Incorporating incretin-based therapies into clinical practice for patients with type 2 diabetes.
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ABSTRACT: Background
Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.Methods
Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.Results
Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.Conclusion
Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.
SUBMITTER: Tibaldi JM
PROVIDER: S-EPMC3961600 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide are incretins secreted from enteroendocrine cells postprandially in part to regulate glucose homeostasis. Dysregulation of these hormones is evident in type 2 diabetes mellitus (T2DM). Two new drugs, exenatide (GLP-1 mimetic) and sitagliptin [dipeptidyl peptidase (DPP) 4 inhibitor], have been approved by regulatory agencies for treating T2DM. Liraglutide (GLP-1 mimetic) and vildagliptin (DPP 4 inhibitor) are expected to arrive on the market soon.The background of incretin-based therapy and selected clinical trials of these four drugs are reviewed. A MEDLINE search was conducted for published articles using the key words incretin, glucose-dependent insulinotropic polypeptide, GLP-1, exendin-4, exenatide, DPP 4, liraglutide, sitagliptin, and vildagliptin.Exenatide and liraglutide are injection based. Three-year follow-up data on exenatide showed a sustained weight loss and glycosylated hemoglobin (HbA(1c)) reduction of 1%. Nausea and vomiting are common. Results from phase 3 studies are pending on liraglutide. Sitagliptin and vildagliptin are orally active. In 24-wk studies, sitagliptin reduces HbA(1c) by 0.6-0.8% as monotherapy, 1.8% as initial combination therapy with metformin, and 0.7% as add-on therapy to metformin. Vildagliptin monotherapy lowered HbA(1c) by 1.0-1.4% after 24 wk. Their major side effects are urinary tract and nasopharyngeal infections and headaches. Exenatide and liraglutide cause weight loss, whereas sitagliptin and vildagliptin do not.The availability of GLP-1 mimetics and DPP 4 inhibitors has increased our armamentarium for treating T2DM. Unresolved issues such as the effects of GLP-1 mimetics and DPP 4 inhibitors on beta-cell mass, the mechanism by which GLP-1 mimetics lowers glucagon levels, and exactly how DPP 4 inhibitors lead to a decline in plasma glucose levels without an increase in insulin secretion, need further research.
| S-EPMC2579648 | biostudies-other
Project description:ObjectiveCombined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain and gastrointestinal side effects in T1DM patients.MethodsWe searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects.ResultsNine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels (weighted mean difference (WMD) -0.17%, 95% confidence interval (CI) -0.24 to -0.11, P < 0.001), total daily insulin dose (WMD -5.53 IU/day, 95% CI -8.89 to -2.17, P = 0.001) and body weight (WMD -3.24 kg, 95% CI -4.43 to -2.04, P < 0.001). Incretins did not increase the risk of severe hypoglycaemia (odds ratio (OR) 0.83, 95% CI 0.60-1.16, P = 0.287) but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20-5.45, P < 0.001).ConclusionsIn T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.
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Project description:Since the early 2000s, an influx of novel glucose-lowering agents has changed the therapeutic landscape for treatment of diabetes and diabetes-related complications. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an important therapeutic class for the management of type 2 diabetes (T2D), demonstrating benefits beyond glycemic control, including lowering of blood pressure and body weight, and importantly, decreased risk of development of new or worsening chronic kidney disease (CKD) and reduced rates of atherosclerotic cardiovascular events. Plausible non-glycemic mechanisms that benefit the heart and kidneys with GLP-1 receptor agonists include anti-inflammatory and antioxidant effects. Further supporting their use in CKD, the glycemic benefits of GLP-1 receptor agonists are preserved in moderate-to-severe CKD. Considering current evidence, major guideline-forming organizations recommend the use of GLP-1 receptor agonists in cases of T2D and CKD, especially in those with obesity and/or in those with high cardiovascular risk or established heart disease. Evidence continues to build that supports benefits to the heart and kidneys of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. Ongoing outcome and mechanistic studies will continue to inform our understanding of the role of GLP-1 and dual GLP-1/GIP receptor agonists in diverse patient populations with kidney disease.
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Project description:Purpose of reviewThe purpose of this review is to correlate predictions based on pre-clinical data with outcomes from clinical trials that examine the effects of incretin-based diabetes treatments on the kidney. The incretin-based treatments include agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of the enzyme, dipeptidyl peptidase-4 (DPP-4). In addition, what is known about the incretin-based therapies will be compared to what is known about the renal effects of SGLT2 inhibitors.Recent findingsLarge-scale clinical trials have shown that SGLT2 inhibitors reduce albuminuria and preserve estimated glomerular filtration rate (eGFR) in patients with diabetic nephropathy. A concise and plausible hemodynamic mechanism is supported by pre-clinical research on the physiology and pharmacology of SGLT2. Large-scale clinical trials have shown that incretin-based therapies mitigate albuminuria but have not shown beneficial effects on eGFR. Research on the incretin-based therapies has yielded a diverse array of direct effects throughout the body, which fuels speculation as to how these drugs might benefit the diabetic kidney and affect its function(s). But in vivo experiments have yet to confirm that the proposed mechanisms underlying emergent phenomena, such as proximal tubular fluid reabsorption, are the ones predicted by cell and molecular experiments. There may be salutary effects of incretin-based treatments on the diabetic kidney, but the system is complex and not amenable to simple explanation or prior prediction. This contrasts with the renal effects of SGLT2 inhibitors, which can be explained concisely.
