Impact of Three Oral Antidiabetic Drugs on Markers of β-Cell Function in Patients with Type 2 Diabetes: A Meta-Analysis

<div><p>Background</p><p>The effect of metformin, pioglitazone and sitagliptin on β-cell function in the treatment of type 2 diabetes is controversial. Therefore, we performed a systematic review and meta-analysis to obtain a better understanding in the β-cell effects of metformin, pioglitazone and sitagliptin.</p><p>Methods</p><p>We searched Pubmed and the Cochrane Center Register of Controlled Trials to identify relevant studies. Trials investigating effects of sitagliptin, metformin or pioglitazone on β-cell function were identified. The primary outcomes were homeostasis model assessment of β-cells (HOMA-β) and proinsulin/insulin ratio (PI/IR). Secondary outcome was hemoglobin A1c level. We used version 2 of the Comprehensive Meta Analysis software for all statistical analyses.</p><p>Results</p><p>Metformin monotherapy was more effective than sitagliptin in improving HOMA-β (18.01% (95% CI 11.09% to 24.94%) vs. 11.29% (95% CI 9.21% to 13.37%), <i>P</i> = 0.040) and more effective (−0.137 (95% CI −0.082 to −0.192)) than both sitagliptin (−0.064 (95% CI −0.036 to −0.092), <i>P</i> = 0.019) and pioglitazone (−0.068 (95% CI −0.044 to −0.093), <i>P</i> = 0.015) in decreasing PI/IR. Metformin and sitagliptin combined (40.23% (95%CI 32.30% to 48.16%)) were more effective than sitagliptin and pioglitazone (11.82% (95% CI 6.61% to 17.04%), <i>P</i> = 0.000) and pioglitazone and metformin(9.81% (95% CI 1.67% to 17.95%), <i>P</i> = 0.022) in improving HOMA-β and decreasing PI/IR (−0.177 (95% CI −0.118 to −0.237); −0.080 (95% CI −0.045 to −0.114), <i>P</i> = 0.007; −0.038 (95% CI, −0.005 to 0.071), <i>P</i> = 0.023).</p><p>Limitations</p><p>The included RCTs were of short duration (12–54 weeks). We could not determine long term effects on β-cells.</p><p>Conclusions</p><p>Metformin improves β-cell function more effectively than pioglitazone or sitagliptin in type 2 diabetes patients. Metformin and sitagliptin improved HOMA-β and PI/IR more than other combinations.</p></div

Meta-analyses for changes in the proinsulin/insulin ratio (PI/IR) for different combined therapies.

<p>Favours Non : favours no medication.</p

Characteristics of relevant primary studies.

<p>NR: not reported.</p

Meta-analyses for changes in the homeostasis model assessment of β-cell (HOMA-β) for different monotherapies.

<p>Favours Non : favours no medication.</p

Results of the article search and outline of the process of searching for articles for this meta-analysis.

<p>Results of the article search and outline of the process of searching for articles for this meta-analysis.</p

Meta-analyses for changes in the homeostasis model assessment of β-cell (HOMA-β) for different combined therapies.

<p>Favours Non : favours no medication.</p

Meta-analyses for changes in the proinsulin/insulin ratio (PI/IR) for different monotherapies.

<p>Favours Non : favours no medication.</p

Subgroup analysis for β-cell function related to HOMA-β and PI/IR.

<p>WMD: weighted mean difference; CI: confidence interval.</p

Extent of linkage disequilibrium, defined by the R² measure, for single nucleotide polymorphisms around (A) rs2046932, (B) rs1491923, (C) rs11835105 and (D) rs11176013 in the vicinity of <i>LRRK2</i> in two populations: HapMap Europeans (CEU – black circles/line); Asians (HapMap JPT, HapMap CHB, SGVP CHS, SGVP MAS, and SGVP INS- red circles/line).

<p>In the upper panel, the vertical dashed line indicates the position of the focal SNP rs2046932/rs1491923/rs11835105/rs11176013, and each vertical dotted line connects the circles corresponding to the same SNP for the different populations. The lower panel shows the same information, except that each line displays the linkage disequilibrium around the focal SNP for a specific population.</p

Comparison of heatmaps between (A) CEU and Asian and (B) JPT and other Asian groups (CHB, CHS, MAS and INS) in terms of r².

<p>Comparison of heatmaps between (A) CEU and Asian and (B) JPT and other Asian groups (CHB, CHS, MAS and INS) in terms of r².</p