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Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria.

ABSTRACT: Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1) dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

SUBMITTER: Haluzik M

PROVIDER: S-EPMC3780627 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria.

Haluzík Martin M Frolík Jan J Rychlík Ivan I

International journal of endocrinology 20130905

Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible pro ...[more]

PMID: 24089613

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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 ?1 that enhances signaling by transforming growth factor-?1 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:IntroductionOral antidiabetes medications, including dipeptidyl peptidase-4 inhibitors (DPP-4is) saxagliptin and sitagliptin, are used for the treatment of type 2 diabetes (T2D). The study objective was to compare all-cause and diabetes-related costs following initiation of saxagliptin or sitagliptin.MethodsPatients aged ≥ 18 years initiating saxagliptin or sitagliptin between January 1, 2009 and January 31, 2012 in the Truven Health MarketScan Commercial and Medicare Supplemental databases were identified. Patients were required to have continuous enrollment for ≥ 365 days before and ≥ 365 days after the index date (date of the first saxagliptin or sitagliptin claim). Additionally, patients were required to have a claim with a T2D diagnosis (ICD-9-CM 250.×0, 250.×2) and no claims for a DPP-4i medication before the index date. All-cause and diabetes-related medical costs and total costs (including pharmacy costs) were captured over the 1-year follow-up period. Generalized linear models with log link and gamma distribution were fit to compare costs between the two cohorts using cost ratios, controlling for patient baseline characteristics. Recycled prediction methods were used to generate adjusted predicted costs and confidence intervals.ResultsThe final sample comprised 3354 saxagliptin initiators and 26,895 sitagliptin initiators. The average age of saxagliptin and sitagliptin initiators was 57 years and just over 50% were males. After adjusting for baseline characteristics, saxagliptin patients had significantly lower average all-cause medical costs (cost ratio = 0.901, P < 0.001; predicted mean costs: $8687 vs. $9646) compared with sitagliptin patients over the 1-year follow-up. Findings were consistent for diabetes-related medical costs (cost ratio = 0.890, P < 0.001; predicted mean costs: $2180 vs. $2450). Total costs were also lower for saxagliptin initiators (cost ratio = 0.950, P = 0.002; predicted mean costs: $13,911 vs. $14,651) over the 1-year follow-up period.ConclusionInitiation of treatment with saxagliptin was associated with lower medical costs over 1 year compared with initiation of sitagliptin among adults with T2D.FundingAstraZeneca.

Dataset Information

Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria.

Publications

Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria.

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