Clinical Investigation
Impact of Sitagliptin on Markers of β-cell Function: A Meta-Analysis

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Abstract

Background

Progressive β-cell dysfunction and β-cell failure are fundamental pathogenic consequences of type 2 diabetes. Dipeptidyl peptidase-IV inhibitors may exhibit improvement on preclinical measures of both β-cell function, homeostasis model assessment of β-cell (HOMA-β) index, and β-cell dysfunction, proinsulin/insulin ratio (PI/IR), correlating to β-cell survival.

Research Design and Methods

A systematic literature search through July 2008 was conducted to extract a consensus of randomized, controlled trials of sitagliptin therapy on measures of β-cell function. A random-effects model meta-analysis evaluated effects on HOMA-β and PI/IR versus placebo. Several subgroup analyses, including active control, were conducted. Studies were included if they met the following criteria: (1) randomized trials on sitagliptin; (2) placebo or active control; and (3) data reported on HOMA-β or PI/IR.

Results

A total of 11 trials (n = 3039) reported effects on HOMA-β and 8 trials (n = 2325) on PI/IR versus placebo. Four trials (n = 1425) were included in the active control subgroup analysis. Sitagliptin significantly improved HOMA-β index by 12.03% [95% confidence interval (CI), 9.45-14.60] versus placebo. Sitagliptin also significantly decreased PI/IR −0.06 (95% CI, −0.08 to −0.04). Sitagliptin was inferior to active control for HOMA-β index [5.64% (95% CI, 0.38-10.90)], but not different in terms of PI/IR [0.01 (95% CI, −0.04 to 0.06)].

Conclusions

Despite significant improvement in HOMA-β index and PI/IR from placebo, there does not seem to be a benefit of dipeptidyl peptidase-IV inhibitors over other agents with respect to β-cell function/activity. Long-term prevention of β-cell dysfunction cannot be ruled out.

Section snippets

Study Selection

A systematic literature search of MEDLINE from 1966 through July 2008; EMBASE from 1990 through July 2008; and the Cochrane Database to identify randomized clinical trials of sitagliptin utilization with a primary or secondary endpoint of HOMA-β or PI/IR was conducted. A search strategy using the MeSH and text keywords MK-431 and sitagliptin was utilized. A manual search of abstracts presented between 2003 and 2007 at the American Diabetes Association Scientific Sessions was conducted. In

RESULTS

Study selection process is described in Figure 1. Of 201 screened articles and abstracts, 150 relevant articles and abstracts were identified, 43 were retrieved for detailed evaluation, and 12 met inclusion criteria. Eleven studies24., 25., 26., 27., 28., 29., 30., 31., 32., 33., 34. (n = 3039) for HOMA-β and 8 studies26., 27., 28., 29., 30., 31., 32., 33. (n = 2325) for PI/IR provided data adequate for meta-analysis in the primary cohort (Table 2). Four studies (n = 1425) were included in the

DISCUSSION

Although some studies did not demonstrate a significant difference versus placebo in HOMA-β26., 31. or PI/IR,30., 33. the totality of data demonstrates a statistically significant improvement in both HOMA-β and PI/IR favoring sitagliptin. The Cardiovascular Health Study indicates that controlling for insulin sensitivity, a 20% decrease in HOMA-β is associated with a 9% increase in both the odds of incident coronary heart disease and 6-year all-cause mortality.36 Although HOMA-β is a significant

CONCLUSIONS

DPP-IV inhibitors seem to benefit short-term surrogate measures of β-cell function (HOMA-β) and dysfunction (PI/IR) versus placebo; thereby representing an agent for early intervention to lower the burden of type 2 diabetes. This effect may be particularly useful in combination with an agent that addresses additional mechanisms of β-cell destruction (TZD) or provides complementary augmentation of GLP-1 (metformin).41., 47. Despite significant improvement in HOMA-β index and PI/IR from placebo,

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    Dr. East has received research funding from Abbott and Novo Nordisk. Dr. East is on the Speaker’s Bureau for Pfizer and Sankyo-Daiichi. Dr. Riche is on the Speaker’s Bureau for Pfizer.

    Abstract was presented at the American College of Clinical Pharmacy Annual Meeting on October 15, 2007.

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