Beyond weight loss: the potential of glucagon-like peptide-1 receptor agonists for treating heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various phenotypes, and obesity is one of the most common and clinically relevant phenotypes of HFpEF. Obesity contributes to HFpEF through multiple mechanisms, including sodium retention, neurohormonal dysregulation, altered energy substrate metabolism, expansion of visceral adipose tissue, and low-grade systemic inflammation. Glucagon-like peptide-1 (GLP-1) is a hormone in the incretin family. It is produced by specialized cells called neuroendocrine L cells located in the distal ileum and colon. GLP-1 reduces blood glucose levels by promoting glucose-dependent insulin secretion from pancreatic ß cells, suppressing glucagon release from pancreatic α cells, and blocking hepatic gluconeogenesis. Recent evidence suggests that GLP-1 receptor agonists (GLP-1 RAs) can significantly improve physical activity limitations and exercise capacity in obese patients with HFpEF. The possible cardioprotective mechanisms of GLP-1 RAs include reducing epicardial fat tissue thickness, preventing activation of the renin-angiotensin-aldosterone system, improving myocardial energy metabolism, reducing systemic inflammation and cardiac oxidative stress, and delaying the progression of atherosclerosis. This review examines the impact of obesity on the underlying mechanisms of HFpEF, summarizes the trial data on cardiovascular outcomes of GLP-1 RAs in patients with type 2 diabetes mellitus, and highlights the potential cardioprotective mechanisms of GLP-1 RAs to give a pathophysiological and clinical rationale for using GLP-1 RAs in obese HFpEF patients.

GLP-1 Receptor Agonists and Cardiovascular Disease: What Do Clinicians Need to Know?

PURPOSE OF REVIEW: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining importance due to their effects on cardiovascular parameters. This review discusses the findings of dedicated cardiovascular outcome trials of GLP-1RAs and summarizes their utility to help clinicians understand their role in cardiovascular disease. RECENT FINDINGS: Patients with diabetes mellitus are at an increased risk of cardiovascular disease. Cardiovascular outcome trials have shown GLP-1RAs decrease the primary composite outcome of the first occurrence of major adverse cardiovascular events (MACE) in patients with diabetes. Additionally, select GLP-1RAs have also shown improved cardiovascular outcomes in patients without diabetes who are either overweight (BMI ≥ 27), or obese (BMI ≥ 30). There have also been encouraging results in patients with heart failure with preserved ejection fraction. There is increasing evidence showing GLP-1RAs are beneficial across the cardiometabolic spectrum of disease. Implementation of these therapeutics into clinical practice is important to improve cardiovascular risk.

Analysis of composite time-to-event endpoints in cardiovascular outcome trials.

Composite time-to-event endpoints are commonly used in cardiovascular outcome trials. For example, the IMPROVE-IT trial comparing ezetimibe+simvastatin to placebo+simvastatin in 18,144 patients with acute coronary syndrome used a primary composite endpoint with five component outcomes: (1) cardiovascular death, (2) non-fatal stroke, (3) non-fatal myocardial infarction, (4) coronary revascularization ≥30 days after randomization, and (5) unstable angina requiring hospitalization. In such settings, the traditional analysis compares treatments using the observed time to the occurrence of the first (i.e. earliest) component outcome for each patient. This approach ignores information for subsequent outcome(s), possibly leading to reduced power to demonstrate the benefit of the test versus the control treatment. We use real data examples and simulations to contrast the traditional approach with several alternative approaches that use data for all the intra-patient component outcomes, not just the first.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Sodium-glucose co-transporter 2 inhibitors in heart failure: an updated evidence-based practical guidance for clinicians.

The sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce risks of clinical events in patients with heart failure (HF), with early and sustained benefits regardless of ejection fraction, diabetic status, and care setting. As part and parcel of the modern foundational HF therapy, clinicians should be familiar with these drugs, in order to implement their use and limit the potential adverse effects. We present an up-to-date review of current evidence and a practical guide for the prescription of SGLT2 inhibitors in patients with HF, highlighting important elements for patient selection, treatment initiation, dosing, and problem solving.

The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. RESULTS: Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. CONCLUSIONS: SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.

Cardiovascular risk profiles: A cross-sectional study evaluating the generalizability of the glucagon-like peptide-1 receptor agonist cardiovascular outcome trials REWIND, LEADER and SUSTAIN-6 to the real-world type 2 diabetes population in the United Kingdom.

