Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodiumglucose cotransporter-2 (SGLT-2) inhibitors have been studied to understand the potential benefits they may have for persons with diabetes and patients without diabetes who may benefit from reductions in cardiovascular risk.
Unmanaged diabetes, defined as an A1C greater than 8%, leads to both macrovascular and microvascular damage affecting the heart and kidneys, which ultimately leads to increased morbidity and mortality. Macrovascular damage manifests as atherosclerotic cardiovascular disease (ASCVD), and microvascular damage results in retinopathy, peripheral and autonomic neuropathies, and nephropathy, which can ultimately lead to chronic kidney disease (CKD). In addition to managing blood glucose and hemoglobin A1C levels in persons with diabetes, it is just as important to consider cardiovascular (CV) and renal protection to prevent the development of these chronic conditions. Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodiumglucose cotransporter-2 (SGLT-2) inhibitors have been studied to understand the potential benefits they may have for persons with diabetes and patients without diabetes who may benefit from reductions in cardiovascular risk.
The GLP-1 RAs are a favored option for the treatment of diabetes due to their glucose control and added benefits of preserving beta-cell function, promoting weight loss, increasing insulin sensitivity, and the potential to improve adherence with once-weekly formulations.1 Along with these potential benefits, GLP-1 RAs have also been thought to have potential CV and renal benefits in patients with type 2 diabetes, which have been the subject of multiple trials.
Dulaglutide, exenatide XR, liraglutide, lixisenatide, and semaglutide are classified as GLP-1 RAs. Dulaglutide, liraglutide, and semaglutide are structurally homologous to native GLP-1. Exenatide XR and lixisenatide are both exendin-4 based GLP-1 RAs. Dulaglutide, exenatide XR, and semaglutide are administered once weekly, whereas liraglutide and lixisenatide are administered once daily.
Until recently, the main role of SGLT-2 inhibitors was in diabetes treatment. As data from clinical trials continue to emerge, its benefits in heart failure have changed the landscape of treatment in this disease state. SGLT-2 inhibitors inhibit the sodium-glucose cotransporter 2 within the kidney, which decreases glucose and sodium concentrations, possibly contributing to its beneficial CV effects. The SGLT-2 inhibitor clinical trials included in this review suggest this class of medications may provide possible renoprotective effects as well. There are many proposed mechanisms as to which SGLT-2 inhibitors provide these renoprotective effects; it is thought that the SGLT-2 inhibitors reduce the pressure within the glomerulus through this process, possibly providing those renoprotective effects. Canagliflozin, dapagliflozin, empagliflozinm and ertugliflozin are classified as SGLT-2 inhibitors.
In this article, we review the important highlights from several key clinical studies evaluating CV and renal outcomes with GLP-1 RAs and SGLT-2 inhibitors, which led to their current place in therapy as options with proven benefits in patients both with and without diabetes.
The REWIND trial2 compared dulaglutide 1.5 mg subcutaneously once weekly to placebo. The population included 9901 patients, and its purpose was to assess whether dulaglutide reduces major CV events and other serious outcomes in patients with type 2 diabetes (when added to their antihyperglycemic regimen). The primary outcome was the first occurrence of any component of the composite outcome, which comprised the following: nonfatal myocardial infarction (MI), nonfatal stroke, and death from CV causes or unknown causes. The results showed a statistically significant difference in patients taking dulaglutide compared to placebo in terms of the primary outcome. In terms of renal outcomes, results were favorable to those in the dulaglutide arm, as evidenced by fewer new cases of albuminuria and a less sustained decline in estimated glomerular filtration rate (eGFR).
