European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients with heart failure

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose‐lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase‐4 (DPP‐4) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA), and sodium–glucose co‐transporter type 2 (SGLT‐2) inhibitors]. Regarding safety of DPP‐4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP‐4 inhibitors. GLP‐1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT‐2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT‐2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT‐2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose‐lowering therapies in patients with HF.     

Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a “cardiac” drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.     

Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30–40% of patients) and associated with a higher risk of HF hospitalization, all‐cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first‐line choice. Sulphonylureas and insulin have been the traditional second‐ and third‐line therapies although their safety in HF is equivocal. Neither glucagon‐like preptide‐1 (GLP‐1) receptor agonists, nor dipeptidyl peptidase‐4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.     

Navigating the “MACE” in Cardiovascular Outcomes Trials and decoding the relevance of Atherosclerotic Cardiovascular Disease benefits versus Heart Failure benefits

The publication of results from recent cardiovascular outcome trials (CVOTs) has transformed the landscape of diabetes treatment. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter-2 (SGLT2) inhibitors have demonstrated CV benefits in large, well-conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are US Food and Drug Administration-approved not only for glucose-lowering, but also to reduce the risk of cardiovascular (CV) events/CV mortality in people with type 2 diabetes (T2DM) and established CV disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the diabetes community, but the replication of the CV benefits with different compounds in the same class alleviated concerns about the CV benefits being chance findings. However, many questions remain. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1RA class and the SGLT2 inhibitor class appear to be more complex. An analysis of major adverse cardiovascular events (MACE) in the CVOTs shows that the CV benefits of GLP-1RAs are predominantly specific to atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). By contrast, the SGLT2 inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function (“the pump”), and not on the “pipes” (coronary arteries). In the present review, we discuss the rationale for the conduct of CVOTs, highlight the inability of the classic three-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially HF in T2DM, and discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus HF, which develops in a sizeable proportion of people with diabetes and without prior ASCVD.     

When and How to Use Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction or Chronic Kidney Disease

The role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in preventing heart failure (HF) in people with type 2 diabetes (T2DM) is now part of current treatment recommendations. Two large clinical trials (DAPA-HF and EMPEROR-Reduced) have recently highlighted the important impact of SGLT2 inhibitors in patients with HF and a reduced ejection fraction (HFrEF), with significant outcome benefits on HF hospitalisations and cardiovascular mortality, and similar effects in patients with and without T2DM. These benefits were observed on top of excellent background HF therapy, and there were no treatment interactions between SGLT2 inhibitors and background HF therapy. There were no increases in adverse events of interest in the SGLT2 inhibitor arm, including volume depletion, adverse renal events, hypoglycemia, amputation, and ketoacidosis, demonstrating the favourable safety profile of this treatment in HFrEF. Approximately 40%-50% of patients with HFrEF have chronic kidney disease (CKD), and the recently reported results of the DAPA-CKD trial indicate that dapagliflozin can prevent renal and cardiovascular outcomes in patients with established CKD, whether diabetes is present or not. Although the mechanisms of action of SGLT2 inhibitors are not fully understood, the hypotheses that have been proposed for their HF outcome benefits include a reduction of preload via osmotic diuresis, lowering of afterload, reduction in myocardial mass, alteration of myocardial energy substrate toward a more efficient glucose metabolism, modulation of renal sympathetic afferent tone, and increased erythropoiesis. We here present a summary of the evidence as well as a practical perspective on prescribing SGLT2 inhibitors in patients with HFrEF, with or without diabetes.     

Impact of empagliflozin in patients with diabetes and heart failure

Heart failure (HF) is a common disease with increased risk for mortality and morbidity among patients with type 2 diabetes mellitus (T2DM). Optimal glycemic control in this patient population is challenging as many available therapies can potentially exacerbate symptoms of HF. Empagliflozin is one in a novel class of agents, the sodium glucose co-transporter 2 (SGLT2) inhibitors, that lowers blood glucose by increasing urinary glucose excretion and improves glycemic control and lowers body weight and blood pressure. In the recent EMPA-REG OUTCOME trial, empagliflozin was shown to improve cardiovascular outcomes in patients with T2DM and established cardiovascular risk where it reduced HF hospitalizations and cardiovascular death, with a consistent benefit among patients both with and without baseline HF. Here, we review the empagliflozin data on HF outcomes and discuss potential mechanisms for its benefits in HF with a focus on the potentially significant impact that empagliflozin may have on the care of patients with T2DM and HF in the future.     

