Dataset Information

Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

ABSTRACT: BACKGROUND:To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. METHODS:MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. RESULTS:We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, -1.11 mL/min/1.73 m²; 95% CI, -1.78 to -0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475). CONCLUSION:DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents.

SUBMITTER: Bae JH

PROVIDER: S-EPMC6435854 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Bae Jae Hyun JH Kim Sunhee S Park Eun Gee EG Kim Sin Gon SG Hahn Seokyung S Kim Nam Hoon NH

Endocrinology and metabolism (Seoul, Korea) 20190301 1

<h4>Background</h4>To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes.<h4>Methods</h4>MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis w ...[more]

PMID: 30912341

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Project description:Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

Project description:BackgroundCardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) in patients without cardiovascular or renal disease, a majority of newly diagnosed patients with type 2 diabetes often excluded from clinical trials on this association, is poorly understood. Thus, we investigate the risk of major adverse cardiovascular events (MACE) associated with DPP-4i in low-risk patients with diabetes.MethodsUsing a new-user retrospective cohort derived from IBM MarketScan Commercial Claims and Encounters (2010-2015), we identified patients aged 35-65 with type 2 diabetes, without cardiovascular or renal disease, initiating DPP-4i, sulfonylureas, or metformin. Primary composite outcome of time to first MACE was defined as the first of any of the following: myocardial infarction, cardiac arrest, coronary artery bypass graft, coronary angioplasty, heart failure, and stroke. Secondary outcomes were time to first heart failure, acute myocardial infarction, and stroke. We compared outcomes for DPP-4i versus sulfonylurea and DPP-4i versus metformin using propensity score weighted Cox proportional hazards, adjusting for demographics, baseline comorbidities, concomitant medications, and cumulative exposure.ResultsOf 445,701 individuals, 236,431 (53.0%) were male, median age was 51 (interquartile range: [44, 57]), 30,267 (6.79%) initiated DPP-4i, 52,138 (11.70%) initiated sulfonylureas, and 367,908 (82.55%) initiated metformin. After adjustment, DPP-4i was associated with lower risk of MACE than sulfonylurea (adjusted hazard ratio (aHR) = 0.87; 95% confidence interval (CI): 0.78-0.98), and similar risk to metformin (aHR = 1.07; 95% CI: 0.97-1.18). Risk for acute myocardial infarction (aHR = 0.70; 95% CI: 0.51-0.96), stroke (aHR = 0.57; 95% CI: 0.41-0.79), and heart failure (aHR = 0.57; 95% CI: 0.41-0.79) with DPP-4i was lower compared to sulfonylureas.ConclusionOur findings show that for this cohort of low-risk patients newly treated for type 2 diabetes, DPP-4i exhibited 13% lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin, suggesting DPP-4i is a low cardiovascular risk option for low-risk patients initiating antihyperglycemic treatment.

Project description:Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as 'gliptins' (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%-0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.

Dataset Information

Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Publications

Effects of Dipeptidyl Peptidase-4 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

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