Shopping Cart

Introduction

Type 2 diabetes mellitus (T2DM) is a chronic condition, which is characterized by hyperglycemia due to insulin resistance and progressive failure of the pancreas to produce insulin. It is estimated that nearly 30 million adults in the United States have T2DM and that almost 100 million have prediabetes, the precursor to developing T2DM.¹ Overweight and obesity are associated with the development and progression of T2DM. Approximately 70% of adults in the United States are either overweight or obese and over the last several years, the rate of overweight and obesity has been on the rise.¹

Patients with T2DM are at risk for both microvascular and macrovascular complications. Microvascular complications include nephropathy, neuropathy and retinopathy. Neuropathy can also contribute to amputation in patients with T2DM. Nephropathy manifests as microalbuminuria and reduced glomerular filtration rate.² Macrovascular complications encompass primarily cardiovascular and cerebrovascular disease.³ T2DM is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and patients with T2DM are at increased risk for cardiovascular death.¹ The risk for ASCVD events increases by 11 – 16% for every 1% increase in hemoglobin A1C (HgbA1C), suggesting a strong association between hyperglycemia and cardiac risk.⁴  Patients with T2DM are also at both increased risk for developing heart failure and for poor heart failure outcomes.¹ Risk for developing heart failure increases by 8% for every 1% increase in HgbA1C.

Hyperglycemia is the central pathological trigger for the development of both microvascular and macrovascular complications. Persistent elevations in blood glucose leads to the production of advanced glycated end products. These are produced when glucose interacts with proteins, lipids and nucleic acids, altering their function and promoting inflammation, cell death, fibrosis and endothelial dysfunction.^2,5 These end products can be directly toxic to cells in the retina, peripheral nervous system and nephrons as well as cardiac cells. ² Glucose metabolites can also alter the function of proteins, resulting in a negative impact on the heart muscle’s ability to effectively contract and relax.⁵ Persistent inflammation can contribute to platelet activation, which could theoretically contribute to myocardial infarction or stroke risk.² Inflammation can also contribute to cardiac fibrosis and remodeling that would support the development of heart failure⁵ It has also been proposed that inflammation alters the function of the renin-angiotensin-aldosterone system, which could contribute to the development of hypertension and cardiac remodeling observed in heart failure. ² 

Given the major role of hyperglycemia in the pathological consequences of T2DM, the primary treatment goal for managing T2DM is glycemic control. Early clinical trials have demonstrated that more intensive glycemic control (HgbA1C ~7% vs. ~9%) results in a lower rate of microvascular complications.⁶ Additionally, some studies suggest that macrovascular complications may also be positively impacted by more intensive glycemic control; however, there is conflicting information in this regard.⁶ Length of follow-up and patient populations included in these studies may provide some explanation for disparate findings in these trials. It is also notable that these trials were completed at a time that precedes the medication classes that will be discussed below.

In 2008, the United States Food and Drug Administration (FDA) issued guidance which required developers of medications for T2DM to take steps to evaluate cardiovascular safety during phase 2 and 3 studies.⁷ This resulted in the completion of many cardiovascular outcome trials that not only demonstrated safety of newer T2DM medications, but also provided signals that the newer medications could actually have a positive impact on cardiovascular risk. The drug classes for which cardiovascular safety has been studied include the dipeptidyl peptidase-4 (DPP-4) inhibitors, the glucagon-like peptide-1 (GLP-1) receptor agonists, and the sodium-glucose cotransporter-2 (SGLT-2) inhibitors. This article will review data that has resulted from this focus on the cardiovascular impact of these newer T2DM therapies. Implications of these data on the care of patients with T2DM and/or cardiovascular disease will also be addressed.

Clinical Trials: Cardiovascular Safety and Risk Reduction

Dipeptidyl peptidase-4 inhibitors

DPP-4 inhibitors approved in the United States are sitagliptin, linagliptin, saxagliptin and alogliptin. The DPP-4 inhibitors were all included in studies to evaluate their cardiac safety. The patient populations included in these studies were generally patients with T2DM who either had established ASCVD or were at high risk for ASCVD.^8-11 Linagliptin, saxagliptin and alogliptin have been shown to have a neutral effect on a three-part major adverse cardiovascular event (MACE-3) endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke.^8-11 Sitagliptin was also found to have a neutral cardiovascular effect, but the endpoint in the study assessing cardiovascular safety with sitagliptin evaluated a primary endpoint with a four part major adverse cardiovascular event (MACE-4) composite endpoint that included MACE-3 events in addition to hospitalization for unstable angina.¹¹