AIMS: To determine the proportion of UK patients with type 2 diabetes (T2D) who meet the cardiovascular (CV) or combined CV/core eligibility criteria used for the CV outcome trials (CVOTs) of UK-marketed glucagon-like peptide-1 receptor agonists (GLP-1RAs) showing CV benefit (dulaglutide in REWIND, liraglutide in LEADER and injectable semaglutide in SUSTAIN-6). MATERIALS AND METHODS: Adults with T2D on/before June 2018 were identified from the UK Clinical Practice Research Datalink GOLD primary care database and linked to Hospital Episode Statistics data (Protocol 19_262). Patient CV and clinical data were evaluated against the CVOT eligibility criteria. Data were analysed descriptively. RESULTS: The study cohort (N = 33 118 patients with T2D) had a mean (standard deviation) age of 66.0 (13.3) years and 56.6% were male. Almost two-thirds (64.5%) of the study cohort met the CV criteria for REWIND, versus 43.0% for both LEADER and SUSTAIN-6. The proportions of the study cohort who met the CVOT criteria of "established CV disease" and "CV risk factors only" for REWIND were 22.4% and 42.1%, respectively, versus 38.7% and 4.3%, respectively, for both LEADER and SUSTAIN-6. The proportions of patients satisfying both CV and core criteria were 44.4% for REWIND, 13.3% for LEADER and 13.5% for SUSTAIN-6. Study findings remained consistent when restricted to GLP-1RA users. CONCLUSIONS: REWIND captured a trial population more representative of the real-world T2D population in the United Kingdom than LEADER or SUSTAIN-6 with regard to both CV and combined CV/core eligibility criteria.

SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs.

BACKGROUND: It has been suggested that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D. METHODS: An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months. RESULTS: Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73-0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I2 = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56-0.75), with moderate heterogeneity (I2 = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I2 = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46). CONCLUSIONS: Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.

BACKGROUND: A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). RESULTS: GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001). CONCLUSIONS: GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression.

BACKGROUND: Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. METHODS: An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS: The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = - 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = - 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. CONCLUSIONS: The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

Pharmacological management of South Asians with type 2 diabetes: Consensus recommendations from the South Asian Health Foundation.

South Asians constitute approximately 1.6 billion people from the Indian subcontinent, comprising Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka; and make up the largest diaspora globally. Compared to the White European population, this group is at a higher risk of developing type 2 diabetes along with cardiovascular, renal and eye complications. Over the recent years, a number of new therapies for type 2 diabetes have become available for which cardiovascular outcome trials (CVOTs) have been published. The recent ADA/EASD consensus guidelines on diabetes, pre-diabetes and cardiovascular diseases' offer a transitional shift in type 2 diabetes management. The new consensus recommendations are based on recent CVOTs, many of which had a representation of South Asian cohorts. In light of this new evidence, there is urgent need for an integrated, evidence-based, cost-effective and individualised approach specific for South Asians. This review takes into consideration the evidence from these CVOTs and provides best practice recommendations for optimal management of South Asian people with type 2 diabetes, alongside the previously published consensus report from South Asian Health Foundation in 2014 [1].

Approvals of type 2 diabetes drugs tested in cardiovascular outcome trials: A tripartite comparison.

AIMS: In 2008, the US Food and Drug Administration (FDA) issued a guidance requiring that cardiovascular outcome trials (CVOTs) be conducted for newer hypoglycaemic drugs for type 2 diabetes (T2D). We aimed to examine the decisions by 3 regulatory authorities in response to identical CVOT data. METHODS: We surveyed ClinicalTrials.gov to identify CVOTs and examined the revision histories of drug labels in databases from the FDA, the European Medicines Agency, and the Pharmaceuticals and Medical Devices Agency in Japan. RESULTS: We selected 14 drugs and corresponding CVOTs, 12 of which were conducted as postmarketing trials. In the USA and the EU, the pre-CVOT indication on all 14 labels was "improvement in glycaemic control". Six drugs showed significant cardiovascular risk reduction, which led to an additional indication regarding reduction of cardiovascular adverse events in the USA, and a change to the EU indication to specify treatment of adults with T2D. The initial indication in Japan, T2D, remained unchanged. Regarding safety, significant increases in heart failure were observed only in the saxagliptin trial. A warning was added to the saxagliptin labels in the EU and Japan, whereas the FDA required a class effect warning to be added to the labels of all 4 dipeptidyl peptidase-4 inhibitors. CONCLUSIONS: Regulatory authorities using identical trial data made substantially different decisions regarding both safety and efficacy of hypoglycaemic drugs. The differences in initial indication wording between Japan and the other authorities suggest that trial data and T2D are interpreted differently in these regions.

Cardiovascular Outcome Trials with Glucose-Lowering Drugs.

