Glucagon-like Peptide-1 Receptor Agonists In Patients Research Articles

SGLT-2 Inhibitors vs. GLP-1 Receptor Agonists for Patients with Diabetes

Among the glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors, several drugs in each class have

Beneficial effects of glucagon-like peptide 1 receptor agonists on glucose control, cardiovascular risk profile, and non-alcoholic fatty liver disease. An expert opinion of the Italian diabetes society

Patients with type 2 diabetes mellitus (T2DM) show an increased risk of cardiovascular diseases (CVD) and mortality. Many factors are implicated in the pathogenesis of CVD in patients with T2DM. Among the factors involved, chronic hyperglycemia and the cluster of CVD risk factors, such as dyslipidemia, hypertension, and obesity, play a major role. For many years, the control of hyperglycemia has been complicated by the fact that the use of many available drugs was associated with an increased risk of hypoglycemia. Paradoxically, hypoglycemia per se represents a risk factor for CVD. Recently, new drugs for the control of hyperglycemia have become available: many of them can determine a good control of hyperglycemia with minor risks of hypoglycemia. Among these new classes of drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer many advantages. In addition to a strong anti-hyperglycemic action, they possess the ability to act on body weight and other relevant risk factors for CVD. Consistently, some of the GLP-1RAs have demonstrated, in RCT designed to assess their safety, to reduce the risk of major adverse cardiovascular events. Furthermore, GLP-1RAs possess properties useful to treat additional conditions, as the capability of improving liver damage in patients with NAFLD or NASH, highly prevalent conditions in people with T2DM.In this document, written by experts of the Italian diabetes society (SID), we will focus our attention on the therapy with GLP-1RAs in patients with T2DM, particularly on the effects on hyperglycemia, cardiovascular disease risk factors, NAFLD/NASH and CVD prevention.

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials

GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes. We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711. Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80-0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all pinteraction≥0·14). GLP-1 receptor agonists reduced all-cause mortality by 12% (HR 0·88 [95% CI 0·82-0·94]; p=0·0001), hospital admission for heart failure by 11% (HR 0·89 [95% CI 0·82-0·98]; p=0·013), and the composite kidney outcome by 21% (HR 0·79 [95% CI 0·73-0·87]; p<0·0001), with no increase in risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR 0·82 [95% CI 0·69-0·98]; p=0·030). GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes. None.

Ventricular-arterial coupling as a potential therapeutic target in diabetes

Patients with type 2 diabetes (T2D) are at high risk of cardiovascular complications. Novel anti-diabetic medications such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to possess cardiac and renal protective effects beyond their ability to lower plasma glucose. Use of SGLT-2i and GLP-1RA in patients with T2D and heart failure reduce cardiovascular risk and heart failure related hospitalizations. SGLT-2i treatment has shown to improve the long-term prognosis of patients with heart failure. Both drugs also have the potential to normalize ventricular-arterial coupling (VAC). VAC is the crosstalk between the left ventricular function and the arterial system, and is an indicator of the global cardiovascular performance. In this overview, we will describe the concept of VAC and the features of diabetic cardiomyopathy, as well as VAC as a potential therapeutic target in diabetes by use of novel anti-diabetic drugs, primarily SGLT-2i and GLP-1RA. Continuous...

Tirzepatide and the new era of twincretins for diabetes

Type 2 diabetes and obesity are responsible for a large global burden of morbidity and mortality in the form of cardiovascular disease, kidney disease, and retinopathy. Analogues of the incretin GLP-1 have helped to transform the face of type 2 diabetes treatment, combining effective reductions in glycaemia with clinically useful weight loss. More importantly, GLP-1 analogues are proven to reduce mortality, the risk of cardiovascular events, and progression of diabetic kidney disease. 1 Kristensen SL Rørth R Jhund PS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019; 7: 776-785 Summary Full Text Full Text PDF PubMed Scopus (355) Google Scholar However, the achievable doses and efficacy of GLP-1 analogues can be limited by their adverse effects, mainly gastrointestinal in nature, such as nausea, vomiting, gastro-oesophageal reflux, and alterations in bowel habit. 2 Sorli C Harashima SI Tsoukas GM et al. Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017; 5: 251-260 Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar In the search for the next step beyond GLP-1, researchers have explored suitable companion treatments to obtain enhanced efficacy. 3 Khoo B Tan TM Combination gut hormones: prospects and questions for the future of obesity and diabetes therapy. J Endocrinol. 2020; 246: R65-R74 Crossref PubMed Scopus (6) Google Scholar The other incretin, glucose-dependent insulinotropic polypeptide (GIP), is, on first look, a natural partner to GLP-1 and is the more dominant insulinotropic hormone in normal physiology. 4 Holst JJ Gasbjerg LS Rosenkilde MM The role of incretins on insulin function and glucose homeostasis. Endocrinology. 2021; 162bqab065 Crossref PubMed Scopus (3) Google Scholar Tirzepatide, a unimolecular dual agonist of GLP-1 and GIP receptors, was developed with this so-called twincretin concept in mind. 5 Coskun T Sloop KW Loghin C et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018; 18: 3-14 Crossref PubMed Scopus (118) Google Scholar Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trialTirzepatide showed robust improvements in glycaemic control and bodyweight, without increased risk of hypoglycaemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment. Full-Text PDF