Impact on kidney function was evaluated in most of the DPP-4 inhibitor studies. The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA) evaluated a secondary composite renal endpoint that included death due to kidney failure, development of end stage renal disease or a 40% reduction in estimated glomerular filtration rate of 40% or more.¹⁰ There was no difference between linagliptin and placebo in the renal endpoint in CARMELINA.¹⁰ Sitagliptin and alogliptin were found to have a negligible effect on estimated glomerular filtration rate.^8,11 There was no mention of the effect of saxagliptin on kidney function in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.⁹

Sitagliptin and linagliptin also had no effect on hospitalization for heart failure.^10,11 Hospitalization for heart failure was higher with saxagliptin than with placebo (3.5% vs. 2.8%, p = 0.007).⁹ In a secondary analysis of the SAVOR-TIMI 53 trial, it was found that patients with a history of heart failure, elevated brain natriuretic peptide levels or a creatinine clearance ≤ 60 mL/min were at greatest risk of heart failure hospitalization.¹² This finding has resulted in a warning in the saxagliptin package insert regarding hospitalization.¹³ In the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial, patients receiving alogliptin were hospitalized for heart failure at a numerically higher rate than those receiving placebo (3.9% vs. 3.3%, p=0.220). This finding was described as a non-significant difference by the authors; however, the FDA required warning labeling regarding risk for heart failure hospitalization as a result of this data.^8,14

As a class, the DPP-4 inhibitors appear to have a neutral effect on ASCVD risk and kidney function. Increased risk of heart failure hospitalization has been observed for 2 agents in the class, saxaglipin and alogliptin. Therefore, these agents should likely be avoided in patients with heart failure. Product labeling for linagliptin suggests caution in patients with heart failure or kidney dysfunction due to the potential for a class effect. Sitagliptin does not carry this same warning. 

Safety and Monitoring of DPP-4 inhibitors

Monitoring parameters, typical dose and notable adverse effects of the DPP-4 inhibitors can be found in Table 1. The DPP-4 inhibitors are generally well tolerated; however, there have been some reports of pancreatitis. HgbA1C should be monitored periodically as with any T2DM medication. All drugs in the class require dosage adjustment for renal function with the exception of linagliptin. As such, kidney function should be monitored on initiation and periodically thereafter.¹⁵ 

Glucagon-like peptide-1 receptor agonists

Six GLP-1 receptor agonists have been evaluated for cardiovascular safety in seven studies.^16-22 The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was one of the first GLP-1 receptor agonist studies to demonstrate improved cardiovascular outcomes, relative to placebo.¹⁶ In the LEADER trial 9340 patients with T2DM (HgbA1C ≥ 7%) and either established cardiovascular disease or at high risk for cardiovascular disease were included. Established cardiovascular disease included coronary artery disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure or chronic kidney disease (≥ stage 3). Included patients were randomized to either liraglutide 1.8 mg daily as a subcutaneous injection or placebo and the primary outcome of the study was a (MACE-3) endpoint. Additional exploratory endpoints of note included hospitalization for heart failure and a renal outcome endpoint that included death from renal disease, development of nephropathy or need for renal replacement therapy. Patients were followed for 3.5 years and the MACE-3 outcome occurred in 13% of patients in the liraglutide arm and 14.9% of patient who received placebo (p < 0.001). The difference in MACE-3 was driven by a significant reduction in cardiovascular death with liraglutide (4.7% vs. 6.0%, p = 0.007) and there was also a significant reduction in all-cause mortality with liraglutide (8.2% vs. 9.6%, p = 0.02). There was also a lower rate of nephropathy with liraglutide, but no difference in heart failure hospitalizations. 

The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) was designed to evaluate the impact of once-weekly subcutaneous Semaglutide on cardiovascular safety.¹⁷ This study included 3297 patients with T2DM (HgbA1C ≥ 7%) and inclusion criteria was similar to that used in the LEADER trial. Patients were randomized to either semaglutide 0.5 or 1 mg weekly by subcutaneous injection or placebo. The primary endpoint was the MACE-3 endpoint used in other studies. Heart failure hospitalizations and development of nephropathy was also evaluated. Patients were followed in the study for a median of 2.1 years. MACE-3 occurred less frequently in the semaglutide group than in the placebo group (6.6% vs. 8.9%, p = 0.02 for superiority analysis). In contrast to the results of the LEADER trial, cardiovascular death was similar between groups in SUSTAIN-6; however, non-fatal stroke rate was less with semaglutide. Hospitalization for heart failure did not differ between groups, but there was a lower rate of nephropathy with semaglutide. The investigators also noted that body weight decreased by 3.6 – 4.9 kg with semaglutide. 