Revitalization of pioglitazone: the optimum agent to be combined with a sodium‐glucose co‐transporter‐2 inhibitor

The recently completed EMPA‐REG study showed that empagliflozin significantly decreased the major adverse cardiac events (MACE) endpoint, which comprised cardiovascular death, non‐fatal myocardial infarction (MI) and stroke, in patients with high‐risk type 2 diabetes (T2DM), primarily through a reduction in cardiovascular death, without a significant decrease in either MI or stroke. In the PROactive study, pioglitazone decreased the MACE endpoint by a similar degree to that observed in the EMPA‐REG study, through a marked reduction in both recurrent MI and stroke and a modest reduction in cardiovascular death. These observations suggest that pioglitazone might be an ideal agent to combine with empagliflozin to further reduce cardiovascular events in patients with high‐risk diabetes as empagliflozin also promotes salt/water loss and would be expected to offset any fluid retention associated with pioglitazone therapy. In the present paper, we provide an overview of the potential benefits of combined pioglitazone/empagliflozin therapy to prevent cardiovascular events in patients with T2DM.     

Novel antidiabetic medications for non‐alcoholic fatty liver disease with type 2 diabetes mellitus

Liver‐related diseases are the leading causes of death in patients with type 2 diabetes mellitus (T2DM) in Japan. Type 2 diabetes mellitus is closely associated with non‐alcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Non‐alcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma and hepatic failure. Non‐alcoholic steatohepatitis can be called “diabetic hepatopathy”. There are no established pharmacotherapies for NAFLD/NASH patients with T2DM. Although metformin is established as the first‐line therapy for T2DM, given its relative safety and beneficial effects on glycosylated hemoglobin, weight, and cardiovascular mortality, this agent is not recommended as specific therapy for NASH/NAFLD due to lack of clinical evidence. The effects of pioglitazone on NASH histology with T2DM have been extensively proved, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. In recent years, novel antidiabetic medications have been approved for T2DM, such as glucagon‐like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium/glucose cotransporter 2 inhibitors. A key clinical question for hepatologists is what kinds of antidiabetic medications are the most appropriate for the treatment of NAFLD accompanied by T2DM, to prevent progression of hepatic fibrosis resulting in HCC/liver‐related mortality without increased risk of cardiovascular events. This review focuses on novel antidiabetic agents and future perspectives on the treatment of NAFLD/NASH with T2DM.     

Metabolic surgery for the treatment of type 2 diabetes in patients with BMI lower than 35 kg/m2: Why caution is still needed

Bariatric surgery has shifted from being a risky procedure to an evidence‐based one, with proven benefits on all‐cause mortality, cardiovascular disease, cancer, and diabetes control. The procedure has an overall positive result on type 2 diabetes mellitus (T2DM), with a substantial number of patients achieving disease remission. This has resulted in several studies assessing possible weight‐independent effects of bariatric surgery on glycemic improvement, in addition to recommendation of the procedure to patients with class 1 obesity and T2DM, for whom the procedure was classically not indicated, and adoption of a new term, “metabolic surgery,” to highlight the overall metabolic benefit of the procedure beyond weight loss. Recently, the Diabetes Surgery Summit (DSS) has included metabolic surgery in its T2DM treatment algorithm. Although the discussion brought by this consensus is highly relevant, the recommendation of metabolic surgery for patients with uncontrolled T2DM and a body mass index of 30 to 35 kg/m² still lacks enough evidence. This article provides an overall view of the metabolic benefits of bariatric/metabolic surgery in patients with class 1 obesity, compares the procedure against clinical treatment, and presents our rationale for defending caution on recommending the procedure to less obese individuals.     

Effect of intensive blood pressure control in patients with type 2 diabetes mellitus over 9 years of follow‐up: A subgroup analysis of high‐risk ACCORDION trial participants

Although guidelines recommend strict blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) and elevated cardiovascular risk, the long‐term effects of this approach are unknown. We investigated the effect of intensive BP control on clinical outcomes in patients with T2DM over 9 years of follow‐up. We included Action to Control Cardiovascular Risk in Diabetes ‐ Blood Pressure participants in the standard glucose control arm who had established cardiovascular disease, chronic kidney disease, were ≥75 years of age or who had a 10‐year coronary heart risk ≥15%. Participants were randomized to either intensive (systolic BP < 120 mm Hg) or standard (systolic BP < 140 mm Hg) BP control for an average of 5 years. Observational follow‐up occurred for an average of 4 years thereafter. After an average total follow‐up of 9 years, intensive BP control reduced the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke by 25% (hazard ratio, 0.75; 95% confidence interval, 0.60‐0.95; P = .02). The overall benefit was driven by a reduction in nonfatal myocardial infarction (P = .01). In this post‐hoc analysis, the benefits of a fixed‐duration intensive BP control intervention in patients with T2DM persisted throughout 9 years of follow‐up.     

