New Perspectives in Management of Cardiovascular Risk Among People With Diabetes

Abstract

Following the publication of results from multiple landmark cardiovascular outcome trials of antihyperglycemic medications over the past 8 years, there has been a major shift in the focus of care for people with type 2 diabetes, from control of hyperglycemia to managing cardiovascular risk. Multiple international cardiology and diabetes society guidelines and recommendations now endorse sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like protein‐1 receptor agonists as first‐line therapies to mitigate cardiovascular risk. The most recent publication is the 2023 European Society of Cardiology guideline on the management of cardiovascular disease in those with type 2 diabetes that, for the first time, recommends use of both classes of medications for the mitigation of cardiovascular risk for those with or at high risk for atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. Here, we review the evidence behind contemporary society guidelines and recommendations for the management of type 2 diabetes and cardiovascular risk.

Nonstandard Abbreviations and Acronyms

ESC

European Society of Cardiology

GLP‐1 RA

glucagon‐like protein‐1 receptor agonist

SGTL2i

sodium‐glucose cotransporter‐2 inhibitor

T2D

type 2 diabetes

The clinical management of people with type 2 diabetes (T2D) has evolved substantially over the past decade. There has been increasing attention to the management of cardiovascular disease (CVD) risk associated with T2D, moving the focus beyond glycemic control to treatments buttressed by randomized clinical trial evidence robustly demonstrating the safety and efficacy of cardiometabolic medications on CVD outcomes. Results from multiple large‐scale randomized trials designed specifically to address the cardiovascular safety and efficacy of novel antihyperglycemic medications have demonstrated the incremental cardiovascular efficacy of selected sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) and glucagon‐like protein‐1 receptor agonists (GLP‐1 RAs), leading to product‐labeled indications for cardiovascular risk reduction for 3 SGLT2is (empagliflozin, canagliflozin, and dapagliflozin) and 3 GLP‐1 RAs (liraglutide, dulaglutide, and injectable semaglutide) in the United States and most countries around the world. ¹ , ² In addition, results from trials of the nonsteroidal mineralocorticoid receptor agonist finerenone have also demonstrated efficacy on cardiovascular and kidney outcomes in people with T2D and diabetic kidney disease. ³ , ⁴ , ⁵

The 2023 European Society of Cardiology (ESC) guidelines for the management of CVD in patients with diabetes provide updated recommendations for the management of people with T2D with a focus on cardiovascular risk mitigation. ⁶ By conceptualizing T2D and CVD as overlapping phenotypes (ie, T2D and atherosclerotic cardiovascular disease [ASCVD], T2D and heart failure [HF], and T2D and chronic kidney disease [CKD]), here we review the evidence for the management of CVD risk in people with T2D and updates from major society guidelines (Table 1).

Table 1.

Updates in Management of Diabetes and CVD Risk

Select updated recommendations for people with type 2 Diabetes to Mitigate CVD Risk
Recommend Systematic Coronary Risk Evaluation‐2 Diabetes score to classify 10‐year risk of ASCVD
Regularly measure blood pressure to detect and treat hypertension
Recommend prescription of SGLT2is and glucagon‐like‐peptide‐1 receptor agonists if clinical ASCVD or high risk for ASCVD is present
Recommend prescription of SGLT2i for people with HF across all ranges of ejection fraction
Recommend SGLT2i and finerenone in people with diabetes and CKD
Screen for atrial fibrillation via ECG or palpation in those with diabetes
Routinely screen for complications of diabetes, including ASCVD, CKD, and HF

ASCVD indicates atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitor.

