Safety and Efficacy of Pioglitazone/Metformin Combination Therapy in Treatment of Type 2 Diabetes: A Rationale for Earlier Use

Although multiple new agents for the management of diabetes have become available in the past decade, less than 50% of diabetics in the United States have Hgb A-1-C levels below 7.0% and far fewer at the newer more stringent targets of 6.0% to 6.5%. It has become increasingly clear that the course of Type 2 diabetes is marked by progressive loss of beta-cell function in the setting of relatively fixed insulin resistance. However, treatment algorithms are based on initial monotherapy, usually with metformin, and only move to combination or add-on therapy when treatment has failed and disease has progressed. Few therapeutic agents address both insulin resistance and beta cell function, and no monotherapeutic agent fully addresses any physiologic defect. Metformin, a well-established therapy for diabetes is effective in reducing hepatic and to a lesser extent muscle insulin resistance primarily through AMP-kinase activation, but has only modest effects on long-term beta-cell function. Pioglitazone, an agent in the thiazolidinedione (TZD) class has mechanistically distinct effects on hepatic, muscle and adipocyte insulin resistance, primarily through PPAR-gamma activation, as well as having somewhat greater effects on beta-cell function and durability of glycemic control. The combination of the two agents, either as initial therapy, or as very rapid add-on therapy for the patient who does not achieve target glycemia soon after initiation of metformin is a mechanistically favorable and useful approach to early and durable glycemic control of many new-onset diabetic patients. The efficacy of both metformin and pioglitazone as monotherapy has been well-documented in numerous studies, and combination studies have demonstrated superiority in efficacy of combination therapy over monotherapy with either agent as well as superiority in durability of response over non-TZD based combinations such as sulfonylurea/metformin. Safety issues with metformin remain primarily tolerability based on GI side effects with the rare risk of lactic acidosis in patients with declining renal function. The safety of the TZD class, while well-documented, does carry the risks of volume expansion and resultant CHF, as well as weight gain, which while troublesome, uniquely does not impair glycemic control in these patients. A more recent concern has been raised regarding fracture risk and decreased bone density, and although the relative impact appears small it remains relevant. These risks may be somewhat balanced by more recent studies suggesting a favorable effect of pioglitazone on multiple metabolic risk factors for CVD such as lipids, C-reactive protein, and adipocytokines such as adiponectin. Recent mechanistic and outcome studies such as PROACTIVE and PERISCOPE which suggest there may also be modest benefit on plaque progression and CVD outcomes. Metformin has beneficial effects on metabolic CVD risk factors, such as triglycerides, insulin and PAI-1 and there is a persistent signal of favorable CV outcomes in metformin treated patients. This review will address the safety and efficacy of the agents as monotherapy as well as in combination, and explain the physiologic rationale for earlier or initial use of pioglitazone/metformin combination therapy for newly diagnosed diabetes as well as the long term potential benefit for ongoing management of the treated diabetic.