The cardiovascular safety of the oral form of semaglutide was evaluated in the Peptide Innovation for Early Diabetes Treatment (PIONEER-6) study.¹⁸ The patient population was similar to that included in the SUSTAIN-6 trial; however, patients were randomized to receive oral semaglutide 14 mg daily or placebo. A total of 3183 patients were included and the follow up time frame was significantly shorter, at 15.9 months, than the previously discussed GLP-1 receptor agonist trials. The MACE-3 composite was the primary endpoint. Heart failure hospitalizations were assessed but there was not a nephropathy endpoint in this trial. MACE-3 occurred in 3.8% of patients receiving semaglutide and 4.8% receiving placebo. The hazard ratio (HR) and 95% confidence interval (95% CI) for the primary endpoint was 0.79 (0.57–1.11) which met the definition of non-inferiority, but oral semaglutide was not superior to placebo. Heart failure hospitalizations were not different between groups. While this study demonstrates cardiovascular safety of oral semaglutide, it is interesting that there is an apparent differential effect between the oral and subcutaneous forms of the medication. Study design differences could be an explanation for these conflicting findings. Patient population was similar between the SUSTAIN-6 and PIONEER-6 studies; however, duration of follow up was different (2.1 years and 15.9 months, respectively). It could be expected that a longer timeframe would allow for more MACE-3 events to occur and this seems to be supported by the overall lower rate of events in the shorter PIONEER-6 trial (3.8%-4.8%), relative to the rates in the longer SUSTAIN-6 trial (6.6%-8.9%). It was also noted in the PIONEER-6 trial, that more patients in the placebo group were taking SGLT-2 inhibitors. As will be discussed below, this could be a confounding factor due to ASCVD benefits of this class of medications. Bioavailability differences between oral and subcutaneous semaglutide has also been suggested as an explanation for different results.

The HARMONY OUTCOMES trial evaluated the cardiovascular safety of albiglutide and included 9463 patients with T2DM (HgbA1C ≥ 7%) and established cardiovascular, cerebrovascular or peripheral vascular disease.¹⁹ Patients with an estimate glomerular filtration rate less than 30 mL/min were excluded from the trial, which is different from previously discussed studies. Patients were randomized to albiglutide 50 mg once weekly by subcutaneous injection or placebo. The primary endpoint was the MACE-3 composite endpoint. Heart failure hospitalization was evaluated in a composite endpoint with cardiovascular death and worsening kidney function was also evaluated as a secondary endpoint. Median follow up was 1.6 years and the primary endpoint occurred in 7% of patients receiving albiglutide and 9% of patients receiving placebo (p = 0.0006 for superiority analysis). Heart failure hospitalization and rate of renal impairment was similar between groups. It should be noted that albiglutide was withdrawn from the United States market in 2017.

The Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial was designed to evaluate cardiovascular safety of the GLP-1 receptor agonist, dulaglitide.²⁰  REWIND enrolled 9901 patients with T2DM (HgbA1C ≤ 9.5%) and either a previous cardiovascular event occurring no less than 2 months prior to enrollment or risk factors for cardiovascular events. Interestingly, patients were required to have a HgbA1C of no greater than 9.5% to participate, with no lower limit, which is different from previously discussed GLP-1 receptor agonist studies. Patients were randomized to dulaglitide 1.5 mg weekly, given as a subcutaneous injection, or placebo. The primary endpoint was MACE-3 and a renal composite endpoint, defined as new onset microalbuminuria, decline in estimated glomerular filtration rate (≥30% from baseline) or need for dialysis or kidney transplant, was also evaluated. Heart failure hospitalization was evaluated as a secondary endpoint. Patients were followed for a median of 5.4 years and median HgbA1C was 7.2% (interquartile range = 6.6% – 8.1%) which is lower than previously discussed GLP-1 inhibitor studies and likely reflects the different HgbA1C inclusion criteria. The primary endpoint occurred in 12% of patients receiving dulaglitide and 13.4% of patients receiving placebo (p = 0.026). The most pronounced effects appeared to be in the reduction of non-fatal stroke. Interestingly, the MACE-3 benefit of dulaglitide was similar whether baseline HgbA1C was above or below 7.2%, suggesting that adding dulaglitide regardless of HgbA1C may be warranted for added cardiovascular risk reduction. Heart failure hospitalization did not differ between groups. However, the renal composite outcome occurred less frequently in the dulaglitide group (17.1%) than the placebo group (19.6%, p = 0.0004). Gastrointestinal adverse effects occurred more frequently in the dulaglitide group; however, serious adverse effects were similar in both groups. This study confirms reduced ASCVD risk with dulaglitide, but is also the only study to demonstrate improved renal outcomes with a GLP-1 receptor agonist. It is unclear if this renal outcome improvement is related to the medication itself, or differences in study design. A notable difference in the design of REWIND is that follow up is longer than any of the other GLP-1 receptor agonist trials and this was the only study, reporting renal outcomes, to include patients with lower HgbA1C values at baseline. 

