Title:Efficacy and Cardiovascular Effects of Dipeptidyl Peptidase-4 (DPP4) Inhibitors: A Systematic Review
Title Characters (excluding spaces):  89 (120 allowed)
Authors: Muhammad Umar Wahab1, Imran Mirza1, Jamie Smith2
Affiliations:1The Diabetes Centre, Pakistan; 2University of Leicester, UK.
Abstract Category: Incretin Therapies

Background:  The dipeptidyl peptidase-4 (DPP4) inhibitors (or “gliptins”) are an important new class of incretin-based therapy for treatment of type 2 diabetes mellitus (T2DM).  These drugs prolong the action of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), by inhibiting their breakdown. The incretin hormones increase insulin secretion and suppress glucagon levels. Evidence on the efficacy of these drugs in controlling glycemic levels in T2DMhas been accumulating.  Furthermore, given that the risk of cardiovascular (CV) disease is substantially greater in people with diabetes compared to those without diabetes, CV safety profiles of these agents have been considered important in their selection for T2DM treatment.
Aims: This paper reviews the efficacy and CV effects of DPP-4 inhibitors from published reports and randomized controlled trials (RCT), e.g. SAVOR-TIMI 53, EXAMINE, and TECOS, for evidence that these drugs are effective in controlling gyclemia and have acceptable CV profiles in adult patients with T2DM.
Method: Relevant studies were searched on Medline, PubMed, Embase and Cochrane Central Register of RCT.  We also searched relevant web sites, citations, references lists, and published abstracts presented at seminars and conferences. We reviewed RCT published in English from 2000-2015 on therapy efficacy and CV effects of DPP-4 Inhibitors.  The inclusion criteria for analysis included study duration of at least 12 weeks and enrolment of more than 30 participants.  HbA1creduction of at least 0.5%-1.0% was selected as efficacy outcome.  CV effects were considered as major adverse cardiovascular events (MACE) in non-pregnant adults with T2DM.  Type 1 diabetes mellitus patients were excluded from this review. 

Results: A total of 59 studies met the selection criteria (Alogliptin 7, Linagliptin 7, Saxagliptin 8, Vildagliptin 15, Sitagliptin 22).  The reviewed studies differed with regard to patient population and duration.  However, DPP-4 inhibitors conclusively showed efficacy in lowering glycemic levels and achieving a meaningful reduction of HbA1c from the baseline when used as a monotherapy or as an add-on therapy, with a majority of T2DM patients achieving HbA1c levels of <7% (Table).

	Sitagliptin	Vildagliptin	Linagliptin	Saxagliptin	Alogliptin
Weighted mean HbA1c change from baseline (95% CI) 	-0.75
(-0.90 to -0.60)	0.67
(-0.87 to ¬0.47) 	-0.74
(-0.96 to¬0.51) 	-0.61
(-0.91 to -0.31) 	-0.74
(-0.99 to -0.49) 
Achieving HbA1c <7% Odds Ratio (95% CI) 	3.64 
(2.18 to 5.71) 	4.02
(2.11 to 6.89) 	3.33
(1.60 to 6.27) 	2.11
(0.86 to 4.39) 	4.29
(2.10 to 8.00) 

The Saxagliptin SAVOR-TIMI 53 trial showed thatthe drugis safe for cardiovascular patients with no significant increase in endpoint of MACE (HR1.02, CI 0.94-1.11, p=0.66), but slightly increases the risk of hospitalization with heart failures. EXAMINE trial using Alogliptin also showed the same results with no significant increase in MACE events as compared to placebo (HR 0.96, p=<0.001).The TECOS trial using Sitagliptin did not show increased risk for major adverse CV events or hospitalization for heart failure.The differences in heart failure outcomes notwithstanding, the studies show similar findings for hospitalization for unstable angina, myocardial infarction, and CV death.
Discussion: DPP-4 Inhibitors have shown proven efficacy in controlling glycemia in T2DM. Results of the major CV outcome trials with three DPP-4 inhibitors reassure that incretin-based therapies have neutral CV safety profiles in patients with T2DM.  The heart failure findings in SAVOR-TIMI 53 require further study of the mechanism of action of saxagliptin on cardiac function in patients with T2DM.

Word Count: 554 (700 allowed)

Efficacy and cardiovascular effects of dipeptidyl peptidase-4 (DPP4) inhibitors: a systematic review