The LEADER trial3 compared liraglutide 1.8 mg subcutaneously daily to placebo. The population included 9340 patients. The primary outcome was the first occurrence of death from CV causes, nonfatal (including silent) MI, or nonfatal stroke. Liraglutide was found to be superior to placebo, as evidenced by a reduction in the frequency of the primary endpoint composite of major adverse cardiovascular events (MACE), which consisted of CV death, MI, and stroke, relative to the control group. The renal outcome was a composite of nephropathy, defined as the new onset of macroalbuminuria or a doubling of the serum creatinine level and an eGFR of ≤45 mL/min per 1.73 m2, the need for continuous renal replacement therapy, or death from renal disease. The renal outcome occurred in fewer participants in the liraglutide group compared to the placebo group. The authors concur that the mechanism behind these effects on renal outcomes is unclear. This study was not powered for analysis of renal outcomes, therefore long-term effects cannot be extrapolated. Also, in the absence of head-to-head comparisons, other direct or indirect drug effects cannot be ruled out.
The SUSTAIN-6 trial4 compared once-weekly subcutaneous semaglutide 0.5 mg and 1.0 mg to placebo. The primary outcome was the first occurrence of death from CV causes, nonfatal MI (including silent), or nonfatal stroke in patients age 50 years and older with preexisting CV disease, congestive heart failure (CHF) stage II or III, or CKD stage 3 or higher or older than 60 with one or more CV risk factors. Statistical significance was found in the semaglutide group in terms of fewer patients experiencing nonfatal stroke, but reductions in cardiac death were not significant between the 2 treatment groups. No changes to the maintenance dose of semaglutide were permitted during the study, and similar risk reductions were observed with both doses of semaglutide. Investigators were encouraged to treat all patients to achieve the most effective glycemic control using antihyperglycemics, with the exception of incretin-based therapies. CV pharmacotherapy was also permitted and included antihypertensives, diuretics, lipid lowering medications, and antithrombotic medications. The renal outcome of persistent macroalbuminuria developed among 2.7% of those that received semaglutide compared to 4.9% of those that received placebo.
The ELIXA trial5 compared 10 mcg of subcutaneous once-daily lixisenatide to placebo. In all, 6068 patients age 30 and older who had type 2 diabetes and an MI or who had been hospitalized for unstable angina within the previous 180 days were included in this study, whose primary outcome was a composite of the first occurrence of any of the following: death from CV causes, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. Significant findings were reported in terms of average differences in systolic blood pressure (SBP) across all visits of −0.8 mm Hg observed in favor of lixisenatide. Glycemic control was managed by the investigators by the adjustment of concomitant glucose-lowering agents or the addition of new antidiabetic medications with the exception of other incretin therapies.
The EXSCEL trial6 compared exenatide extended-release (XR) 2 mg subcutaneously once-weekly injection to placebo. In all, 14 752 patients of any age with type 2 diabetes with 73.1% of the population having ASCVD were included. The primary outcome was the first occurrence of any component of the composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke. No significant differences were found in the rate of death from CV cause, first occurrence of nonfatal or fatal MI, and nonfatal or fatal stroke. Mean values were lower with exenatide than with placebo for SBP (−1.57 mmHg), low-density lipoprotein cholesterol (−1.5 mg/dL), and triglycerides (−1.8 mg/dL). Values were higher in the exenatide group than in the placebo group for diastolic blood pressure (DBP; difference of 0.25 mmHg) and heart rate (difference of 2.51 bpm). The use of open-label glucose-lowering agents (including DPP-4 inhibitors but not including GLP-1 RAs) was encouraged to help patients reach clinically appropriate glycated hemoglobin targets. Compared with placebo, there was higher use in the exenatide group of the SGLT-2 inhibitor dapagliflozin. The authors pointed out that exenatide XR failed to demonstrate superiority at preventing adverse CV events and was noninferior to placebo for the primary composite outcome of MACE. A composite of 40% eGFR decline, renal replacement, renal death, or new macroalbuminuria was significantly reduced when exenatide was added (Table 1).