Definitions and Risk Stratification

Following the diagnosis of T2D, further assessment of risk for micro‐ and macrovascular complications through evaluation of ASCVD risk and disease and target organ damage (eg, reduced estimated glomerular filtration rate [eGFR], micro‐ or macroalbuminuria, diabetic retinopathy, left ventricular hypertrophy, etc) is essential to inform clinical decision‐making. The American Diabetes Association society professional recommendations endorse using the American College of Cardiology/American Heart Association ASCVD pooled cohort risk calculator to estimate the 10‐year risk among adults with T2D but with the noted limitation that this risk calculator is not specific to people with T2D. ⁷ The 2022 American Heart Association statement on CVD risk and T2D highlights that coronary artery calcium score may sufficiently add to the classification of CVD risk among people with T2D to inform an actionable trigger for prescription of a statin, inform the low‐density lipoprotein cholesterol target, and decide whether or not to prescribe aspirin for high‐risk primary prevention in people with T2D. ⁷ , ⁸

The 2023 ESC guidelines classify risk using the categories of low, moderate, high, and very high CVD risk based on the presence of established ASCVD, target organ damage, and the Systematic Coronary Risk Evaluation 2‐Diabetes algorithm/model that was developed in conjunction with and by members of the ESC Task Force for the 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. The Systematic Coronary Risk Evaluation 2‐Diabetes model considers regional variation of CVD risk across each of the European countries, with uncertain accuracy of application of the model beyond the European Union. ⁹ As it is contemporary and specific to people with T2D, despite uncertain accuracy of risk estimation across non‐European populations, this seems to be the most useful cardiovascular risk model available, and it is accessible online at https://www.escardio.org/Education/ESC‐Prevention‐of‐CVD‐Programme/Risk‐assessment/esc‐cvd‐risk‐calculation‐app.

Diabetes and ASCVD

A diagnosis of T2D has implications for recommendations for several ASCVD risk‐mitigating therapies, including high‐intensity statin therapy and nonstatin low‐density lipoprotein cholesterol‐lowering therapy with more aggressive low‐density lipoprotein cholesterol targets compared with people without T2D; the use of angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker independent of blood pressure consideration; and consideration for a more aggressive systolic blood pressure target versus the population without T2D. SGLT2is and GLP‐1 RAs should now be considered extensions of these essential therapies in people with T2D with or at high risk for ASCVD. ⁶

Aside from counseling on healthy lifestyle, including recommendations for systematic engagement of physical activity for health, focus on a healthy diet, weight management, and smoking abstinence, the ESC guidelines recommend the prescription of both an SGTL2i and a GLP‐1 RA to achieve cardiovascular risk reduction in people with T2D with or at high risk for ASCVD based on an abundance of data from randomized controlled trials. ⁶ A meta‐analysis of 6 randomized controlled trials that studied the cardiovascular safety and efficacy of SGLT2is in people with T2D with or at high‐risk for ASCVD demonstrated a reduction in the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR], 0.90 [95% CI, 0.85–0.95]). ² A separate Cochrane Database meta‐analysis demonstrated that SGLT2is reduce the risk of cardiovascular mortality (odds ratio [OR], 0.92 [95% CI, 0.70–0.95], “moderate certainty” evidence), reduce all‐cause mortality (OR, 0.84 [95% CI, 0.74–0.96], “moderate certainty” evidence), and reduce the risk of HF hospitalization (OR, 0.65 [95% CI, 0.59–0.71], “high certainty” evidence). However, this meta‐analysis showed that SGLT2is do not reduce the risk of MI (OR, 0.97 [95% CI, 0.84–1.12], “high certainty” evidence). ¹⁰ Last, a meta‐analysis of 13 studies of 32 949 patients showed that SGLT2is led to a risk reduction in both major adverse cardiovascular events (risk ratio [RR], 0.85 [95% CI, 0.75–0.96]) and kidney events (RR, 0.68 [0.59–0.78]). ¹¹