472-P: Online Patient Education on GLP-1 Receptor Agonists in Patients with T2D and CVD Prompts Real-Life Changes

We sought to measure the impact of online education for patients on knowledge, confidence, and prompting change in daily life. Two educational activities were available online, comprised of text and integrated visuals as well as either a patient or clinician video. Demographic questions were asked prior to starting the education. A knowledge question was asked both before and after the activity to assess learning gains, as well as intent to change and confidence questions at the end. Absolute improvements were calculated for pre/post questions. The activities launched in August, 2020, and preliminary data collected through November, 2020. Activity 1: To date, 28,983 learners have participated in the patient/caregiver activity, “How is Diabetes Related to Heart Disease?” Of which, 4,912 completed all questions (included in outcomes analysis): 51% male; 51% white, non-Hispanic; 66% over the age of 54; 71% have diabetes, 18% were interested in learning more about diabetes and heart disease. Intent-to-act: 85% plan to talk to their HCP about their risk for heart disease. Confidence changes: 87% reported increased confidence talking to my doctor or healthcare provider about how to lower their risk for heart disease. Activity 2: To date, 40,812 learners have participated in the patient/caregiver activity, “How Can I Make my Heart Healthier and Control my Sugar Better at the Same Time?” Of these, 10,233 completed all questions (included in outcomes analysis): 52% female; 53% white, non-Hispanic; 66% over the age of 54; 69% have diabetes, 22% were interested in learning more about ways to treat diabetes and heart disease. Knowledge changes: 54% improvement in recognizing GLP-1 RAs can treat T2D and lower the risk for heart disease (12% pre to 66% post). The metrics and outcomes gathered in this assessment are a strong indicator that these patient-focused online educational activities improved knowledge, confidence, and prompted intent to act by patients related to T2D and CVD risk reduction. Disclosure A. Larkin: None. A. Le: None. Funding Novo Nordisk

Protective properties of GLP-1 and associated peptide hormones in neurodegenerative disorders.

Type 2 diabetes mellitus and the associated desensitisation of insulin signalling has been identified as a risk factor for progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and others. Glucagon-like peptide 1 (GLP-1) is a hormone that has growth factor-like and neuroprotective properties. Several clinical trials have been conducted, testing GLP-1 receptor agonists in patients with Alzheimer's disease, Parkinson's disease or diabetes-induced memory impairments. The trials showed clear improvements in Alzheimer's disease, Parkinson's disease and diabetic patients. Glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) is the 'sister' incretin hormone of GLP-1. GIP analogues have shown neuroprotective effects in animal models of disease and can improve on the effects of GLP-1. Novel dual GLP-1/GIP receptor agonists have been developed that can enter the brain at an enhanced rate. The improved neuroprotective effects of these drugs suggest that they are superior to single GLP-1 receptor agonists and could provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Insulin Withdrawal in Diabetic Kidney Disease: What Are We Waiting for?

The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20–40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m2 and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m2. Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.

Meta-analyses of Results From Randomized Outcome Trials Comparing Cardiovascular Effects of SGLT2is and GLP-1RAs in Asian Versus White Patients With and Without Type 2 Diabetes.