The DECLARE-TIMI trial7 included patients 40 years of age or older with type 2 diabetes (T2DM) who had multiple risk factors for ASCVD or had established ASCVD and a creatinine clearance of at least 60 mL/min per 1.73 m2. The primary safety outcome was MACE, and primary efficacy outcomes were MACE and a composite of CV death or hospitalization for heart failure. Although dapagliflozin did not lower MACE outcomes compared to placebo, dapagliflozin resulted in a lower rate of CV death or hospitalization for heart failure than placebo, which was found to be statistically significant. Outcomes were driven by a lower rate of hospitalization for heart failure. There were no differences between groups in the rate of CV death. Other outcomes for dapagliflozin were reductions in glycated hemoglobin levels, weight, SBP, and DBP. Cardio-renal effects were assessed by sustained decline of at least 40% in eGFR to less than 60 ml/min, end-stage renal disease, or death from renal or CV causes. Dapagliflozin also showed preventive and reduced progression of kidney disease compared with placebo in patients with or without established ASCVD.
The CANVAS trial8,9 included patients with T2DM and were either 30 years or older with a history of ASCVD or 50 years or older with 2 or more CV risk factors. The primary outcome was a composite of death from CV causes, nonfatal MI, or nonfatal stroke. The primary outcome occurred in significantly fewer patients in the canagliflozin group compared with placebo. No significant differences between groups for death from any cause or death from CV causes were found. The composite outcomes occurred less frequently in the canagliflozin group compared to placebo, as evidenced by an annual eGFR decline that was slower and mean urine albumin to creatinine ratio was 18% lower in participants treated with canagliflozin than in those treated with placebo. Based on these outcomes, the authors stated that canagliflozin treatment is associated with possible renoprotective effects in patients with T2DM.9
The EMPA-REG OUTCOME trial10,11 included patients with T2DM and established CV disease who were at least 18 years of age. The purpose was to assess the effect of empagliflozin, an SGLT-2 inhibitor, in reducing the risk of major adverse CV events in patients with T2DM. The primary outcome was a composite of death from CV causes, nonfatal MI, or nonfatal stroke. Although the primary outcome occurred in 10.5% of the empagliflozin group versus 12.1% of the placebo group, a difference that was statistically significant, differences between groups for both fatal and nonfatal MI and stroke were not significantly different. Empagliflozin was associated with reductions in weight, waist circumference, SBP, and DBP compared to placebo. There was an increase in LDL and HDL cholesterol levels in the empagliflozin group. The long-term renal effects were then analyzed by prespecified components. In the trial, patients had an eGFR of at least 30 mL/min per 1.73 m2 of body-surface area and were to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria were considered the renal outcomes. Incident or worsening nephropathy occurred in 12.7% in the empagliflozin group and 18.8% in the placebo group, results that were statistically significant. Doubling of the serum creatinine level occurred less in the empagliflozin group than in the placebo group, with a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 0.3% in the empagliflozin group and in 0.6% in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant difference in albuminuria or adverse events in the groups. The authors concluded that patients with T2DM treated with empagliflozin were associated with slower progression of kidney disease and lower rates of renal events.10
The EMPEROR-REDUCED Trial12 included Class II-IV heart failure with an ejection fraction less than or equal to 40% receiving empagliflozin 10 mg once daily compared to placebo. The primary outcome of this study was a composite of death due to CV causes or an exacerbation of heart failure symptoms requiring hospitalization. The primary outcome occurred in 19.4% of patients in the empagliflozin group compared to 24.7% of patients in the placebo group, and patients enrolled in this study did not require a diagnosis of diabetes to be included. Hospitalizations for heart failure were also lower in the empagliflozin group compared to placebo. Another component evaluated in this study was the annual rate of decline in estimated glomerular filtration rate, which was slower in the empagliflozin group.
The DAPA-HF trial13,14 included NYHA Class II-IV heart failure with an ejection fraction less than or equal to 40% to receive either dapagliflozin or placebo. The primary outcome was a composite of CV death or worsening heart failure. The primary outcome was found to occur in 16.3% of patients in the dapagliflozin group compared to 21.2% of patients in the placebo group, results that were statistically significant. Subjects enrolled in this study were not required to have a diagnosis of diabetes. The outcomes of the DAPA-HF trial13,14 showed promise in patients without diabetes, resulting in dapagliflozin receiving approval from the Food and Drug Administration (FDA) to be used as an adjunct agent (already on guideline-directed medical therapy) in heart failure patients with reduced ejection fraction in preventing hospitalization.