Two cardiovascular safety studies of GLP-1 receptor agonists have been found to have a neutral effect on cardiovascular risk, in contrast with most of the studies of GLP-1 receptor agonists described above. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial evaluated the cardiovascular safety of lixisenatide and the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) Study evaluated the cardiovascular safety of exenatide.^21,22 ELIXA included 6060 patients with a median follow up of 25 months and EXSCEL included 10,782 patients with a median follow up of 3.2 years. ELIXA was unique among the GLP-1 receptor agonist cardiovascular safety studies, in that patients were required to have experienced a cardiac event within the 6 months prior to study enrollment.²¹  EXSCEL planned to enroll at least 70% of patients who have had a cardiac event.²² ELIXA used a MACE-4 composite primary endpoint, while EXSCEL used a MACE-3 composite primary endpoint.^21,22 Lixisenatide was found to be non-inferior to placebo in the MACE-4 primary endpoint, suggesting there is no increased cardiovascular risk with the medication, but also no cardiovascular risk reduction. There was also no impact of lixisenatide on heart failure hospitalization or renal endpoints.²¹ Exenatide was also found to be non-inferior to placebo for the MACE-3 primary endpoint and there was no impact on heart failure hospitalization.²² It is unclear why these two GLP-1 receptor agonist studies differed from most of the other studies of drugs in the class. It is possible that by requiring patients to have had a fairly recent cardiac event for entry into ELIXA could have selected a more severely ill patient population for inclusion in that study. The authors of EXSCEL postulate that a high rate of patient drop out and shorter duration of study follow up could have impacted results. 

In general, the GLP-1 receptor agonists appear to provide cardiovascular risk reduction to patients who either have established cardiovascular disease or who are at high risk for cardiovascular disease. However, not all medications in the class have shown this benefit, making it difficult to assume this is class effect. Overall, each of the currently available GLP-1 receptor agonists have proven cardiovascular safety in high risk patients. However, only dulaglitide, liraglutide and subcutaneous semaglutide can be considered for reduction of cardiovascular risk. Given that the REWIND trial included patients whose T2DM could have been in control, it may be suitable to use the GLP-1 receptor agonists regardless of glycemic control for added ASCVD risk reduction. Dulaglitide is unique in the class in that a renal outcome benefit was observed and perhaps could be considered if both cardiovascular and renal risk reduction is desired.

Mechanism of Benefit of GLP-1 Receptor Agonists

GLP-1 receptor agonists treat hyperglycemia by increasing insulin secretion and decreasing glucose secretion. ASCVD risk may be mediated through decreased body weight, blood pressure or triglycerides. Anti-inflammatory properties have also been proposed as a mechanism of cardiovascular benefit.²³

Safety and Monitoring of GLP-1 Receptor Agonists

Monitoring parameters, typical dose and notable adverse effects of the GLP-1 receptor agonists can be found in Table 1. The most common adverse effects associated with this class are gastrointestinal. Pancreatitis has been reported rarely and some agents in the class carry a black box warning due to the development of thyroid cancer in animals. In addition to HgbA1C, kidney function should be monitored, especially when new onset nausea or vomiting occurs. Exenetide and lixisenetide should both be avoided when estimated glomerular filtration rate is ≤ 30 mL/min.¹⁵

Sodium-glucose cotransporter-2 inhibitors

There are four available SGLT-2 inhibitors in the United States. The SGLT-2 inhibitor class includes empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. Several studies have been completed with this class of T2DM medications that demonstrate reduced risk of ASCVD events, improved renal outcomes and improved heart failure outcomes. 