Diabetes and obesity: therapeutic targeting and risk reduction – a complex interplay

Obesity is a major risk factor for the development of diabetes and predisposes individuals to hypertension and dyslipidaemia. Together these pathologies increase the risk for cardiovascular disease (CVD), the major cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). Worsening trends in obesity and T2DM raise a serious conundrum, namely, how to control blood glucose, blood pressure, and lipids when many antidiabetic agents cause weight gain and thereby exacerbate other cardiovascular risk factors associated with T2DM. Further, evidence suggests that some established antihypertensive agents may worsen glucose intolerance. Many patients who are obese, hypertensive, and/or hyperlipidaemic fail to achieve blood pressure, lipid and glycaemic goals, and this failure may in part be explained by physician reluctance to utilize complex combination regimens for fear of off‐target effects. Thus, a clear need exists for clinicians to understand the risks and benefits of different pharmacologic, and indeed non‐pharmacologic, options in order to maximize treatment outcomes. While intensive lifestyle modification remains an elusive gold standard, newer diabetes targets, including the incretin axis, may offer greater cardiovascular risk reduction than other antidiabetes therapies, although definitive clinical trial data are needed. The glucagon‐like peptide‐1 (GLP‐1) receptor agonists exenatide and liraglutide and the dipeptidyl peptidase‐4 (DPP‐4) inhibitors sitagliptin and vildagliptin effectively lower HbA1c; exenatide and liraglutide reduce weight and blood pressure and improve lipid profiles. Sitagliptin and vildagliptin are weight neutral but also appear to improve lipid profiles. Integration of incretin therapies into the therapeutic armamentarium is a promising approach to improving outcomes in T2DM, and perhaps even in reducing complications of T2DM, such as co‐morbid hypertension and dyslipidaemia. Additional long‐term studies, including CVD end‐point studies, will be necessary to determine the appropriate places for incretin‐based therapies in treatment algorithms.     

Management of heart failure and type 2 diabetes mellitus: Maximizing complementary drug therapy

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease and occurs in ~25% of patients with heart failure (HF). Patients with co-morbid HF and T2DM are at elevated risk of adverse outcomes, making optimization of complementary drug therapies essential. While research is ongoing, recent advances in drug therapy, including the introduction of sacubitril/valsartan for HF with reduced ejection fraction and the finding of positive cardiovascular effects of glucose-lowering agents (particularly sodium-glucose co-transporter-2 [SGLT2] inhibitors) have the potential to transform pharmacologic management of co-morbid HF and T2DM. In this review, we provide a comprehensive overview of cardiovascular clinical trials of therapies for HF and diabetes mellitus to date and identify areas requiring further investigation. We also discuss the pathophysiologic overlap of the two diseases and explore the complementary therapeutic effects of HF and T2DM drugs, with a particular focus on sacubitril/valsartan and SGLT2 inhibitors.     

The emerging role of novel antihyperglycemic agents in the treatment of heart failure and diabetes: A focus on cardiorenal outcomes

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two global pandemics, affecting over 25 and 420 million people, respectively. The prevalence of comorbid HF and T2DM is rising, and the prognosis remains poor. One central area of overlap of these two disease processes is renal dysfunction, which contributes to poor cardiovascular outcomes and mortality. As such, there is a growing need for antihyperglycemic agents with cardio‐ and renoprotective effects. Three classes of novel antihyperglycemic agents, sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), and dipeptidyl peptidase‐4 (DPP4) inhibitors have demonstrated varied cardiorenal outcomes in recent cardiovascular outcomes trials. Understanding the differential effects of these agents, together with their proposed mechanisms, is crucial for the development of safe and effective treatment regimens and future pharmacologic targets for HF and T2DM. In this review, we discuss the overlapping pathophysiology of HF and T2DM, summarize outcomes data for the novel antihyperglycemic agents and proposed mechanisms of action, and review how the current evidence informs future management of comorbid HF and T2DM.     

Risk stratification tools for heart failure in the diabetes clinic

The advent of Sodium Glucose Transporter 2-inhibitors (SGLT2-i) in recent years gave endocrinologists the opportunity to actively treat and prevent heart failure (HF) in patients with type 2 diabetes (T2DM). While the relationship between T2DM and HF has been extensively reviewed, previous works focused mostly on epidemiology, pathophysiology and treatment of HF in T2DM.The aim of our work was to aid health care professionals in identifying individuals at high risk for this dreadful complication. Recent guidelines recommend to use drugs with proven cardiovascular benefits (Glucagon-like peptide-1 receptor agonists (GLP1-RA) and SGLT2-i) in patients with previous cardiovascular disease (CVD) and to prefer SGLT2-i in patients with known HF. In everyday clinical practice, the choice between these two drug classes in patients without known HF or atherosclerotic CVD is mostly arbitrary and based on the side effect profile.Recently, risk stratification tools to estimate HF incidence have been developed in order to guide treatment with a view to bring precision medicine into diabetes care. With this purpose, we provide a review of the tools able to predict HF incidence for patients in primary CVD prevention as well as risk of future hospitalizations for patients with known HF.     

Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials

BackgroundTo investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.MethodsElectronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).ResultsA total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72–0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62–0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76–0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77–0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86–0.93).ConclusionsCompared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.     

Surgical treatment of type 2 diabetes: the surgeon perspective

Type 2 diabetes mellitus (T2DM) is a major health priority globally, having achieved pandemic status in the twenty-first century. Several gastrointestinal procedures that were primarily designed to treat morbid obesity result in dramatic remission of diabetes. Studies in experimental rodent models and humans have shown that the glycemic benefits of surgery are at least in part weight-independent and extend to non-morbidly obese subjects with T2DM. Bariatric procedures differ in their ability to ameliorate type 2 diabetes, with intestinal bypass procedures being more effective than purely restrictive procedures. Several studies have demonstrated that the benefits of bariatric surgery extend beyond amelioration of hyperglycemia and include improvement in other cardiovascular risk factors such as dyslipidemia and hypertension. The safety and cost-effectiveness of bariatric surgery are also well established by several studies. In this paper, the authors present the surgeon perspective on the management of type 2 diabetes focusing on the efficacy, safety and cost-effectiveness of metabolic surgery. The available evidence warrants the inclusion of metabolic surgery in the treatment algorithm of type 2 diabetes.     

Effects of sodium glucose cotransporter type 2 inhibitors on heart failure

Heart failure (HF) is emerging as one of the most common cardiovascular (CV) events in patients with type 2 diabetes (T2D), and the one associated with the worst prognosis. T2D and insulin resistance are strong predictors of incident HF, especially HF with preserved ejection fraction (HFpEF). Recent data suggest that even when all traditional risk factors for ASCVD are well controlled, patients with T2D continue to have a substantially greater risk of developing HF—indicating that traditional risk factor control is insufficient from a HF prevention standpoint, and highlighting the need for novel, more effective strategies for both prevention and treatment of heart failure in patients with T2D. Until recently, medications developed for glucose-lowering had, at best, neutral effect on heart failure outcomes in patients with T2D, while several classes of T2D medications had little data in regards to HF risk, and others actually increased the risk of HF hospitalization. Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) have a novel and unique mechanism of action. By inhibiting sodium and glucose reabsorption in the proximal tubule, SGLT-2i result in a number of downstream effects, including glucosuria, weight loss, osmotic diuresis and natriuresis, which should theoretically be beneficial in HF. Three CVOTs of various SGLT-2i (EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58) enrolled markedly different patient populations in terms of ASCVD risk, but have demonstrated robust and consistent benefits in reduction of hospitalization for HF. In a meta-analysis of the three outcomes trials, SGLT-2i significantly reduced the risk of cardiovascular death or hospitalization for HF by 23% and hospitalization for HF by 31%. Although the declines in HF hospitalization with SGLT-2is are impressive, only a small proportion of patients with established HF were enrolled in these trials, and these benefits, therefore, represent primarily a HF prevention signal. Whether this prevention of HF benefit will translate to better outcomes for those patients with established HF (with or without diabetes), and whether it will extend across the spectrum of HF phenotypes (HFrEF and HFpEF) is yet to be determined, and is being actively investigated in several large ongoing trials.     

Use of sodium–glucose co‐transporter‐2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure

Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with recent reports indicating that HF with preserved ejection fraction (HFpEF) may be more common than HF with reduced ejection fraction (HFrEF) in patients with T2D. T2D and HF result in worse outcomes than either disease alone. Sodium–glucose co‐transporter‐2 inhibitors (SGLT‐2is) have significantly improved HF outcomes in patients with T2D and may represent a new therapeutic alternative for patients with T2D at risk for or with HF. Current guidelines recommend prevention of HF through risk factor management. Once developed, treatment of HFrEF should include neurohormonal and haemodynamic modulations; however, there are no specific treatments available for HFpEF. SGLT‐2is are the first class of glucose‐lowering therapy to prevent HF in clinical trials and real‐world studies in patients with T2D (with or without established cardiovascular disease and with or without baseline HF). Mechanistic studies suggest that SGLT‐2is have beneficial effects on both systolic and diastolic function and additional systemic effects that could benefit HF outcomes. In patients with HFrEF, SGLT‐2i treatment as add‐on to standard HF therapy has had beneficial effects on HF outcomes, irrespective of T2D status. These results and those of ongoing outcomes trials with SGLT‐2is may help establish this drug class as a treatment for HF in patients with HFrEF and HFpEF, as well as HF in patients without T2D.     

GLP‐1 Receptor Agonists: Effects on Cardiovascular Risk Reduction

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease‐related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) liraglutide and exenatide are incretin‐based antidiabetes agents. This review examines CV‐associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP‐1 RAs in reducing hyperglycemia. Further, GLP‐1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.