The DAPA-CKD trial15 primary outcome was a composite of sustained decline in the eGFR of at least 50%, the onset of end-stage kidney disease, or death from either renal or CV causes. Patients enrolled in this study were not required to have a diagnosis of diabetes but did have an eGFR of 25 to 75 mL/min per 1.73 m2 of body-surface area and presence of albuminuria. The primary outcome occurred in 9.2% of patients in the dapagliflozin group compared to 14.5% in the placebo group, results that were statistically significant.
The CREDENCE trial16 evaluated renal outcomes with the use of canagliflozin, including a composite of end-stage kidney disease (dialysis, transplantation, or a sustained eGFR of <15 mL/min per 1.73 m2), a doubling of serum creatinine levels, or death from renal or CV causes. The trial was stopped early after an interim analysis found that the relative risk of the primary outcome was significantly lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patientyears, respectively (hazard ratio = 0.70; 95% confidence interval [CI], 0.59-0.82; P = .00001). In this study, the risk for developing the primary outcome was lower in the canagliflozin treatment arm compared to placebo, which was found to be statistically significant.
The VERTIS CV trial17 evaluated ertugliflozin in patients with T2DM and ASCVD. The primary objective of this study was to demonstrate noninferiority of ertugliflozin to placebo for the primary endpoint of MACE and secondary outcomes including a composite of death from CV causes or hospitalization for heart failure. Lower rates of hospitalizations were found in the ertugliflozin group compared to placebo. Patients were found to have an increased risk of genital infections and urinary tract infections.
The EMPEROR PRESERVED trial18 evaluated empagliflozin in patients with an ejection fraction greater than or equal to 40% (heart failure with preserved ejection fraction). The primary outcome was a composite of CV death or hospitalization for heart failure. Empagliflozin was found to reduce heart failure hospitalizations in patients and thus found to be superior to placebo in improvements related to heart failure outcomes. Empagliflozin has received FDA approval to be used as part of routine heart failure regimen in conjunction with other evidence-based therapies regardless of the patient’s ejection fraction. A pooled analysis of the EMPEROR-Reduced and EMPEROR-Preserved trials19 revealed sustained decreases in eGFR or renal replacement therapy in patients taking empagliflozin compared to placebo. The authors stated that this finding was primarily in patients with heart failure with reduced ejection fraction (Table 2).19
The main adverse event associated with GLP-1 RAs in clinical trials were gastrointestinal upset (ie, nausea, vomiting, diarrhea), and this was often a common reason for stopping therapy. Doses of GLP-1 RAs are titrated up to help minimize these side effects. In severe cases of gastrointestinal effects, dehydration may lead to acute kidney injury. Another adverse effect seen in many trials was injection site reactions. Although not common, hypoglycemia was also observed. Hypoglycemia was usually observed when the GLP-1 RAs were used in combination with other medications that could cause hypoglycemia. Use of GLP-1 RAs may be associated with an increased risk of gallbladder or biliary disease due to GLP-1s inhibiting gallbladder motility. Pancreatitis was also observed in some of the clinical trials. Although the true relationship is unknown, medullary thyroid carcinoma has been observed in mice using GLP-1 RAs; therefore if the patient has medullary thyroid carcinoma or a family history, it is a contraindication to using GLP-1 RA therapy.1 These are a few of the main adverse effects associated with GLP-1 RAs and not a conclusive list.