Empagliflozin

The first cardiovascular safety study completed with an SGLT-2 inhibitor was the EMPA-REG OUTCOME trial.²⁴ EMPA-REG OUTCOME included 7020 patients with T2DM (HgbA1C between 7% and 9%) and established cardiovascular disease. Patients were excluded if estimated glomerular filtration rate was ≤ 30 mL/min. Over 99% of included patients had established ASCVD. Patients were randomized to Empagliflozin 10 mg or 25 mg daily or placebo and the primary endpoint was MACE-3. Heart failure hospitalization was also assessed as a secondary endpoint and renal outcomes were described in a secondary publication of a planned sub-analysis of EMPA-REG OUTCOME.²⁵ The composite renal outcome in this secondary analysis included development of macroalbuminuria, doubling of serum creatinine with estimated glomerular filtration rate ≤ 45 mL/min, need for renal replacement or death from kidney disease. The median treatment duration was 2.6 years. The MACE-3 primary endpoint occurred less often in the patients receiving empagliflozin (10.5%) than those receiving placebo (12.1%, p = 0.04 for superiority analysis).²⁴ These findings were similar for both the 10 mg and 25 mg dose groups. Cardiovascular death and all cause mortality were both reduced by empagliflozin (p < 0.001 for both) and hospitalization for heart failure occurred in 2.7% of patients receiving empagliflozin and 4.1% of patients receiving placebo (p=0.002). The renal outcome composite endpoint occurred less frequently among patients randomized to empagliflozin than among those randomized to placebo (HR [95% CI]=0.61 [0.53-0.70]). This difference occurred in both patients with and without underlying heart failure and was more pronounced in patients with heart failure.²⁵ Genital infection was the only safety event that occurred more frequently in the empagliflozin group. 

The finding of reduced heart failure hospitalizations in EMPA-REG OUTCOME, prompted development of the EMPEROR-REDUCED trial.²⁶ EMPEROR-REDUCED included 3730 patients with class II-IV heart failure. Patients were only eligible if they had been admitted to the hospital for heart failure within the last 12 months or if they had a high level of brain natriuretic peptide. Patients were not required to have a diagnosis of T2DM for entry into the study. Patients were randomized to either empagliflozin 10 mg daily or placebo. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Estimated glomerular filtration decline was also evaluated. The median follow-up period was 16 months and only 49.8% of patients had T2DM. The primary endpoint occurred in 19.4% of the empagliflozin patients and 24.7% of the placebo patients (p<0.001). This benefit occurred whether patients had T2DM or not. The rate of decline of estimated glomerular filtration rate was slower in the empagliflozin group as well. Genital infection was reported more frequently with empagliflozin in this study as well.

Based on the entirety of the data available with empagliflozin, certainly appears safe in patients with cardiovascular disease. In fact, empagliflozin reduced ASCVD risk and risk of both heart failure hospitalization and decline in kidney function among patients with T2DM. It is unclear whether empagliflozin would be useful to prevent decline in kidney function among patients with chronic kidney disease, regardless of T2DM-status. However, this question may be answered with the ongoing EMPA-KIDNEY trial.²⁷ The data discussed above also demonstrates that outcomes in patients with heart failure with reduced ejection fraction (HFrEF) were improved regardless of whether a patient with heart failure has T2DM, expanding the patient population that can benefit from this medication. The EMPEROR-PRESERVED trial, which will evaluate the impact of empagliflozin on patients with heart failure with preserved ejection fraction (HFpEF), will hopefully provide more insight into the management of this challenging patient population.²⁸

Canagliflozin

Canagliflozin cardiovascular safety was studied in The Canagliflozin Cardiovascular Assessment Study (CANVAS).²⁹ This was a randomized, double-blind, placebo controlled study in which 10,142 patients with T2DM (HgbA1C = 7% - 10.5%) and either symptomatic ASCVD or high risk for ASCVD were included. Patients were excluded if estimated glomerular filtration rate was ≤ 30 mL/min. Approximately 72% of included patients had ASCVD. Patients were randomized to either canagliflozin 100 mg or 300 mg daily or placebo. The primary outcome was MACE-3 and progression of albuminuria and heart failure hospitalizations were also evaluated. Median follow-up was 126 weeks. The primary outcome occurred in 26.9% of patients randomized to canagliflozin and 31.5% of patients randomized to placebo (p = 0.02 for superiority). Hospitalization for heart failure also occurred less frequently in the canagliflozin group (HR [95% CI] = 0.67 [0.52–0.87]). Progression of albuminuria was also less likely in the canagliflozin group (HR [95% CI] = 0.73 [0.67 to 0.79]). Genital infection, volume depletion and amputation were all reported more frequently in the canagliflozin group. 