Similarly, multiple meta‐analyses have been published examining outcomes of GLP‐1 RAs in individuals with T2D. A meta‐analysis of the results of 8 randomized placebo‐controlled cardiovascular outcome trials in people with T2D with or at high risk of ASCVD evaluating GLP‐1 RAs versus placebo showed reduction in the composite outcome of cardiovascular death, MI, and stroke (HR, 0.86 [95% CI, 0.80–0.93]). ¹ A Cochrane Database meta‐analysis showed that GLP‐1 RAs reduce the risk of cardiovascular mortality (OR, 0.87 [95% CI, 0.79–0.95], “high certainty” evidence), all‐cause mortality (OR, 0.88 [95% CI, 0.82–0.95], “high‐certainty” evidence), and stroke (OR, 0.87 [95% CI, 0.77–0.98], “high certainty” evidence). However, the meta‐analysis showed GLP‐1 RAs probably do not reduce the risk of MI (OR, 0.89 [95% CI, 0.78–1.01], “moderate certainty” evidence) or hospitalization for HF (OR, 0.95 [95% CI, 0.85–1.06], “high certainty” evidence). ¹⁰ Of note, a separate meta‐analysis showed that GLP‐1 RAs did not reduce cardiovascular events (RR, 0.91 [95% CI, 0.80–1.04]) or renal events (RR, 0.86 [95% CI, 0.72–1.03]). ¹¹ Notably, only the first meta‐analysis included the AMPLITUDE‐O (Effect of Efpeglenatide on Cardiovascular Outcomes) trial, published in 2021, which examined the use of the GLP‐1 RA efpeglenatide in 4076 patients and demonstrated a reduction in major adverse cardiovascular events (HR, 0.73 [95% CI, 0.58–0.92]) and the kidney outcome of a decrease in kidney function or macroalbuminuria (HR, 0.68 [95% CI, 0.57–0.79]). ¹²

Empagliflozin and canagliflozin improve ASCVD‐based composite outcomes, and dapagliflozin and ertugliflozin do not. The prescription of evidence‐based SGLT2is has a class I recommendation in the 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes to reduce cardiovascular events in people with T2D with or at high risk for ASCVD, independent of baseline or target hemoglobin A1c (HbA1c), and independent of all background antihyperglycemic medications. ⁶ Similarly, GLP‐1 RAs with proven cardiovascular benefit (liraglutide, injectable semaglutide, and dulaglutide) are now recommended in people with T2D with or at high risk for ASCVD to reduce the risk for ASCVD‐related outcomes, independent of target HbA1c (class 1 recommendation in ESC guidelines and level A in American Diabetes Association recommendations). ⁶ , ⁷

Although the 2023 American Diabetes Association and ESC recommendations are mostly similar with regard to use of SGLT2is and GLP‐1 RAs, notably, the ESC guidelines recommend use of both agents as a level 1A recommendation for people with T2D with or at risk for ASCVD independent of HbA1c and independent of background metformin use. ⁶ The use of SGLT2is and GLP‐1 RAs should be considered independently, much like clinical decision‐making is applied with regard to prescribing each of the 4 pillar therapies of guideline‐directed medical therapy for HF with reduced ejection fraction.

SGLT2is and GLP‐1 RAs have been shown to affect outcomes outside of 3‐point major adverse cardiovascular events, HF, and kidney outcomes. A cohort study of >3 million patients with T2D showed that SGLT2i use was associated with a lower incidence of diabetic retinopathy than dipeptidyl peptidase‐4 inhibitors, pioglitazone, and sulfonylurea use. ¹³ A meta‐analysis of trials reporting diabetic retinopathy outcomes showed that the incidence of diabetic retinopathy did not differ between SGLT2i and non‐SGLT2i users (OR, 0.80 [95% CI, 0.61–1.06]). However, among those with T2D duration <10 years, those who used SGLT2is had less incidence of diabetic retinopathy compared with nonusers (OR, 0.32 [95% CI, 0.13–0.76]). ¹⁴