The findings within the SGLT-2 inhibitor clinical trials on incidence of adverse effects were consistent with previous findings. These adverse effects may limit their use in certain patient populations. In the CANVAS trial, there were some serious adverse effects observed, such as cancer, fracture, amputation, and diabetic ketoacidosis. Canagliflozin was associated with an increased risk of amputations and fractures. The FDA initially listed this as a black box warning but has since removed this due to a lack of evidence in other agents within this class. In the DECLARE-TIMI 58 trial, the dapagliflozin group did have more patients experience an adverse event that led to drug discontinuation compared to the placebo group. Diabetic ketoacidosis and genital infection occurred more frequently in the treatment group and were statistically significant. In the EMPAREG trial, more patients in the empagliflozin group experienced genital infections, and more females experienced urinary tract infections, which were statistically significant compared to the placebo group. In early 2020, the FDA issued a statement recommending that SGTL-2 inhibitors be held for 3 to 4 days prior to surgery because surgical diabetic patients are at a greater risk of developing diabetic ketoacidosis if they continue these medications preoperatively. Once risk factors for diabetic ketoacidosis have resolved, the medications may safely be restarted.
Despite the overwhelming evidence in support of its use, the financial impact of prescribing these agents should be noted because generic formulations are not readily available and often may not be covered by many insurance formularies, posing an additional burden to the patient.
Select GLP-1 RAs may confer CV outcome benefits, but this has not been shown to be a class effect. Only liraglutide reduced the frequency of MACE. Once-weekly semaglutide, lixisenatide, and exenatide XR were noninferior compared to placebo for the primary composite outcome of MACE. Dulaglutide was associated with a significant decrease in the primary endpoint but not in mortality.
Besides the HARMONY study, the GLP-1 RAs were associated with protective renal benefits. The GLP-1 RAs demonstrated a significantly lower incidence of the composite renal outcomes. Each study varied in the definition of the renal outcome. In the HARMONY study, worsening of renal function was evaluated as a safety outcome. There was a decreased incidence of acute kidney injury and renal impairment in the treatment group, but this was not statistically significant. Many of the studies referenced in this article excluded patients with renal impairment, which impedes its use in this patient population. Recently, the FDA approved liraglutide and semaglutide in the treatment of chronic weight management as an adjunct to diet and exercise in patients with CV comorbidities.
Despite the overwhelming evidence in support of its use, the financial impact of prescribing these agents should be noted because generic formulations are not readily available and often may not be covered by many insurance formularies, posing an additional burden to the patient. With well over 30 million people in the United States diagnosed with T2DM,20 according to the 2020 National Diabetes Statistics Report, the GLP-1 RAs have shown significant benefits beyond solely lowering A1C, and the trials for SGLT-2 inhibitors show an overall benefit for hospitalization and heart failure, in addition to renal protection, offering promise in not only managing diabetes but also in preventing microvascular and macrovascular complications.
As part of a patient-centered care approach, health care professionals are encouraged to assess the benefits and risks of initiating these agents and incorporate a close evaluation of renal and CV factors in their decision-making.
The FDA recently approved the use of the SGLT-2 inhibitors dapagliflozin and empagliflozin for patients with heart failure with preserved ejection fraction, with outcomes driven primarily by reduced hospitalizations, which is known to improve the quality of life for patients, showing further benefits of the use of these agents in clinical practice.
As part of a patient-centered care approach, health care professionals are encouraged to assess the benefits and risks of initiating these agents and incorporate a close evaluation of renal and CV factors in their decision-making. Future studies investigating these agents should focus on areas outside heart failure and MI, such as arrhythmias and other cardiac disorders, and agents that can be safely used in patients with declining kidney function.
Samuel M. John, PharmD, BCPS, is with Northside Forsyth Hospital in Cumming, GA. Megan Fulwood, PharmD, is with Walmart Pharmacy in Rome, GA. Kendra Ford, PharmD, is with Wellstar Kennestone Regional Medical Center in Marietta, GA.
The authors declare having no professional or financial association or interest in an entity, product, or service related to the content or development of this article.
The authors declare having received no specific grant from a funding agency in the public, commercial, or not-for-profit sectors related to the content or development of this article.
Samuel M. John https://orcid.org/0000-0002-0372-2450