Due to the renal outcome observations from CANVAS and other studies of SGLT-2 inhibitors the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was developed.³⁰ CREDENCE included 4401 patients with T2DM (HgbA1C = 6.5% - 12%) and chronic kidney disease (estimated glomerular filtration rate = 30 – 90 mL/min + significant albuminuria). Patients were randomized to canagliflozin 100mg daily or placebo and randomization was stratified by estimate glomerular filtration rate at study entry. The primary outcome was a composite renal outcome that included development of end stage renal disease, sustained doubling of serum creatinine or death from renal or cardiovascular disease. Several cardiovascular outcomes were evaluated as secondary endpoints. Median follow up was 2.6 years and the trial was stopped after a planned interim analysis suggested that threshold for early discontinuation had been met. The risk for developing the primary composite renal outcome was significantly less in the canagliflozin arm (HR [95% CI] = 0.70 [0.59 to 0.82]). Canagliflozin had a similar impact on MACE-3 and heart failure hospitalization in CREDENCE, as was observed in CANVAS. Dissimilar from CANVAS, amputation was not more common with canagliflozin in CREDENCE. However, there was a slightly higher rate of diabetic ketoacidosis with canagliflozin. 

Like empagliflozin, canagliflozin exhibits cardiovascular safety and in fact appears to provide risk reduction for ASCVD in patients with T2DM. Canagliflozin also reduced heart failure hospitalizations in a general population of patients with T2DM as well as patients with T2DM and significant chronic kidney disease. It remains unknown whether canagliflozin can be used to treat patients with heart failure in the absence of T2DM. Finally, canagliflozin has robust data to suggest that it is effective in slowing progression of kidney function decline, both in a general T2DM patient population and in patients with both T2DM and chronic kidney disease. 

Dapagliflozin

The cardiovascular safety of dapagliflozin was evaluated in the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial.³¹ DECLARE-TIMI 58 included 17,160 patients with T2DM (HgbA1C = 6.5% - 12%) and either established ASCVD (~40%) or with multiple risk factors for cardiovascular disease. Patients were also required to have an estimated glomerular filtration rate ≥ 60 mL/min for inclusion. Patients were randomized to receive dapagliflozin 10 mg daily or placebo. The primary endpoint was MACE-3 and a composite endpoint of cardiovascular death or heart failure hospitalization was also evaluated. A renal composite outcome of decline in kidney function (≥ 40% decrease in estimated glomerular filtration rate to less than 60 mL/min), development of end stage renal disease, or kidney related death. Median patient follow up was 4.2 years and the primary MACE-3 endpoint occurred in 8.8% of patients receiving dapagliflozin and 9.4% of patients receiving placebo (p = 0.17). This result met the threshold for non-inferiority, but not for superiority of dapagliflozin. The composite of cardiovascular death and heart failure hospitalization was improved with dapagliflozin (HR [95% CI] = 0.83 [0.73−0.95], p = 0.005) and heart failure hospitalization alone was also lower with dapagliflozin (HR [95% CI] = 0.73 [0.61−0.88]). The composite renal outcome was also significantly impacted by dapagliflozin (HR [95% CI] = 0.53 [0.43−0.66]). Similar to the CREDENCE study, diabetic ketoacidosis occurred more frequently with dapagliflozin (HR [95% CI] = 2.18; [1.10 to 4.30], p = 0.02). Genital infections also occurred more frequently with dapagliflozin, as with other SGLT-2 inhibitors. 

Similar to the study of empagliflozin in the EMPEROR-REDUCED trial, dapagliflozin has been studied for the treatment of heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial.³² DAPA-HF included 4744 patients with New York Heart Association class II-IV heart failure with an ejection fraction ≤ 40%. Patients were also required to have an elevated brain natriuretic peptide level (≥ 600 pg/mL or ≥ 400 pg/mL if recently hospitalized). Patients were not required to have T2DM to be included in this trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Worsening heart failure was defined as being hospitalized or acutely needing to receive intravenous vasoactive medications during an urgent visit. A composite renal outcome was also evaluated and included a sustained 50% reduction in estimated glomerular filtration rate, development of end stage renal disease or kidney related death. Patients with T2DM made up 41.8% of the patient population and patients were generally taking guideline directed medical therapy for heart failure at high rates (70.6% – 96.2% of patients taking an ace inhibitor, angiotensin receptor blocker, sacubitril-valsartan, a heart failure beta blocker or mineralocorticoid receptor antagonist). Median follow up was 18.2 months. The composite primary event occurred less frequently in the dapagliflozin group, than in the placebo group (16.3% vs. 21.2%, p<0.001). Worsening heart failure and cardiovascular death were also both improved in the dapagliflozin group separately as well. The composite renal endpoint was not different between groups. The overall findings were also similar in those with or without T2DM. No adverse effects were reported more frequently in the dapagliflozin group. 

