Abstract

Background: Mounting evidence indicates that Type 2 diabetes mellitus (T2DM) is a public healthchallenge globally, and its occurrence is anticipated to surge in the forthcoming years. Dipeptidyl peptidase‐4 (DPP‐4) serves as a target for its treatment, with its inhibitors effectively preserving the levels of glucose‐dependentinsulinotropic peptide and glucagon‐like peptide 1(GLP‐1). This review presents an overview of the therapeutic possibilities of six frequently employed DPP‐4 inhibitors (DPP‐4is) (Sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin and teneligliptin) in managing T2DM, focussing on their characteristics, mechanism of action, advantages and side effects in comparison with alternative oral antidiabetic drugs as well as the possibility of using in silico method in advancing its timely and cost‐effective production.

Methods: A literature search was conductedusing the major search engines such as PubMed/Medline, Scopus, and Google Scholar, etc. employing terms like ‘Type 2 diabetes mellitus (T2DM), DPP‐4 inhibitors, and Dipeptidyl peptidase‐4’, etc. to identify relevant studies.

Results: Our findings indicate that DPP‐4is stimulate secretion of insulin and suppress secretion of glucagon by elevating endogenous GLP‐1 concentrations without an intrinsic hypoglycaemia risk. Although these agents share a common mechanism of action, their considerable structuralheterogeneity may lead to distinct pharmacological characteristics. Literature shows that DPP‐4is have a promising safety profile in comparison with other oral antidiabetic medications, however, certain safety aspects require additional exploration. Different DPP‐4is havedemonstrated comparable safety and tolerability, whether used alone or in combination with other antidiabetic medications. Besides, it has been shown that in silico method could be employed in development of DPP‐4is. Further research is necessary to ascertain whether differences amongDPP‐4 inhibitors might influence the occurrence of specific adverse effects.

Conclusion: DPP‐4 inhibitors remain effective and well tolerated options for managing T2DM.

Abstract

Aims: Guidelines for type 2 diabetes recommend add-on agents when metformin alone fails to provide adequate glycaemic control. However, early combination therapy may benefit health outcomes. We conducted a systematic review and meta-analysis to investigate this question.

Methods: We searched MEDLINE and Cochrane CENTRAL (up to July 2012) without language restrictions. We sought randomized controlled trials (RCTs) evaluating initial combination therapy with metformin versus metforminmonotherapy in patients with untreated type 2 diabetes. Weighted mean differences (WMDs) for changes from baseline and relative risks (RRs) [with 95% confidence intervals (CIs)] were calculated using random-effects model.

Results: In 15 RCTs (N = 6693), the mean age range was 48.4–62.7 years; mean baseline glycosylated haemoglobin (A1c) was 7.2–9.9% and mean diabetes duration was 1.6–4.1 years, with median follow-up of 6 months and with 13 comparisons for A1c change, 14 comparisons for A1c goal attainment of <7% and 13 comparisons for change in fasting plasma glucose (FPG). Drugs combined with metformin included thiazolidinediones (TZDs), insulin secretagogues, dipeptidylpeptidase-4 (DPP-4) inhibitors or sodium glucose transporterase (SGLT-2) inhibitors. Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in A1c (WMD −0.43%, 95% CI −0.56, −0.30), increases in attainment of A1c goal of less than 7% (RR 1.40, 95% CI 1.33–1.48) and reductions in FPG (WMD −14.30 mg/dl, 95% CI −16.09, −12.51).

Conclusions: These results suggest a potential benefit of initial combination therapy on glycaemic outcomes in diabetes compared to metformin monotherapy across awide range of baseline A1c levels. Further research should explore if early combination treatment may also affect longer term health outcomes in diabetes.

Abstract

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain.

Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes.

Study Selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials.

Main Outcomes and Measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta analyzed across trials.

Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Qstatistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI,0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify theassociation with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalentatherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction).

Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.