PURPOSE OF REVIEW: This review summarizes recent cardiovascular outcome trials (CVOTs) with glucose-lowering drugs. RECENT FINDINGS: The majority of recent CVOTs with glucose-lowering drugs have tested dipeptidyl peptidase-4 inhibitors (DPP4-i), glucagon-like peptide-1 receptors agonists (GLP1-RA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i), but studies have also been performed with other agents including thiazolidinediones and insulin. All CVOTs with DPP4-I, GLP1-RA, and SGLT2-i have demonstrated the cardiovascular (CV) safety of these agents compared to usual care. However, certain GLP1-RAs (liraglutide, subcutaneous semaglutide, albiglutide, dulaglutide) and SGLT2-i (empagliflozin, canagliflozin) have demonstrated a CV benefit, showing significant reductions in composite cardiovascular outcomes. Furthermore, all SGLT2-i also significantly decreased the risk for hospitalization for heart failure. Results from these studies have altered clinical guidelines worldwide and have resulted in new indications for some glucose-lowering drugs. In patients with T2D and high risk for CVD, GLP-1RA or SGLT2-i with proven cardiovascular benefit are recommended, irrespective of glycemic control.

Generalizability of sodium-glucose co-transporter-2 inhibitors cardiovascular outcome trials to the type 2 diabetes population: a systematic review and meta-analysis.

BACKGROUND: Cardiovascular outcome trials of sodium-glucose co-transporter-2 inhibitors (SGLT2i CVOTs) found the agents to be associated with clinical benefits in terms of cardiovascular and renal outcomes. We performed a meta-analysis to assess and compare the overall prevalence of eligibility for the enrollment criteria of CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, and VERTIS-CV among unselected patients with type 2 diabetes. METHODS: This meta-analysis was registered in PROSPERO (CRD42020172032). PubMed, CENTRAL, Scopus and Web of Science were researched in March 2020. Studies evaluating the prevalence of eligibility for each SGLT2i CVOT were selected. Endpoints were estimated using a random-effects model. RESULTS: Five studies, evaluating 1,703,519 patients with type 2 diabetes, were included. Overall, the prevalence of eligible patients according to the enrollment criteria of CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, and VERTIS-CV was 36.4%, 49.5%, 17.0% and 19.0%, respectively. In head-to-head comparisons, DECLARE-TIMI 58 was associated with the highest odds of eligibility (1.74 versus CANVAS, 5.15 versus EMPA-REG OUTCOME and 4.81 versus VERTIS-CV), followed by CANVAS and EMPA-REG OUTCOME/VERTIS-CV. A high heterogeneity was found for all the outcomes. CONCLUSIONS: The present review showed that a considerable number of patients counseled in clinical practice could have been eligible for SGLT2i CVOTs. Particularly, dapagliflozin was shown to be the SGLT2i with the largest generalizability of findings from its CVOT according to the odds ratio of eligibility for the enrollment criteria among unselected patients with type 2 diabetes. Further country- or region-specific studies are needed to confirm the applicability of our results.

Relationship between improvement of glycaemic control and reduction of major cardiovascular events in 15 cardiovascular outcome trials: A meta-analysis with meta-regression.

AIM: In order to disclose relations between reduction of haemoglobin A1c (HbA1c) levels and risk of major cardiovascular events (MACE), we performed a meta-analysis with metaregression of all cardiovascular outcome trials (CVOTs) so far published in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: An electronic search up to February 10, 2020 was conducted to determine eligible trials. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS: The 15 CVOTs included evaluated 138,250 patients. In the pooled analysis, the risk of MACE was significantly reduced by 9% (hazard ratio, HR = 0.91, 0.87-0.95, P <0.001) as compared with placebo, with significant heterogeneity between trials (I2 = 44%, P = 0.060) There was a robust relation between the reduction in achieved HbA1c at the end of the trial and the HR reduction for MACE (beta = -0.3169, P = 0.029), explaining most (78%) of the between-study variance; this relation was totally driven by the risk reduction of non-fatal stroke only, which explained 100% of between-study variance, and apparently restricted to the class of glucagon-like peptide 1 receptor agonists (GLP-1RAs). There was no relation between the reduction in achieved HbA1c and the HR for heart failure (variance explained = 0%) or all-cause mortality (variance explained = 6%). CONCLUSION: The blood glucose reduction observed in CVOTs may play some role in reducing the risk of non-fatal stroke, at least during treatment with GLP-1RAs, without affecting the other two components of MACE.

Novel antidiabetic drugs in diabetic kidney disease accompanying type 2 diabetes - a minireview.