The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial was designed to evaluate the efficacy of dapagliflozin in patients with chronic kidney disease.³³ In contrast to the chronic kidney disease study of canagliflozin, CREDENCE, the DAPA-CKD didn’t require that patients have T2DM. DAPA-CKD included 4304 patients with and estimated glomerular filtration rate of 25 – 75 mL/min and a higher degree of albuminuria, regardless of whether T2DM was present. Patients were required to take either an angiotensin converting enzyme inhibitor or angiotensin receptor blocker or have a documented contraindication or intolerance to be enrolled. Patients were randomized to dapagliflozin 10 mg daily or placebo and the primary endpoint was a composite renal endpoint that included a sustained 50% decline in estimated glomerular filtration rate, onset of end stage renal disease or kidney related death. The composite of cardiovascular death and heart failure hospitalization was also evaluated. Approximately 67% of the patients included in the trial had T2DM and nearly half had an estimated glomerular filtration rate of 30 – 45 mL/min on study entry. Patients were followed for a median of 2.4 years and the primary composite endpoint occurred in 9.2% of the dapagliflozin group and 14.5% of the placebo group (p<0.001). Each of the components of the composite endpoint was also improved with dapagliflozin and the primary endpoint findings were similar to the overall results, regardless of T2DM-status. The composite of heart failure hospitalizations or cardiovascular death was also improved with dapagliflozin (HR [95% CI] = 0.71 [0.55 - 0.92] p = 0.009). There were no significant differences between groups in reported adverse effects. 

Dapagliflozin is safe in patients with or at high risk for ASCVD; however, there was not a significant improvement in major adverse cardiovascular events. Therefore, the finding of ASCVD risk reduction does not seem to be a class effect with the SGLT-2 inhibitor class. Dapagliflozin did produce a reduction in heart failure hospitalization among patients with T2DM and prevented both worsening of heart failure and cardiovascular death in patients who had heart failure, but not necessarily T2DM. Dapagliflozin also prevented kidney function decline in both patients with T2DM and patients with chronic kidney disease. 

Ertugliflozin

The newest SGLT-2 inhibitor to be approved in the United States is ertugliflozin. The cardiovascular safety study for ertugliflozin was the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV).³⁴ VERTIS CV included 8246 patients with T2DM (HgbA1C = 7% - 10.5%) and established ASCVD (coronary, cerebrovascular or peripheral arterial disease). Patients were excluded if estimated glomerular filtration rate was ≤ 30 mL/min. By virtue of the inclusion criteria, all patients had some form of ASCVD. Patients were randomized to receive either ertugliflozin 5mg or 15mg daily or placebo. The primary endpoint was MACE-3 and secondary endpoints included a composite of cardiovascular death or heart failure hospitalization and a renal composite endpoint that included renal death, need for renal replacement therapies or doubling of serum creatinine. Mean follow up duration was 3.5 years. The primary endpoint of MACE-3 occurred in 11.9% of patients in both groups (p<0.001 for non-inferiority). The composite of death from cardiovascular causes and heart failure hospitalization, as well as the renal composite endpoints were similar between the ertugliflozin and placebo groups. When heart failure hospitalization was evaluated separately, there was a lower risk of hospitalization in the ertugliflozin group (HR [95% CI] = 0.70 [0.54–0.90]). An exploratory analysis of the VERTIS CV trial suggests that the effect of ertugliflozin on heart failure hospitalization was greater in patients with worse kidney function.³⁵ Similar to other SGLT-2 inhibitor studies, there was an increased risk of genital infections, as well as urinary tract infections with ertugliflozin. 

The cardiovascular safety of ertugliflozin is demonstrated by the non-inferior finding for the MACE-3 endpoint in the VERTIS CV trial. However, similar to dapagliflozin, there does not appear to be ASCVD risk reduction with ertugliflozin. There may be some beneficial effects of ertugliflozin on heart failure outcomes based on the reduction in heart failure hospitalizations in VERTIS CV. It is unclear, at this point, whether ertugliflozin has any therapeutic role in the management of heart failure regardless of T2DM-status, as has been demonstrated with empagliflozin and dapagliflozin. Further study is needed. 

