Addition of a dipeptidyl peptidase‐4 inhibitor, sitagliptin, to ongoing therapy with the glucagon‐like peptide‐1 receptor agonist liraglutide: A randomized controlled trial in patients with type 2 diabetes

Aim To evaluate the effects of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon‐like peptide‐1 (GLP‐1) signalling, in people with type 2 diabetes (T2DM). Methods A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double‐blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9–39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose‐regulatory hormones were evaluated. Results Intraduodenal fat increased plasma GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP‐1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP‐1 (both total and intact), and energy expenditure were higher during intravenous exendin (9–39) than saline (all P < 0.05). Conclusions In well‐controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP‐1.

Section: Discussionsupporting

confidence: 89%

Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes

Xie

Wang

Jones

et al. 2019

“…In a similar vein, Nauck et al studied sitagliptin given 60 minutes prior to an MMT in non‐operated individuals treated with the GLP‐1 agonist liraglutide and with metformin. Their data showed higher levels of intact GLP‐1 and gastric inhibitory polypeptide concentrations after sitagliptin, but without added benefit with regard to glycaemic control.…”

Section: Discussionmentioning

confidence: 99%

“…Their data showed higher levels of intact GLP‐1 and gastric inhibitory polypeptide concentrations after sitagliptin, but without added benefit with regard to glycaemic control. The authors proposed that GLP‐1 receptors were already maximally stimulated by liraglutide therapy, leaving little room for benefit to be achieved with the addition of sitagliptin . There may be a comparable situation after RYGB, in which maximal postprandial levels of GLP‐1 already exist.…”

Section: Discussionmentioning

confidence: 99%

Effect of sitagliptin on glucose control in type 2 diabetes mellitus after Roux‐en‐Y gastric bypass surgery

Shah

Levesque

Pierini

et al. 2017

The present study was a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self-monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon-like peptide-1 and β-cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m2), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β-cell function did not differ between the placebo and sitagliptin groups at pre-intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β-cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose-lowering effect, with no identified improvement in β-cell function.

“…The therapeutic administration of GLP‐1 receptor agonists (eg, exenatide, liraglutide and semaglutide) produces substantially greater degrees of GLP‐1 receptor stimulation than can be expected from inhibition of DPP‐4 . Inhibition of DPP‐4 in patients already receiving GLP‐1 receptor agonists does not lead to additional glucose‐lowering effects . Conversely, the full spectrum of the effects of DPP‐4 inhibitors (eg, sitagliptin, saxagliptin and alogliptin) probably includes actions that are related to the potentiation of peptides other than GLP‐1…”

Section: Effect Of Drugs Used In Diabetes On the Sodium‐hydrogen Exchmentioning

confidence: 99%

“…[38][39][40][41][42] 3.2 | Incretin-based treatments agonists does not lead to additional glucose-lowering effects. 45 Conversely, the full spectrum of the effects of DPP-4 inhibitors (eg, sitagliptin, saxagliptin and alogliptin) probably includes actions that are related to the potentiation of peptides other than GLP-1. 44,46 These pharmacological differences may explain differences in the effects of GLP-1 receptor agonists and DPP-4 inhibitors on the kidney in clinical trials.…”

Section: Ras Inhibitors Neprilysin Inhibitors Mr Antagonists Amiloridmentioning

confidence: 99%

Role of the sodium‐hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes

Packer

2018

Diabetes is characterized by increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.