Though long‐term glycemic control reduces the risk of diabetic retinopathy, acute glucose control intensification starting in the setting of marked hyperglycemia can worsen the risk of diabetic retinopathy, a phenomenon known as “early worsening” known to occur with insulin use for decades. In SUSTAIN‐6 (Trial to Evaluate Cardiovascular and Other Long‐Term Outcomes With Semaglutide in Subjects with Type 2 Diabetes), rates of retinopathy complications, including vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation, were higher in the treatment arm (HR, 1.76 [95% CI, 1.11–2.78]). ¹⁵ A meta‐analysis of clinical trials of GLP‐1 RAs showed that GLP‐1 RA use was significantly associated with increased risk of early‐stage diabetic retinopathy (RR, 1.31 [95% CI, 1.01–1.68]); however, analysis of individual trials showed that albiglutide was primarily responsible for this trend. ¹⁶ A separate meta‐analysis of 6 cardiovascular outcome trials studying GLP‐1 RAs showed no association between GLP‐1 RA treatment and retinopathy (OR, 1.10 [95% CI, 0.93–1.30]). ¹⁷ However, there was an association between retinopathy risk and average HbA1c reduction. The median follow‐up across studies was 3.4 years, and longer‐term follow‐up is needed to assess the impact of GLP‐1 RA therapy on retinopathy outcomes. ¹⁷

Diabetes and Heart Failure

Diabetes is associated with a 2 to 5 times higher risk of HF versus those without T2D, including both HF with reduced and preserved ejection fraction. ¹⁸ , ¹⁹ People without any signs or symptoms of HF but with T2D or selected other risk factors for HF are classified as Stage A HF (“at risk”); and those without signs or symptoms of HF but with evidence of structural heart disease, elevated natriuretic peptide, or elevated cardiac troponin level are classified as Stage B HF (“pre‐HF”). ⁶ Routine and iterative systematic screening for and identification of HF signs and symptoms in clinical encounters with people with T2D is essential to identify those at highest risk for or with preclinical HF.

In the 2023 ESC guidelines for diabetes and CVD risk, SGLT2is have a class IA recommendation for use in people with prevalent HF across the spectrum of ejection fraction, in harmony with the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines recommending the same independent of T2D status. ⁶ , ⁸ In people with HF with reduced ejection fraction, these recommendations are supported by the results of 2 large‐scale randomized trials that examined the effects of dapagliflozin and empagliflozin versus placebo among people with HF with reduced ejection fraction with or without T2D. A meta‐analysis of these trials demonstrated a 13% reduction in all‐cause death (pooled HR, 0.87 [95% CI, 0.77–0.98]) and a 14% reduction in cardiovascular death (pooled HR, 0.86 [95% CI, 0.76–0.98]), regardless of T2D diagnosis. ²⁰ Furthermore, SGTL2is reduced the risk of HF hospitalizations and the kidney composite outcome of a sustained 50% or greater decline in eGFR, end‐stage kidney disease defined by initiation of kidney replacement therapy or kidney transplant, or kidney‐related death.

The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial studied people with ejection fraction >40% with and without T2D and found an 18% reduction in the primary composite outcome of HF hospitalization, urgent visit for HF, or cardiovascular death (HR, 0.82 [95% CI, 0.73–0.92]) for dapagliflozin compared with placebo. ²¹ The EMPEROR‐PRESERVED (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) trial similarly found a 21% reduction in the primary outcome (HR, 0.79 [95% CI, 0.69–0.90]) with use of empagliflozin compared with placebo. ²² Notably, in both trials, the effects were consistent regardless of the presence or absence of T2D.

Two trials have assessed the use of SGLT2is in the setting of acutely worsened/decompensated HF. Based on the results of the SOLOIST‐WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) trial, which showed that sotaglifozin versus placebo reduced the risk for the primary outcome of cardiovascular death or HF hospitalization (HR, 0.67 [95% CI, 0.52–0.85]) when used during or just after hospitalization for HF, independent of HF cause or presence or absence of T2D, the use of sotaglifozin is recommended in the 2023 ESC guidelines for people with T2D and acute worsening/hospitalization for HF. ⁶ , ²³ Notably, the results of this trial also demonstrated the safety of initiating SGLT inhibition during or soon after an episode of acute decompensated HF, with findings supported by results of the EMPULSE (A Multicentre, Randomised, Double‐Blind, 90‐Day Superiority Trial to Evaluate the Effect on Clinical Benefit, Safety and Tolerability of Once Daily Oral Empagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for Acute Heart Failure [de Novo or Decompensated Chronic HF] Who Have Been Stabilised) trial that evaluated empagliflozin versus placebo in patients hospitalized for HF. ²⁴

