Glucagon-Like Peptide-1 Receptor Agonists for Diabetes Mellitus

Smilowitz, Nathaniel R.; Donnino, Robert; Schwartzbard, Arthur

doi:10.1161/circulationaha.113.006985

Cited by 36 publications

(32 citation statements)

References 88 publications

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“…This effect on incretin also accounts for the greater weight loss experienced by patients who receive GLP-1RAs versus the neutral weight effects produced by DPP-4is 65,66. Glycemic control was also mostly similar to that with insulin, largely driven by improvements in postprandial glucose with the short-acting GLP-1RAs, with similar effects on FG as insulin.…”

Section: Discussionmentioning

confidence: 88%

Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research

Levin¹,

Nguyen²,

Wittbrodt³

et al. 2017

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BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) act by increasing insulin secretion, decreasing glucagon secretion, slowing gastric emptying, and increasing satiety.ObjectivePublished evidence directly comparing GLP-1RAs with other approved treatments for type 2 diabetes (T2D) was systematically reviewed.MethodsA literature search was performed using MEDLINE and Embase databases to identify papers comparing GLP-1RAs with other classes of glucose-lowering therapy in patients with T2D.ResultsOf the 1303 papers identified, 57 met the prespecified criteria for a high-quality clinical trial or retrospective study. The efficacy and tolerability of approved GLP-1RAs (exenatide twice daily or once weekly, dulaglutide, liraglutide, lixisenatide, and albiglutide) were compared with insulin products (23 prospective studies + seven retrospective studies), dipeptidyl peptidase-4 inhibitors (11 prospective studies + three retrospective studies), sulfonylureas (nine prospective studies + one retrospective study), thiazolidinediones (five prospective studies), and metformin (two prospective studies). GLP-1RAs are effective as a second-line therapy in improving glycemic parameters in patients with T2D. Reductions in glycated hemoglobin from baseline with GLP-1RAs tended to be greater or similar compared with insulin therapy. GLP-1RAs were consistently more effective in reducing body weight than most oral glucose-lowering drugs and insulin and were associated with lower hypoglycemia risk versus insulin or sulfonylureas. GLP-1RAs improved cardiovascular risk factors, and preliminary data suggest they improve cardiovascular outcomes in patients with T2D compared with oral glucose-lowering drugs. However, results from ongoing studies are awaited to confirm these early findings.ConclusionThis systematic review found that GLP-1RAs are an effective class of glucose-lowering drugs for T2D.

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Section: Discussionmentioning

confidence: 88%

Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research

Levin¹,

Nguyen²,

Wittbrodt³

et al. 2017

DMSO

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“…An increased serum GLP-1 concentration was suggested to be one of the underlying mechanisms, and GLP-1 does reportedly contribute to the prevention of cardiovascular events (41). Understandably, serum active GLP-1 was elevated from ϳ12 to 25 pg/ml by administration of anagliptin (Fig.…”

Section: Discussionmentioning

confidence: 94%

DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation

Shinjo

Nakatsu

Iwashita

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF-κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.

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“…2,37 The few favorable demonstrations of reduced rates of cardiovascular events with predominantly glucose-lowering therapies have required more protracted follow-up than routinely occurs in clinical trials. 4,7 Although our study had only approximately 2 years of follow-up, sufficient numbers of cardiovascular events were observed so that we could reasonably exclude a major nonglycemic cardiovascular benefit 21 as well as an unanticipated harm of lixisenatide.…”

Section: Discussionmentioning

confidence: 99%

“…These drugs lower glucose levels by inhibiting the secretion of glucagon, promoting the release of insulin in response to hyperglycemia, slowing gastric emptying, and augmenting satiety. 14 On the basis of some evidence of cardioprotection in preliminary studies in animal models 15,16 and in pilot studies of myocardial ischemia 17,18 and heart failure in humans, 19 it was postulated 20,21 that in addition to improving glycemic control and promoting weight loss, GLP-1-receptor agonists may improve cardiovascular outcomes.…”

mentioning

confidence: 99%

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

Pfeffer¹,

Claggett²,

Dı́az³

et al. 2015

N Engl J Med

202

360

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BACKGROUND: Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes, particularly those with concomitant cardiovascular diseases, than in most other populations. We assessed the effects of lixisenatide, a glucagon-like peptide 1-receptor agonist, on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event. METHODS: We randomly assigned patients with type 2 diabetes who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined standards of care. The trial was designed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo, as defined by an upper boundary of the 95% confidence interval for the hazard ratio of less than 1.3 and 1.0, respectively, for the primary composite end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. RESULTS: The 6068 patients who underwent randomization were followed for a median of 25 months. A primary end-point event occurred in 406 patients (13.4%) in the lixisenatide group and in 399 (13.2%) in the placebo group (hazard ratio, 1.02; 95% confidence interval [CI], 0.89 to 1.17), which showed the noninferiority of lixisenatide to placebo (P<0.001) but did not show superiority (P=0.81). There were no significant between-group differences in the rate of hospitalization for heart failure (hazard ratio in the lixisenatide group, 0.96; 95% CI, 0.75 to 1.23) or the rate of death (hazard ratio, 0.94; 95% CI, 0.78 to 1.13). Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions than was placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent acute coronary syndrome, the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events. (Funded by Sanofi; ELIXA ClinicalTrials.gov number, NCT01147250.). Jean-Claude (2015). Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.

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Glucagon-Like Peptide-1 Receptor Agonists for Diabetes Mellitus

Cited by 36 publications

References 88 publications

Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research

Glucagon-like peptide-1 receptor agonists: a systematic review of comparative effectiveness research

DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-κB activation

Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome

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