Results of cardiovascular outcome trials (CVOTs) suggest Asians may derive greater benefit than Whites from newer classes of antihyperglycemic medications. To provide summary hazard ratio (HR) estimates for cardiovascular efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) stratified by race (Asian vs. White). A systematic review performed in PubMed from 1 January 2015 to 8 December 2020. Randomized placebo-controlled CVOTs of SGLT2is and GLP-1RAs that reported HRs (95% CIs) for 1) major adverse cardiovascular event (MACE) in patients with diabetes and 2) cardiovascular (CV) death/hospitalization for heart failure (HHF) in patients with HF and reduced ejection fraction (HFrEF). HRs (95% CIs) for selected outcomes in Asians and Whites were extracted from each trial, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects meta-analyses were performed to examine differences between the selected outcomes in Asians versus Whites. In four SGLT2i trials in type 2 diabetes, the MACE outcome HR (95% CI) in 3,298 Asians versus 20,258 Whites was 0.81 (0.57, 1.04) vs. 0.90 (0.80, 1.00), respectively (P interaction = 0.46). In two SGLT2i trials in patients with HFrEF, the CV death/HHF outcome HR in 1,788 Asians versus 5,962 Whites was 0.60 (0.47, 0.74) vs. 0.82 (0.73, 0.92), respectively (P interaction = 0.01). In six GLP-1RA trials, the MACE outcome HR in 4,195 Asians versus 37,530 Whites was 0.68 (0.53, 0.84) vs. 0.87 (0.81, 0.94), respectively (P interaction = 0.03). Lack of individual patient-level data, relatively short duration of trial observation, and lack of granular categorization of race within broadly defined Asian subgroups. Compared with Whites, Asians may derive greater CV death/HHF benefit from SGLT2is in patients with HFrEF, and MACE benefit from GLP-1RAs in patients with type 2 diabetes.

Prescription Patterns of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in Patients with Coronary Artery Disease.

To assess real-world data on the clinical implementation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in cardiovascular patients and to investigate barriers to prescribe these agents. Patients presenting with coronary artery disease (CAD) and type 2diabetes mellitus (T2DM) between 01/2014 and 04/2020 were included in the present analysis and followed prospectively. All first-time prescriptions of SGLT2i and GLP-1RA were identified. Among 1498 patients with CAD and T2DM, 17.6% of patients received an SGLT2i and 5.5% a GLP-1RA. The prescription of SGLT2i (+38.7%; p < 0.001) and GLP-1RA (+8%; p = 0.007) significantly increased during the observation period. Considering remuneration criteria for SGLT2i therapy, lowering the GFR cut-off to 30 ml/min/1.73 m2 would allow additional 26.6% of patients to qualify for an SGLT2i therapy. While SGLT2i therapy was inversely associated with CV mortality (adjusted hazard ratio of 0.18 [95% CI: 0.05-0.76]; p = 0.019), GLP-1RA therapy showed a trend for risk reduction. The present analysis revealed an infrequent prescription of SGLT2i and GLP-1RAs in patients with T2DM and CAD in clinical practice. Remuneration regulations that better reflect the inclusion criteria of the CV outcome trials would allow more patients at high risk to receive these CV protective drugs. Most importantly, while GLP-1RA therapy showed a trend for risk reduction of cardiovascular mortality, the use of SGLT2i had a strong inverse impact on cardiovascular mortality from a long-term perspective.

Insulin Dosage Adjustments After Initiation of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes

Background: Combination of insulin and GLP-1RAs have shown reductions in the HbA1c, body weight, and the risk of hypoglycemia. To date, there are conflicting data regarding the effect of GLP-1RAs on insulin dosage(s). Objective: The objective of this study was to evaluate adjustments of insulin doses upon initiation of GLP-1RAs. Methods: This was a retrospective chart review of patients on insulin therapy initiated on GLP-1RAs at NYU Langone Health. Patients were included in the study if they were at least 18 years of age, history of type 2 diabetes, and were on concurrent basal or mixed insulin therapy. 45 patients met inclusion criteria and were included in the study analysis. The primary endpoint was the median change in overall basal insulin doses. Secondary endpoints included median changes in total basal, mixed, and bolus insulin doses, oral antidiabetic medications and GLP-1RA doses, HbA1c, body weight, fasting glucose, and creatinine clearance. Safety results included any adverse reactions to insulin and/or GLP-1RA. Results: In the per-protocol analysis, there was a significant reduction in overall total basal insulin doses from baseline to week 24 (50 units vs. 44 units, p < 0.05). There was a median reduction in patients receiving glargine (50 units vs. 44 units) and detemir (29 units vs. 21.5 units). Conclusions: Use of GLP-1RAs after 24 weeks resulted in a statistically significant reduction in overall total basal insulin dosages from baseline. The median HbA1C in our patient population was >8%. Consider a ≥10% reduction in the overall basal insulin dose upon initiation of GLP-1RA in patients with a HbA1C >8%.

Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis

BackgroundEmerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.MethodsWe performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.ResultsThirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75–0.96] and 0.68 [0.59–0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80–1.04] and 0.86 [0.72–1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78–1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63–0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69–0.95]), while exendin-4 analogues did not (RR 1.03 [0.88–1.20]).ConclusionsIn patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

Efficacy and Cardiovascular Safety of SGLT2 Inhibitors.

Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these endpoints. Moreover, an ideal drug should have weight reducing benefits. Recently published outcome trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review, we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

Cardiovascular Outcomes with SGLT-2 Inhibitors vs. GLP-1 Receptor Agonists in Patients with Type 2 Diabetes and CKD: A Systematic Review and Network Meta-Analysis

Cardiovascular Outcomes with SGLT-2 Inhibitors vs. GLP-1 Receptor Agonists in Patients with Type 2 Diabetes and CKD: A Systematic Review and Network Meta-Analysis

Cardiorenal Protection With the Newer Antidiabetic Agents in Patients With Diabetes and Chronic Kidney Disease: A Scientific Statement From the American Heart Association.

Chronic kidney disease (CKD) with type 2 diabetes (T2D) is a major public health problem, resulting in significant cardiovascular and kidney adverse outcomes worldwide. Despite the widespread use of standard-of-care therapies for CKD with T2D over the past few decades, rates of progression to end-stage kidney disease remain high with no beneficial impact on its accompanying burden of cardiovascular disease. The advent of the newer classes of antihyperglycemic agents, including SGLT2 (sodium glucose cotransporter 2) inhibitors and GLP-1 (glucagon-like peptide-1) receptor agonists, has changed the landscape of therapeutic options for patients with CKD with T2D, with demonstration of significant reductions in cardiovascular adverse events and progression to end-stage kidney disease. Several potential mechanisms exist through which these beneficial effects are achieved in both drug classes, which may be independent of their antihyperglycemic effects. This scientific statement summarizes the current literature on the cardiorenal protective effects with SGLT2 inhibitors and GLP-1 receptor agonists in patients with CKD and T2D. It reviews potential mechanistic pathways that may drive these benefits and summarizes the literature on adverse effects in patients with CKD and T2D at risk for or with established cardiovascular disease. Last, it provides practical guidance on a proposed collaborative care model bridging cardiologists, nephrologists, endocrinologists, and primary care physicians to facilitate the prompt and appropriate integration of these therapeutic classes in the management of patients with T2D and CKD.

Antihyperglycemic Therapies With Expansions of US Food and Drug Administration Indications to Reduce Cardiovascular Events: Prescribing Patterns Within an Academic Medical Center.

Sodium-glucose cotransport protein-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce cardiovascular events in high-risk patients with type 2 diabetes mellitus (T2DM). We examined real-world use of these agents at a US academic medical center in the state of Mississippi. Prescriptions, provider specialty, and insurance status of users of SGLT2is and GLP-1RAs in patients with T2DM, and T2DM and cardiovascular disease (CVD) seen from 1st January 2013 to 30th June 2019 were obtained by electronic health records review. We identified 21,173 patients with T2DM and CVD. Overall, 306 (1.4%) and 349 (1.6%) patients received a SGLT2i and GLP-1RA, respectively. After the US Food and Drug Administration (FDA) expanded empagliflozin and liraglutide indications, a mean difference of 19.2 and 12.7 greater quarterly new prescriptions was noted, respectively, whereas no such rise in canagliflozin was observed. Primary care physicians accounted for 53.4% SGLT2i prescriptions, endocrinology for 30.3%, and cardiology for 6.0%. Primary care physicians accounted for 45.1% GLP-1RA prescriptions, endocrinology for 45.0%, and cardiology for 1.4%. Prescription patterns did not largely differ by patient insurance status. In conclusion, prescription of evidence-based therapies to improve CVD outcomes in high-risk patients with T2DM remains very low after several years of evidence generation. Low uptake was evident across insurance types. Modest increases in use were observed after regulatory expansions in labeling; however, cardiologists rarely engaged in prescription, underscoring the need for widespread implementation strategies across health care systems.

Indirect comparison of glucagon like peptide-1 receptor agonists regarding cardiovascular safety and mortality in patients with type 2 diabetes mellitus: network meta-analysis