Diabetes and Chronic Kidney Disease

Approximately 30% to 40% of individuals with T2D will develop CKD. ²⁵ Screening for CKD in individuals with T2D has a class I indication in the 2023 ESC guidelines and the 2022 Kidney Disease Improving Global Outcomes guidelines: routine screening using eGFR as calculated by the CKD‐Epidemiology Collaboration formula as well as urine albumin to creatinine ratio testing is recommended. ⁶ , ²⁶

The aforementioned kidney‐protective effects of SGTL2is support a class I indication in the ESC guidelines for those with CKD (eGFR <60 mL/min per 1.73 m² or albuminuria >30 mg/g) and eGFR >20 mL/min per 1.73 m², ⁶ , ²⁷ concordant with the 2022 Kidney Disease Improving Global Outcomes Guidelines recommendations. SGTL2is should be used in combination with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers and finerenone as the contemporary 3 pillars of evidence‐based kidney‐protective therapies in individuals with T2D and CKD. ²⁶ Additionally, GLP‐1 RAs have a class Ia recommendation to achieve adequate glycemic control in individuals with eGFR >15 mL/min per 1.73 m². ⁶ The FLOW (Effect of Semaglutide Versus Placebo on the Progression of Renal Impairment in Subjects With Type 2 Diabetes and Chronic Kidney Disease) trial compared injectable semaglutide 1.0 mg with placebo and assessed prevention of progression of renal impairment and risk of renal and cardiovascular mortality in individuals with T2D and CKD. ²⁸ Based on an interim analysis, the trial was stopped early; however, full outcomes data on kidney outcomes and impact on renal impairment are pending. ²⁸

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist. Results from 2 cardiovascular and kidney outcomes trials studying finerenone versus placebo were pooled for analyses in the FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO‐DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease] and FIGARO‐DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]) Trial Program Analysis. ³ , ⁴ , ⁵ In each trial with consistency of efficacy confirmed by meta‐analyses, finerenone reduced the risk for the composite outcome of cardiovascular death, MI, stroke, or HF hospitalization and the risk of the kidney composite outcome of decline in eGFR, kidney failure, or death from kidney failure. Based on these data, finerenone has US product‐labeled indications to reduce risk of cardiovascular disease and of CKD progression in adult patients with CKD associated with T2D—with no mention of severity of CKD or presence or absence of albuminuria. Finerenone has a class I recommendation in the 2023 ESC guidelines and a level A recommendation in the American Diabetes Association Standards of Medical Care recommendations to be used in addition to an angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker/SGTL2i in those with eGFR >60 mL/min per 1.73 m² with a urine albumin to creatinine ratio ≥300 mg/g, or eGFR 25 to 60 mL/min per 1.73 m² and ≥30 mg/g for people with T2D. ⁶ , ⁷ This mirrors a recommendation from the 2022 Kidney Disease Improving Global Outcomes guideline to add a nonsteroidal mineralocorticoid antagonist (finerenone) if urine albumin to creatinine ratio is ≥30 mg/g with normal potassium levels. ²⁶

