GLP-1 based therapies: clinical implications for gastroenterologists

Smits, Mark M.; Raalte, Daniël H. van; Tonneijck, Lennart; Muskiet, Marcel H.A.; Kramer, Mark H. H.; Cahen, Djuna L.

doi:10.1136/gutjnl-2015-310572

Cited by 38 publications

(26 citation statements)

References 160 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lack of effect of liraglutide on gastric emptying in the current study underlines this hypothesis. The DPP‐4 inhibitor sitagliptin had no effect on gallbladder emptying, which is in line with the current paradigm that these agents have little to no effect on proximal gastro‐intestinal motility …”

Section: Discussionsupporting

confidence: 83%

See 1 more Smart Citation

Biliary effects of liraglutide and sitagliptin, a 12‐week randomized placebo‐controlled trial in type 2 diabetes patients

Smits

Tonneijck

Muskiet

et al. 2016

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

AimsTreatment with glucagon‐like peptide (GLP)‐1 receptor agonists or dipeptidyl peptidase (DPP)‐4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile.Materials and methodsA total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m2; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12‐week randomized, placebo‐controlled, double‐blind, single‐centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP‐1 receptor agonist liraglutide, the DPP‐4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high‐fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236).ResultsNeither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027‐0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22‐68.21), p = 0.005] and in faeces [ratio 1.5 (1.03‐2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33‐8.79), p = 0.012], cholic acid [ratio 3.32 (1.26‐8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44‐10.14), p = 0.008].ConclusionsNeither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

show abstract

Section: Discussionsupporting

confidence: 83%

“…The DPP-4 inhibitor sitagliptin had no effect on gallbladder emptying, which is in line with the current paradigm that these agents have little to no effect on proximal gastro-intestinal motility. 19 The effects of liraglutide and sitagliptin on bile acids differed.…”

Section: Discussionmentioning

confidence: 99%

Biliary effects of liraglutide and sitagliptin, a 12‐week randomized placebo‐controlled trial in type 2 diabetes patients

Smits

Tonneijck

Muskiet

et al. 2016

Diabetes Obesity Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, GLP-1RAs activate several anti-inflammatory pathways, including reductions in oxidative stress via reactive oxygen species, nuclear factor-kB binding/activation, expression of inflammatory cytokines and C-reactive protein, and increases in adiponectin (37). Also, GLP-1RAs seem to have beneficial effects on NASH and NAFLD by reductions in body weight, de novo hepatic lipogenesis, oxidative stress, inflammatory cytokines, and endoplasmatic reticulum stress and improvements in hepatic insulin sensitivity, triglyceride handling, and neural regulation of hepatic metabolism (38,39). In the Liraglutide Efficacy and Action in Non-Alcoholic Steatohepatitis (LEAN) trial, liraglutide reduced liver enzymes and oxidative stress and improved liver histology in patients NAFLD and T2D (40 , in which drug B reduces the effect of drug A threefold (indicated by the red inhibition line) but has no effect on its own, and interference (bottom), in which drug B reduces the effect of drug A threefold (indicated by the red inhibition line), preventing it from exerting its full response, but drug B nonetheless has a beneficial effect on its own.…”

Section: Sglt2 Inhibition In Combination Therapymentioning

confidence: 99%

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

et al. 2018

View full text Add to dashboard Cite

The progressive nature of type 2 diabetes (T2D) requires practitioners to periodically evaluate patients and intensify glucose-lowering treatment once glycemic targets are not attained. With guidelines moving away from a one-size-fits-all approach toward setting patient-centered goals and allowing flexibility in choosing a second-/third-line drug from the growing number of U.S. Food and Drug Administration-approved glucose-lowering agents, keen personalized management in T2D has become a challenge for health care providers in daily practice. Among the newer generation of glucose-lowering drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which enhance urinary glucose excretion to lower hyperglycemia, have made an imposing entrance to the T2D treatment armamentarium. Given their unique insulin-independent mode of action and their favorable efficacy-to-adverse event profile and given their marked benefits on cardiovascular-renal outcome in moderate-to-high risk T2D patients, which led to updates of guidelines and product monographs, the role of this drug class in multidrug regimes is promising. However, despite many speculations based on pharmacokinetic and pharmacodynamic properties, physiological reasoning, and potential synergism, the effects of these agents in terms of glycemic and pleiotropic efficacy when combined with other glucose-lowering drug classes are largely understudied. In this perspective, we review the currently emerging evidence, discuss prevailing hypotheses, and elaborate on necessary future studies to clarify the potential risks and benefits of using an SGLT2i in dual combination with metformin and triple combination with a glucagon-like peptide 1 receptor agonist, dipeptidyl peptidase 4 inhibitor, or other glucose-lowering agent that is recommended by the American Diabetes Association and European Association for the Study of Diabetes (i.e., a sulfonylurea, thiazolidinedione, or insulin) to treat patients with T2D.

show abstract

“…For example, although the short-acting GLP-1 receptor agonist exenatide reduces gastric emptying rate, this does not occur with the long-acting GLP-1 receptor agonist liraglutide or sitagliptin. 37 Alternatively, the effects seen with acute intervention wane over time.…”

Section: Discussionmentioning

confidence: 99%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

Self Cite

View full text Add to dashboard Cite

Objective— To assess the effects of glucagon-like peptide (GLP)-1–based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results— We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m 2 ; HbA 1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo ( P >0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P <0.05). After the meal, exenatide increased endothelial domain power ( P <0.05). In the 12-week study, no effects on vasomotion were observed. Conclusions— Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1–based therapies on glucose are not mediated through microvascular responses.

show abstract

GLP-1 based therapies: clinical implications for gastroenterologists

Cited by 38 publications

References 160 publications

Biliary effects of liraglutide and sitagliptin, a 12‐week randomized placebo‐controlled trial in type 2 diabetes patients

Biliary effects of liraglutide and sitagliptin, a 12‐week randomized placebo‐controlled trial in type 2 diabetes patients

SGLT2 Inhibitors in Combination Therapy: From Mechanisms to Clinical Considerations in Type 2 Diabetes Management

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Contact Info

Product

Resources

About