Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide.
OBJECTIVE
The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM.


METHODS
References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included.


RESULTS
T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA(1c)) < 7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study.


CONCLUSIONS
Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.
Schwartz
Stanley
S
University of Pennsylvania, Philadelphia, PA, USA. stan.schwartz@uphs.upenn.edu
D000465:Algorithms; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology*; D004338:Drug Combinations; D000077270:Exenatide; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects; D058990:Molecular Targeted Therapy / Q000379:methods*; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects; D000077205:Pioglitazone; D011908:Rationalization; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects; D014688:Venoms / Q000008:administration & dosage* / Q000009:adverse effects
D004338:Drug Combinations; D007004:Hypoglycemic Agents; D010455:Peptides; D045162:Thiazolidinediones; D014688:Venoms; D000077270:Exenatide; D000077205:Pioglitazone