Pharmacology of SGLT2is and GLP‐1 RAs

SGLT2is and GLP‐1 RAs have unique mechanisms of action that have been hypothesized to underly their cardioprotective benefits. There are 2 main SGLTs: SGLT1 and SGLT2. SGLT1 is found in the gastrointestinal tract and SGLT2 is found uniquely in renal tissue. SGLT2is block glucose reabsorption from the urine filtrate in the proximal convoluted tubule, leading to glucosuria. Dapaglifozin, empaglifozin, and canaglifozin inhibit SGLT2, whereas sotaglifozin inhibits glucose reabsorption at both SGLT2 in the kidney and SGLT1 in the gastrointestinal tract. However, the cardioprotective and kidney‐protective effects of SGLT2is have been hypothesized to be independent of the glucose‐lowering effect. In the EMPA‐REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) trial, the effects of empaglifozin on cardiovascular risk were independent of baseline HbA1c and reduction in HbA1c level. ²⁹ , ³⁰ Aside from glycemic control, SGLT2is lead to reductions in body mass index, systemic blood pressure, and circulating blood volume among myriad other effects that may contribute to their benefits on atherosclerotic, HF, and kidney outcomes. ³¹ , ³² By decreasing intravascular volume by increasing glucosuria and natriuresis, SGLT2is have been hypothesized to improve hemodynamics and myocardial energy supply and reduce sympathetic tone to the heart. ³³ , ³⁴ , ³⁵

GLP‐1 is an incretin released from specialized neuroendocrine mucosal cells, the L‐cells, in the colon and ileum after meals. GLP‐1 RAs activate the GLP‐1 receptor and lead to increased glucose‐dependent insulin secretion from beta cells in the pancreas and delay gastric emptying, leading to earlier satiety. Additionally, GLP‐1 RAs suppress pancreatic alpha cells, leading to reduced glucagon secretion and decreased liver glucose production. ³⁶ Multiple direct and indirect actions of GLP‐1 RAs underpin their cardiovascular benefits. By acting centrally at the nervous system, they may act on the dopamine reward system and reduce appetite and cravings. By reducing hepatic steatosis, they may also lead to improvements in circulating lipid profiles. ³⁷ At the level of the blood vessels, they improve blood flow and reduce atherosclerosis. By directly acting on pancreatic islet cells, gastric emptying, and the central nervous system, GLP‐1 RAs improve glucose homeostasis, decrease blood pressure, and decrease inflammation. ³⁷

Beyond Diabetes

The cardioprotective and kidney‐protective effects of SGLT2is have been demonstrated to be independent of glycemic control, raising the question of their benefits in individuals without T2D. Dapagliflozin and empagliflozin have each demonstrated efficacy for the treatment of people with HF and treatment of CKD independent of diabetes status, leading to product‐labeled indications for their use in such patients; sotagliflozin is also indicated for the treatment of HF independent of diabetes status. ²¹ , ²² , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ As such, multiple guidelines, including guidelines on chronic coronary disease, CKD, and HF, recommend use of SGLT2is independent of T2D status. ⁸ , ⁴² A meta‐analysis of SGLT2i trials and HF and kidney outcomes using patient‐level data showed similar risk reduction in CKD progression, HF hospitalization, and cardiovascular death in patients with and without T2D. ⁴³ The meta‐analysis demonstrated no risk reduction in noncardiovascular death in both patients with and without T2D. ⁴³

The Kidney Disease Improving Global Outcomes guideline emphasizes that SGLT2is should be used for patients with T2D and CKD, regardless of their glycemic status, and has moved recommendations regarding SGLT2is from their “glucose‐lowering therapies” section to “comprehensive care.” ⁴⁴

GLP‐1 RAs have been studied primarily in individuals without diabetes who have obesity. In the STEP (Semaglutide Treatment Effect in People With Obesity) trial, which enrolled individuals without T2D, semaglutide 2.4 mg weekly was associated with sustained body weight reduction. ⁴⁵ The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity) trial studied the use of semaglutide 2.4 mg compared with placebo in patients with preexisting cardiovascular disease and overweight or obesity without diabetes. Over a mean follow‐up of 39.8 months, the primary cardiovascular end point of a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke occurred in 6.5% of the semaglutide group and 8% in the placebo group (HR, 0.80 [95% CI, 0.72–0.90]). ⁴⁶ These data led to the first product‐labeled indication for semaglutide for cardiovascular risk reduction in patients with obesity and also led Medicare to announce coverage of semaglutide for individuals with body mass index >27 kg/m² with ASCVD, the first drug ever to be covered for obesity. ⁴⁷ Similarly, the STEP‐HFpEF (Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects With Obesity‐Related Heart Failure With Preserved Ejection Fraction) trial, which enrolled individuals without T2D, showed reductions in symptoms of HF, physical limitations, and weight and improvements in exercise function. ⁴⁸