BackgroundThe cardiovascular outcome trials (CVOTs) have shown that glucagon like peptide-1 receptor agonists (GLP1RAs) have varying degrees of cardiovascular (CV) safety in patients with type 2 diabetes mellitus (T2DM.) The lack of any head-to-head comparative trials among GLP1RAs urged the need for an indirect comparison of these agents. Therefore, this study was conducted to indirectly compare the CV safety and mortality effects among different GLP1RAs in patients with T2DM using network meta-analysis (NMA).MethodsMedline was searched to identify GLP1RA CVOTs to date. The outcomes of interest were CV death, myocardial infarction (IM), stroke, and death from any cause. An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. This NMA was reported in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA-NMA).ResultsA total of seven GLP1RA CVOTs were included having 56,004 patients. The NMA results showed that oral semaglutide was statistically better than exenatide (OR 0.47, 95% CI 0.21–0.99), dulaglutide (OR 0.46, 95% CI 0.20–0.97), albiglutide (OR 0.45, 95% CI 0.19–0.97), lixisenatide (OR 0.43, 95% CI 0.19–0.92) in reducing CV death events. No significant differences were detected between most of the treatments regarding reducing death from any cause, MI and stroke events. The ranking results showed that oral semaglutide had the highest probability to be ranked first (> 90%) in reducing CV death and death from any cause. Moreover, once weekly semaglutide had the highest probability to be ranked first in reducing MI and stroke events.ConclusionThe GLP1RAs have shown significant benefits in terms of CV safety. The indirect comparison and ranking probability results have shown that one weekly semaglutide and oral semaglutide seems to be the preferred option in patients with T2DM and established or at high risk of CVD. This result can aid health care providers, pharmacy and therapeutics committees in hospitals, and insurance companies when deciding which GLP1RA to start or add to their formulary.

974-P: Network Meta-analysis of Once Weekly Glucagon-Like Peptide-1 Receptor Agonists: A Focus on Cardiovascular Safety and Mortality

Objective: To indirectly compare once weekly exenatide, semaglutide, albiglutide and dulaglutide regarding cardiovascular (CV) safety and mortality using network meta-analysis (NMA). Methods: PubMed was searched to identify glucagon like peptide-1 receptor agonists (GLP-1RA) outcome trials (CVOTs) to date. The outcomes of interest were CV death, myocardial infarction (IM), nonfatal MI, stroke, nonfatal stroke, death from any cause, and hospitalizations for heart failure (HF). An NMA with binomial likelihood logit link model was used for the binary outcomes. We conducted both fixed effects and random effects models for each outcome, and selected the best model based on the deviance information and the average posterior residual deviance. Data were extracted by two independent reviewers and risk of bias was assessed in the same manner. Results: The NMA results showed no significant differences among the four GLP-1RAs regarding most of the outcomes. However, albiglutide when compared to exenatide was associated with lower risk of MI (HR 0.76, 95% Cl: 0.60-0.96)] and nonfatal MI (HR 0.76, 95% Cl: 0.60-0.97). The ranking probability showed that semaglutide had the highest probability to be ranked first in reducing MI (55%), nonfatal MI (55%), stroke (87%), and nonfatal stroke events (87%). For CV death and death from any cause, exenatide had the highest probability to be ranked first at 30% and 45% respectively. Lastly, for hospitalizations for HF, albiglutide was ranked first with a probability of 55% followed by placebo. Conclusion: This NMA did not show significant differences among the treatments. However, based on the ranking results, semaglutide seems to be the preferred agent over the other once weekly GLP-1RAs in patients with diabetes and CV risk. Disclosure O. Alfayez: None. O.A. Almohammed: None. O. Alkhezi: None. M.S. Al Yami: None.

Effects of oral antidiabetic drugs and glucagon-like peptide-1 receptor agonists on left ventricular diastolic function in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis.

The present study aimed to compare the effects of oral antidiabetic drugs (OADs) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on left ventricular diastolic function in patients with type 2 diabetes mellitus using a network meta-analysis of randomized controlled trials (RCTs). Literature searches were conducted on Medline, the Cochrane Controlled Trials Registry, and ClinicalTrials.gov . RCTs that assessed the effects on left ventricular diastolic function of OADs and GLP-1RAs in patients with type 2 diabetes were included. The outcome was the value (E/e') obtained by dividing peak early diastolic transmitral flow velocity (E) by the mitral annular early diastolic velocity (e'). Standardized mean differences (SMD) and 95% confidence intervals (CIs) were calculated from a random-effects network meta-analysis. Eight RCTs (592 patients) identified in a literature search met the eligibility criteria for this study and were included in the network meta-analysis. Compared with placebo, liraglutide was the only drug that caused a significant improvement in left ventricular diastolic function (SMD, - 0.65; 95% CI, - 1.23 to - 0.08). In addition, when the effects on left ventricular diastolic function were evaluated across drugs, liraglutide alone caused a significant improvement in left ventricular diastolic function compared with OADs (sitagliptin, linagliptin, pioglitazone, rosiglitazone, voglibose, and glimepiride). From the perspective of preventing the onset of heart failure, the administration of liraglutide for type 2 diabetes is promising.

Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection.

ABSTRACTSodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.