Intensive hypoglycemic treatment is the strongest preventive strategy against the development of microvascular complications of type 2 diabetes (T2DM), including diabetic nephropathy. However, some antidiabetic drugs, i.e. sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have an additional renoprotective effect beyond glucose control by itself. Similar, both SGLT-2i and GLP1-RA have been demonstrated to decrease the risk of adverse cardiovascular (CV) events in CV outcome trials. Nevertheless, there are relevant differences in CV and renal effects of SGLT-2i and GLP1-RA. First, SGLT2i reduced the incidence and progression of albuminuria and prevented loss of kidney function, while predominant renal benefits of GLP1-RA were driven by albuminuria outcomes. Second, the risk of heart failure (HF) hospitalizations decreased on SGLT2i but not on GLP1-RA, which gives priority to SGLT2i in T2DM and HF, especially with depressed EF. Third, either GLP1-RA (reducing predominantly atherosclerosis-dependent events) or SGLT-2i, should be used in T2DM and established atherosclerotic CV disease (ASCVD) or other indicators of high CV risk. In this review, we have briefly compared clinical practice guidelines of the American Diabetes Association (2020 and 2021 versions), Polish Diabetes Association (2020) and the European Society of Cardiology/European Association for the Study of Diabetes (2019), with a focus on the choice between SGLT-2i and GLP1-RA in patients with diabetic kidney disease.

Class effects of SGLT2 inhibitors on cardiorenal outcomes.

BACKGROUND: To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. RESULTS: The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m2 for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g). CONCLUSIONS: Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

Second-line Glucose-Lowering Therapy in Type 2 Diabetes Mellitus.

PURPOSE OF REVIEW: There is consensus that metformin should be the first-line pharmacological therapy for type 2 diabetes. Although new evidence on effective treatments for type 2 diabetes is rapidly evolving, there is uncertainty regarding the optimal choice of second-line therapy. Our aim was to review the current major guidelines for second-line therapy in type 2 diabetes, along with findings from the recent cardiovascular outcome trials, focusing on two particularly promising classes of glucose-lowering drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP1 RAs). RECENT FINDINGS: In the recent randomized controlled trials, two SGLT2 inhibitors (i.e., empagliflozin and canagliflozin) and two GLP1 RAs (i.e., liraglutide and albiglutide) reduced cardiovascular events in patients with type 2 diabetes, of whom most had established atherosclerotic cardiovascular disease. Some clinical guidelines have changed their recommendations for second-line therapy based on these findings. The first choice for a second-line therapy by the new American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) guidelines is SGLT2 inhibitors or GLP1 RAs for patients with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease. For patients without these conditions, the ADA/EASD lists five options of noninsulin second-line therapy without a suggested hierarchy of use. On the other hand, the 2019 consensus statement from the American Association of Clinical Endocrinologists/American College of Endocrinology lists nine hierarchical options, with GLP1 RAs as the first recommended therapy, followed by SGLT2 inhibitors and dipeptidyl peptidase 4 (DPP4) inhibitors, and sulfonylurea as the last option. The American College of Physicians recommends four oral treatment options, which do not include GLP1 RAs. The International Diabetes Federation recommends sulfonylureas, DPP4 inhibitors, or SGLT2 inhibitors as preferred second-line drugs with GLP1 RAs as an alternative in obese patients. The World Health Organization strongly recommends sulfonylureas in low-resource settings. The National Institute for Health and Care Excellence in the UK recommends DPP4 inhibitors, thiazolidinediones, or sulfonylureas, with use of SGLT2 inhibitors only under special circumstances. Clinical guidelines for the choice of second-line therapy in type 2 diabetes are inconsistent. A comprehensive assessment of the risks and benefits of second-line therapy is needed to address knowledge gaps that underlie core clinical practice.

Bridging the Gap for Patients with Diabetes and Cardiovascular Disease Through Cardiometabolic Collaboration.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in individuals with type 2 diabetes (T2D). Recent cardiovascular outcome trials (CVOTs) have established sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1 RA) as powerful medications that can lower glucose as well as reduce the risk of complications of CVD in many individuals with T2D. The combination of glycemic and cardiovascular benefits of SGLT2i and GLP1 RA has highlighted the importance of collaborative care of patients by diabetes and cardiovascular specialists. We review several models of cardiometabolic care for patients with diabetes and CVD and discuss practical ways in which diabetes and cardiovascular specialists can work together to improve cardiometabolic care. RECENT FINDINGS: CVOTs for SGLT2i and GLP1 RA have demonstrated a significant reduction in major adverse cardiovascular events in individuals with T2D and CVD, in addition to their beneficial effects on glucose lowering and weight loss. Additionally, several models of care, including population health screening models with or without a remote management intervention, multidisciplinary clinics, and combined cardiometabolic training, have been proposed to better facilitate the multifaceted care that individuals with diabetes and CVD require. Innovative models of cardiometabolic care have the potential to improve the quality of care that individuals with diabetes and CVD receive. Through collaboration and co-management, diabetes specialists, cardiovascular specialists, and primary care providers have the ability to optimize diabetes and cardiovascular care.