Safety of SGLT2is and GLP‐1RAs

The safety profiles of SGLT2is and GLP‐1 RAs have been reported across trials, and both short‐term and long‐term adverse events have been reported in observational studies. Across 6 trials examining SGLT2is, the median follow‐up ranged from 2.4 to 4.2 years, and across 8 trials examining GLP‐1 RAs, the median follow‐up ranged from 1.3 to 5.4 years. ¹ , ² The safety of these drugs must continue to be evaluated as longer term data become available.

For SGLT2is, concerns regarding urinary and mycotic genital infections, hypoglycemia, mildly hyperglycemic diabetic ketoacidosis, and lower limb amputation have been raised. ⁴⁹ A review of urinary tract and genital tract infections and SGLT2is showed that SGLT2is do not significantly increase the risk of urinary tract infections (RR, 1.05 [95% CI, 0.98–1.12], “moderate quality” evidence); however, they are associated with increased likelihood of mycotic genital infections (RR, 3.30 [95% CI, 2.74–3.99], “moderate quality” evidence). ⁵⁰ This has been hypothesized to be due to the natriuresis and glucosuria that result from SGLT2 inhibition. Mildly hyperglycemic diabetic ketoacidosis has been reported across trials and is thought to occur due to SGLT2is leading to urinary glucose excretion that results in reduced insulin secretion and increased free fatty acid production. ⁵¹ To limit the risk of diabetic ketoacidosis, patients should maintain adequate hydration and not take the medication during illness or decreased oral intake for any reason. Education for redoubling urinary hygiene, for men and women, decreases the risk for mycotic genital infections.

The risk of lower limb amputation and SGLT2i use was raised following publication of the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program, which revealed an increased risk of lower limb amputation with use of canagliflozin (HR, 1.97 [95% CI, 1.41–2.75]), mostly at the level of the toe or metatarsal. ⁵² In the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), there were no differences in the risk of amputation in the canagliflozin and placebo groups; however, there was a protocol amendment in which investigators examined participants' feet and withheld the study drug if there was any active condition that might lead to amputation. ⁵³ However, further pooled analysis of CANVAS and CREDENCE showed no evidence that the foot disease management protocols implemented in CREDENCE ameliorated amputation risk. ⁵⁴ Meta‐analyses have shown that there is no significant association across trials between SGLTL2i use and amputation. ⁵⁵ , ⁵⁶

Safety concerns raised in studies examining GLP‐1 RAs have focused on risk of pancreatitis, gastroparesis, and biliary disease. Pooled analyses of cardiovascular outcome trials have not shown an increased risk of acute pancreatitis or pancreatic cancer with GLP‐1 RA therapy. ⁵⁷ However, there have been recent reports on increased risk of biliary disease with use of GLP‐1 RAs. An analysis of 76 randomized controlled trials showed that GLP‐1 RA therapy was associated with increased risk of gallbladder and biliary disease, including cholelithiasis and cholecystitis (RR, 1.37 [95% CI, 1.23–1.52]), in a dose‐dependent manner. ⁵⁸ This effect was associated with increased risk in trials specifically for weight loss. ⁵⁸ A separate claims database study found that use of GLP‐1 RAs for weight loss compared with use of bupropion‐naltrexone was associated with increased risk of gastroparesis and bowel obstruction but not biliary disease. ⁵⁹ Although observed only in rodents, GLP‐1 RAs were shown to increase the risk of C‐cell thyroid cancers. In an abundance of caution, GLP‐1 RAs are contraindicated in patients with a personal or family history of medullary thyroid cancer or in patients with multiple endocrine neoplasia syndrome type 2 for the same concern. ⁶⁰ Due to reported cases of reports of suicidal ideation and self‐injury among individuals using GLP‐1 RAs, the European Medicines Agency and the Food and Drug Administration have both launched reviews. A preliminary report from the Food and Drug Administration noted that there was not a clear relationship between suicidal thoughts and GLP‐1 RAs based on available trial and postmarketing data, although the agency planned to continue investigation of the possible association. ⁶¹ , ⁶² , ⁶³

