Inhibition of Dipeptidyl Peptidase-4 Reduces Glycemia, Sustains Insulin Levels, and Reduces Glucagon Levels in Type 2 Diabetes

Åhrén, Bo; Landin‐Olsson, Mona; Jansson, Per Anders; Svensson, Maria; Holmes, David; Schweizer, Anja

doi:10.1210/jc.2003-031907

Cited by 658 publications

(570 citation statements)

References 28 publications

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“…There is no definitive explanation for this difference. However, vildagliptin has been shown to improve both beta cell [1,14] and alpha cell function [2]. In the present study, such an improvement of beta cell function may make a lesser contribution to the efficacy of vildagliptin, due to chronic exposure of patients to high insulin levels of exogenous origin.…”

Section: Discussionmentioning

confidence: 58%

“…Thus vildagliptin has been shown both to increase beta cell responsiveness to glucose [1] and to suppress the inappropriate glucagon secretion seen in patients with type 2 diabetes [2]. Vildagliptin reduces HbA 1c when given as monotherapy [3,4] or in combination with metformin [5], but its efficacy is unknown in patients who have a long history of disease requiring insulin therapy.…”

Section: Introductionmentioning

confidence: 99%

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Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

et al. 2007

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Aims/hypothesis Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. Materials and methods This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallelgroup study in patients with type 2 diabetes that was inadequately controlled (HbA 1c =7.5-11%) by insulin. Patients received vildagliptin (n=144; 50 mg twice daily) or placebo (n=152) while continuing insulin therapy.Results Baseline HbA 1c averaged 8.4 ± 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMΔ) in HbA 1c was −0.5±0.1% and −0.2± 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p=0.01). In patients aged ≥65 years, the AMΔ HbA 1c was −0.7±0.1% in the vildagliptin group vs −0.1±0.1% in the placebo group (p<0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p<0.001) and less severe (p<0.05) in patients receiving vildagliptin than in those receiving placebo. Conclusions/interpretation Vildagliptin decreases HbA 1c in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

et al. 2007

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“…As with other small molecule DPP-4 inhibitors, vildagliptin has good oral availability; therefore, unlike the native peptide and peptide agonists, it does not require parenteral administration. Treatment with vildagliptin over 4 weeks in drug-naïve patients with type 2 diabetes increased circulating levels of intact GLP-1, and decreased plasma glucagon and glucose during a standardised meal challenge [110]. A similar effect of vildagliptin was recently reported in patients with type 1 diabetes [111], suggesting that the effect on the alpha cell did not require endogenous insulin.…”

Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 52%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

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Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

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“…Given the glucagon‐suppressing 24, 25, 26 and insulin‐stimulating effects that have been demonstrated with DPP‐4 inhibition, a DPP‐4 inhibitor co‐administered with an SGLT2 inhibitor could counterbalance – to some extent – the decreased plasma insulin/glucagon ratio, and enhance the glucose‐lowering effects of SGLT2 inhibitor treatment.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

Woo

2015

Int J Clin Pract

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SummaryBackgroundThe availability of a dual sodium glucose co‐transporter 2/dipeptidyl peptidase‐4 inhibitor combination in a single‐tablet combination (STC) represents a new therapeutic option for patients with type 2 diabetes. Empagliflozin/linagliptin STC has been recently approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).AimThe aim of this study was to describe the latest clinical evidence on the efficacy and safety profiles of empagliflozin/linagliptin STCs in comparison with the individual components. Juxtaposition of the STC with dapagliflozin/saxagliptin combination was also presented.ResultsEmpagliflozin/linagliptin STC given as initial therapy or on metformin background lowered mean glycated haemoglobin (HbA1c) by approximately 1.1% (mean baseline HbA1c, 8.0%). Furthermore, the STC reduced mean body weight by 2.0–3.0 kg from baseline. With the STC treatment, no confirmed incidents of hypoglycaemia were reported in drug‐naïve patients; in patients taking metformin hypoglycaemia occurred at low rates which were comparable with monotherapy. Use of STCs in the treatment of T2DM can simplify drug dosing regimen, reduce pill burden and increase treatment adherence. Empagliflozin/linagliptin STC is a combination that offers potential additional benefits such as body weight loss and moderate reductions in blood pressure, without increasing risk of hypoglycaemia.ConclusionEmpagliflozin/linagliptin STC appears to be a rational choice for a wide range of patients in need of multiple agents for controlling hyperglycaemia. The STC should be particularly useful in patients in whom hypoglycaemia, weight gain and treatment adherence are of concern.

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Inhibition of Dipeptidyl Peptidase-4 Reduces Glycemia, Sustains Insulin Levels, and Reduces Glucagon Levels in Type 2 Diabetes

Cited by 658 publications

References 28 publications

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Empagliflozin/linagliptin single‐tablet combination: first‐in‐class treatment option

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