7.0%, while decreasing the dose of INS. Weight gain was avoided when MET therapy preceded the addition of TGZ therapy. The addition of TGZ resulted in the greatest reductions in HbA lc levels and insulin dose. Triple therapy using INS, MET, and a thiazolidinedione (such as TGZ) can be a safe and effective treatment in type 2 diabetes. RESULTS Diabetes Care 27:1577-1583, 2004R esearch in the previous decade has conclusively demonstrated the benefit of improved blood glucose control in the prevention of diabetes complications (1,2). Efforts to advance our ability to achieve near normal glycemic control have resulted in an array of pharmaceutical interventions that not only lower blood glucose levels, but also have beneficial effects on comorbid conditions such as hypertension and hyperlipidemia. In the treatment of type 2 diabetes, health care providers have the option of using insulin (INS), sulfonylureas, thiazolidinediones, biguanides such as metformin (MET), and other oral agents to achieve treatment goals (3,4).MET has been shown to lower blood glucose levels by sensitizing the liver to the effects of insulin, thus suppressing hepatic glucose output. It also has mild effects on promoting glucose utilization (5,6). Thiazolidinediones, like troglitazone (TGZ), improve insulin sensitivity by enhancing insulin-mediated glucose disposal, resulting in reduced plasma insulin concentrations. Thiazolidinediones may also have modest effects on lowering hepatic glucose production (7-9). In addition, studies have shown that thiazolidinediones enhance ␤-cell responsiveness and may prolong ␤-cell survival (10,11). Several randomized, placebocontrolled studies have demonstrated the effectiveness of dual therapy using oral sulfonylureas or INS in combination with either MET or TGZ in lowering blood glucose levels in type 2 diabetic subjects (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Studies of the combined use of MET plus a thiazolidinedione have also shown improved glycemic control when compared with MET alone (23-26). Thiazolidinediones added to treatment with sulfonylureas and MET resulted in significant improvements in HbA 1c leve...

Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy

“…In general, antihyperglycaemic drugs with different mechanisms of action will have the greatest synergy. Insulin plus metformin [73] and insulin plus a TZD [74] are particularly effective means of lowering glycaemia. The increased risk of fluid retention with the latter combination must be considered.…”

Achieving Glycemic Goals in Type 2 Diabetes

“…Raskin pointed out that there was no weight gain in the metformin group, while those receiving insulin alone gained 3 kg. In a study of 28 individuals receiving insulin with metformin, or insulin with troglitazone, and subsequently given both sensitizers with continued insulin administration, Raskin showed evidence suggesting that the TZD combination with insulin more effectively lowered glucose levels than that with metformin, with administration of both sensitizers with insulin leading to still better A1C levels (9). He noted that although the TZD was more potent in glucose lowering, the approach best minimizing weight gain was to first give insulin with metformin and then to add troglitazone.…”

The Effect of Rosiglitazone on Overweight Subjects With Type 1 Diabetes

“…The insulin sensitizer metformin has resulted in improved glycemic control without weight gain in type 2 diabetic subjects, both as dual insulin and metformin therapy (18,25) and as triple therapy when metformin was added to insulin therapy and later combined with a thiazolidinedione (26). Studies of normalweight type 1 diabetic subjects (BMI Յ26 kg/m 2 ) given metformin resulted in no weight gain, but the subjects also experienced only small if any improvement in glycemic control (15)(16)(17).…”