Future Directions

Though SGLT2is and GLP‐1 RAs have several class I indications for cardiovascular and kidney disease risk mitigation across multiple international society guidelines and recommendations, prescriptions from cardiologists remain low, with most prescriptions at least in the United States written by internists and endocrinologists. Several barriers to uptake by cardiologists have been identified (Table 2). ⁶⁴ , ⁶⁵ Interventions to optimize the uptake of cardiovascular preventive therapies have been proposed (Table 3). For example, the COORDINATE (Coordinating Cardiology Clinics Randomized Trial of Interventions to Improve Outcomes)‐Diabetes studied the effects of clinician education and coordination of care between cardiologists, endocrinologists, and primary care clinicians. In this cluster‐randomized trial randomizing cardiology clinics to intervention versus control, the intervention arm underwent development of local interdisciplinary care pathways to address barriers for prescription of preventive therapies including SGLT2is and GLP‐1 RAs. ⁶⁶ Within the follow‐up of 12 months, the clinics receiving the implementation intervention were 23% more likely to prescribe all 3 of the evidence‐based therapies: high‐intensity statin, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and an SGTL2i or a GLP‐1 RA. ⁶⁶ Continued conceptual evolution in considering these medications from T2D/antihyperglycemic medications to cardiometabolic and cardiovascular risk‐mitigating medications remains essential in the understanding that prescription of these medications is within the scope of the cardiologist.

Table 2.

Barriers to Prescription of SGLT2is and GLP‐1 RAs

Requirement of prior authorization and high cost

Unfamiliarity with antihyperglycemic medications

Concern with introducing confusion into antihyperglycemic management for type 2 diabetes

Communication concerns between endocrinologist, cardiologist, and primary care provider

Injection phobia for GLP‐1 RAs at both patient and prescriber level

GLP‐1 RA indicates glucagon‐like‐peptide‐1 receptor agonist; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitor.

Table 3.

Potential Solutions to Barriers to Prescription of SGLT2is and GLP‐1 RAs

Dedicated pharmacy technician or clinical pharmacist support

Access to certified diabetes care/education specialists

Increased clinician education

Pathways for prior authorization and patient assistance programs

Coordination of diabetes care between specialists

Enhanced communication in the care team

GLP‐1 RA indicates glucagon‐like‐peptide‐1 receptor agonist; and SGLT2i, sodium‐glucose cotransporter‐2 inhibitor.

Sources of Funding

None.

Disclosures

Dr McGuire reports honoraria for clinical trial leadership from Novo Nordisk, Lilly USA, Pfizer, Boehringer Ingelheim, NewAmsterdam, AstraZeneca, CSL Behring, and Esperion and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Novo Nordisk, Bayer, Lexicon, Altimmune, Esperion, Intercept Pharmaceuticals, Amgen, Neurotronics Applied Therapeutics, and Merck & Co. Dr Kohli reports Speaker's Bureau/Advisory Board/Honoraria from Boston Scientific, Amarin, Esperion, Astra Zeneca, Merck, Astra Zeneca, Zoll, Boston Scientific, Esperion, Doximity (unpaid), American College of Cardiology/American Board of Internal Medicine Question Writing, Amgen, Medscape, American College of Cardiology, Agepha Pharma, Clinical Options, and Bristol‐Myers Squibb Company. The remaining authors have no disclosures to report.