Cardiovascular Effects of Dipeptidyl Peptidase-4 Inhibitors: From Risk Factors to Clinical Outcomes

Scheen, André

doi:10.3810/pgm.2013.05.2659

Cited by 80 publications

(41 citation statements)

References 126 publications

(136 reference statements)

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“…Several studies have demonstrated that DPP-4 inhibitors offer a wide range of cardiovascular benefits by ameliorating risk factors such as high blood pressure, postprandial lipemia, inflammatory markers, oxidative stress, and platelet aggregation [19]. Recently, sitagliptin has shown to significantly reduce visceral adiposity, as measured with bioelectric impedance analysis (BIA) in overweight type 2 diabetes mellitus patients [20].…”

Section: Introductionmentioning

confidence: 99%

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

Lima-Martínez

Paoli

Rodney³

et al. 2015

Endocrine

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The aim of the study was to assess the effect of sitagliptin addition on the epicardial adipose tissue (EAT) thickness in subjects with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. This was a 24-week interventional pilot study in 26 consecutive type 2 diabetic patients, 14 females and 12 males average age of 43.8 ± 9.0 years, with Hemoglobin A1c (HbA1c) ≥ 7% on metformin monotherapy. Subjects who met the inclusion criteria were added on sitagliptin and started on sitagliptin/metformin combination at the dosage of 50 mg/1000 mg twice daily. EAT and visceral and total body fat were measured, respectively, with echocardiography and bioelectrical impedance analysis at baseline and after 24 weeks of sitagliptin/metformin treatment in each subject. HbA1c and plasma lipids were also measured. EAT decreased significantly from 9.98 ± 2.63 to 8.10 ± 2.11 mm, p = 0.001, accounting for a percentage of reduction (∆%) of -15% after 24 weeks of sitagliptin addition, whereas total body fat percentage, visceral fat, and body mass index (BMI), decreased by 8, 12, and 7%, respectively (p = 0.001 for all). After 6 month, EAT ∆% was significantly correlated with ∆% of visceral fat (r = 0.456; p = 0.01), whereas no correlation with either BMI ∆% (r = 0.292; p = 0.147) or HbA1c ∆% was found. The addition of Sitagliptin produced a significant and rapid reduction of EAT, marker of organ-specific visceral fat, in overweight/obese individuals with type 2 diabetes inadequately controlled on metformin monotherapy. EAT as measured with ultrasound can serve as no invasive and accurate marker of visceral fat changes during pharmaceutical interventions targeting the fat.

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Section: Introductionmentioning

confidence: 99%

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

Lima-Martínez

Paoli

Rodney³

et al. 2015

Endocrine

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“…DPP-4 inhibitors are also expected to have beneficial cardiovascular effects [37,38]. However, two recent trials with DPP-4 inhibitors, SAVOR-TIMI 53 and EXAMINE trials, showed that saxagliptin and alogliptin did not increase or decrease ischemic events in patients with type 2 diabetes [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, sitagliptin and voglibose might have cardiovascular benefits in low-risk and mild-risk patients with type 2 diabetes. Further studies are needed to clarify the long-term benefits for cardiovascular disease [37].…”

Section: Discussionmentioning

confidence: 99%

DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes (EDGE study)

Kihara¹,

Nakamura

et al. 2013

European Heart Journal

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Background: Alpha glucosidase inhibitor (GI) attenuates postprandial hyperglycemia (PPH) and reduces the risk of cardiovascular events in patients with impaired glucose tolerance or type 2 diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors also attenuate PPH. PPH is one of the factors leading to endothelial dysfunction which is an early event in the pathogenesis of atherosclerosis. Furthermore, DPP-4 inhibitors protect endothelial function through a GLP-1-dependent mechanism. However, the impact of these two types of drugs on endothelial dysfunction in patients with type 2 diabetes has not been fully elucidated. We compared the effects of sitagliptin, a DPP-4 inhibitor, and voglibose, an alpha GI, on endothelial function in patients with diabetes.

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“…Due to the multifarious roles played by the DPP4 enzyme 10– 12 , the possible side effects of these drugs (acute pancreatitis, pancreatic cancer, etc. 13– 15 ) are strongly contested by researchers who argue that current statistics are insufficient 16, 17 to conclusively attribute these side effects to the otherwise beneficial GLP-1 drugs 18 . Compound promiscuity is another phenomenon that might play a crucial role in determining the side effects of these therapies, although this aspect has rarely been pursued intensively 19 .…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Chakraborty¹,

Rendón-Ramírez²,

Ásgeirsson³

et al. 2015

F1000Res

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The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

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Cardiovascular Effects of Dipeptidyl Peptidase-4 Inhibitors: From Risk Factors to Clinical Outcomes

Cited by 80 publications

References 126 publications

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

Effect of sitagliptin on epicardial fat thickness in subjects with type 2 diabetes and obesity: a pilot study

DPP-4 inhibitor and alpha-glucosidase inhibitor equally improve endothelial function in patients with type 2 diabetes (EDGE study)

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

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