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Project description:Patients with type 2 diabetes mellitus are at risk for accelerated cognitive decline and dementia. Furthermore, their risk of stroke is increased and their outcome after stroke is worse than in those without diabetes. Incretin-based therapies are a class of antidiabetic agents that are of interest in relation to these cerebral complications of diabetes. Two classes of incretin-based therapies are currently available: the glucagon-like-peptide-1 agonists and the dipeptidyl peptidase-4 -inhibitors. Independent of their glucose-lowering effects, incretin-based therapies might also have direct or indirect beneficial effects on the brain. In the present review, we discuss the potential of incretin-based therapies in relation to dementia, in particular Alzheimer's disease, and stroke in patients with type 2 diabetes. Experimental studies on Alzheimer's disease have found beneficial effects of incretin-based therapies on cognition, synaptic plasticity and metabolism of amyloid-β and microtubule-associated protein tau. Preclinical studies on incretin-based therapies in stroke have shown an improved functional outcome, a reduction of infarct volume as well as neuroprotective and neurotrophic properties. Both with regard to the treatment of Alzheimer's disease, and with regard to prevention and treatment of stroke, randomized controlled trials in patients with or without diabetes are underway. In conclusion, experimental studies show promising results of incretin-based therapies at improving the outcome of Alzheimer's disease and stroke through glucose-independent pleiotropic effects on the brain. If these findings would indeed be confirmed in large clinical randomized controlled trials, this would have substantial impact.
| S-EPMC4718099 | biostudies-literature
Project description:Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.
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Project description:As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.
| S-EPMC6844583 | biostudies-literature
Project description:OBJECTIVES:To compare population-based incidence rates of new-onset depression or self-harm in patients initiating incretin-based therapies with that of sulfonylureas (SU) and other glucose-lowering agents. DESIGN:Population-based cohort study. SETTING:Patients attending primary care practices registered with the UK-based Clinical Practice Research Datalink (CPRD). PARTICIPANTS:Using the UK-based CPRD, we identified two incretin-based therapies cohorts: (1) dipeptidyl peptidase-4 inhibitor (DPP-4i)-cohort, consisting of new users of DPP-4i and SU and (2) glucagon-like peptide-1 receptor agonists (GLP-1RA)-cohort, consisting of new users of GLP-1RA and SU, between January 2007 and January 2016. Patients with a prior history of depression, self-harm and other serious psychiatric conditions were excluded. MAIN OUTCOME MEASURES:The primary study outcome comprised a composite of new-onset depression or self-harm. Unadjusted and adjusted Cox proportional hazards regression was used to quantify the association between incretin-based therapies and depression or self-harm. Deciles of High-Dimensional Propensity Scores and concurrent number of glucose-lowering agents were used to adjust for potential confounding. RESULTS:We identified new users of 6206 DPP-4i and 22?128 SU in the DPP-4i-cohort, and 501 GLP-1RA and 16?409 SU new users in the GLP-1RA-cohort. The incidence of depression or self-harm was 8.2 vs 11.7 events/1000 person-years in the DPP-4i-cohort and 18.2 vs 13.6 events/1000 person-years in the GLP-1RA-cohort for incretin-based therapies versus SU, respectively. Incretin-based therapies were not associated with an increased or decreased incidence of depression or self-harm compared with SU (DPP-4i-cohort: unadjusted HR 0.70, 95% CI 0.51 to 0.96; adjusted HR 0.80, 95%?CI 0.57 to 1.13; GLP-1RA-cohort: unadjusted HR 1.36, 95% CI 0.72 to 2.58; adjusted HR 1.25, 95%?CI 0.63 to 2.50). Consistent results were observed for other glucose-lowering comparators including insulin and thiazolidinediones. CONCLUSIONS:Our findings suggest that the two incretin-based therapies are not associated with an increased or decreased risk of depression or self-harm.
| S-EPMC6194463 | biostudies-literature
Project description:In Brief Sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies (dipeptidyl peptidase-4 [DPP-4] inhibitors and glucagon-like peptide-1 [GLP-1] receptor agonists) are widely used to treat patients with type 2 diabetes. In clinical and real-world studies, canagliflozin, an SGLT2 inhibitor, has demonstrated superior A1C lowering compared to the DPP-4 inhibitor sitagliptin. Canagliflozin can also promote modest weight/fat loss and blood pressure reduction. The addition of canagliflozin to treatment regimens that include a DPP-4 inhibitor or a GLP-1 receptor agonist has been shown to further improve glycemic control, while still maintaining beneficial effects on cardiometabolic parameters such as body weight and blood pressure. Overall, the available clinical and real-world evidence suggests that canagliflozin is a safe and well-tolerated treatment option that can be considered either in addition to or instead of incretin-based therapies for patients with type 2 diabetes.
| S-EPMC5510927 | biostudies-literature
Project description:Patients with type 2 diabetes mellitus (T2DM) experience many cardiovascular complications. Several studies have demonstrated the cardioprotective effects of incretin-based therapies; however, there are few studies on the effects of long-term incretin-based therapies on cardiovascular events. Therefore, the present study conducted a systematic review and network meta-analysis to evaluate the effects of long-term incretin-based therapies on ischaemic diseases. We searched PubMed, CENTRAL, and Clinicaltrial.gov to retrieve randomised control trials reported until December 2016 and enrolled only RCTs with more than a 1-year follow-up. The network meta-analysis was performed using R Software with a GeMTC package. A total of 40 trials were included. Dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 agonists were associated with a lower risk of myocardial infarction (MI) than were sulfonylureas (odds ratio [95% credible interval] 0.41 [0.24-0.71] and 0.48 [0.27-0.91], respectively). These results suggested that patients with T2DM receiving long-term incretin-based therapies have a lower risk of MI than do those receiving sulfonylurea-based therapy. These findings highlight the risks of cardiovascular events in patients who receive long-term incretin-based therapies, and may provide evidence for the selection of antidiabetic therapy in the future.
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