Mechanism of Benefit of SGLT-2 inhibitors

SGLT-2 inhibitors work to treat hyperglycemia by promoting glucosuria through inhibition of the sodium-glucose co-transporter-2. The mechanism to explain some of the positive cardiovascular and renal benefits of this class are less clear. Overall, there is modest blood pressure and body weight reduction with these agents, which could play some role. In addition, the SGLT-2 inhibitors induce diuresis and natriuresis. A potential impact of these medications on cardiac cell metabolism and the development of fibrosis have also been proposed as potential mechanisms of benefit.²³

Safety and Monitoring of SGLT-2 inhibitors

Monitoring parameters, typical dose and notable adverse effects of the SGLT-2 inhibitors can be found in Table 1. The most common adverse effect associated with this class is development of genitourinary infections. Volume depletion and diabetic ketoacidosis have also been reported. In addition to monitoring HgbA1C, serum creatinine should be monitored, as all 4 SGLT-2 inhibitors require renal dose adjustment. All are contraindicated at some level of more severe kidney dysfunction as well.¹⁵

Management and Prevention of T2DM Complications and Comorbidities 

Applying Evidence-Based Guidelines to Practice

Several evidence-based guidelines related to both T2DM management and cardiovascular risk reduction have been updated to reflect the most recent clinical trial data discussed above. Specifically, American Diabetes Association¹⁵ and the American Association of Clinical Endocrinologists/American College of Endocrinology³⁶ provide algorithms for selecting T2DM therapies in patients at high risk for complications and comorbidities, such as ASCVD, heart failure and chronic kidney disease. These guidelines address the use of the DPP-4 inhibitors, GLP-1 receptor agonists and the SGLT-2 inhibitors. The American College of Cardiology (ACC) and American Heart Association (AHA) updated guidelines for primary prevention of cardiovascular disease in 2019³⁷ and the ACC also published a focused expert consensus decision pathway for cardiovascular risk reduction in T2DM.²³ Both of these documents provide recommendations for use of the GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular risk reduction. Finally, the ACC has provided a 2021 update of the 2017 expert consensus decision pathway for heart failure management, which addresses the use of dapagliflozin or empagliflozin as a treatment for HFrEF.³⁸ These guidelines and decision pathways, in addition to the clinical trials summarized above, provide guidance for patient care in the following scenarios.

T2DM with ASCVD or Multiple ASCVD Risk Factors

For patients with T2DM with ASCVD or who have multiple risk factors for ASCVD, who require additional control, it is safe to initiate a DPP-4 inhibitor, GLP-1 receptor agonist or a SGLT-2 inhibitor.³⁷ However, given the high risk of ASCVD events in patients with T2DM, the GLP-1 receptor agonists or SGLT-2 inhibitors that have been shown to provide cardiovascular risk reduction would be preferred (Table 1).^15,23,36 The American Diabetes Association guidelines also suggest that, if a patient is already at goal HgbA1C and additional cardiovascular risk reduction is desired, a GLP-1 receptor agonist or SGLT-2 inhibitor could be substituted for a medication that does not provide cardiovascular benefit.¹⁵ It should also be noted that since most of the cardiovascular outcomes trials involving these two classes of medications included patients with T2DM and HgbA1C at or below 7%, guidelines frequently recommend adding medications with ASCVD benefit regardless of degree of glycemic control.^15,36

T2DM with Heart Failure

For patients with T2DM and concurrent heart failure, who required added glycemic control, it would be safe to add any of the GLP-1 receptor agonists.²³ The only DPP-4 inhibitors that could be added would be linagliptin or sitagliptin, as the other 2 in the class were found to increase hospitalizations for heart failure (Table 1).^8,9 However, given that patients with T2DM are at risk for poor outcomes with heart failure, it would probably be best to select a SLGT-2 inhibitor since all have been shown to reduce heart failure hospitalizations.²³ Dapagliflozin and Empagliflozin have the best evidence for benefit for patients with HFrEF, regardless of T2DM status and should be preferred.^15,38 HFpEF patients were included in the cardiovascular outcomes trials that demonstrated reduced heart failure hospitalizations, so it is reasonable to consider any of the SGLT-2 inhibitors for HFpEF patients with T2DM.

T2DM with Chronic Kidney Disease

For patients with T2DM and chronic kidney disease, who require added glycemic control, any of the 3 classes could be used safely.^15,23,36 However, prevention of decline in kidney function is often a goal of therapy for patients with T2DM. Therefore, addition of dapagliflozin, canagliflozin or empagliflozin should be considered. It should be noted that both dapagliflozin and canagliflozin were studied specifically to evaluate impact on renal outcomes; while empagliflozin was found to improve renal outcomes in a cardiovascular outcome study, so it may be warranted to consider empagliflozin if the other two are unavailable. ^15,23,36 The American Diabetes Association guidelines recommend that patients who cannot use an SGLT-2 inhibitor should receive a GLP-1 receptor agonist with proven ASCVD benefit.¹⁵ Given that dulaglitide is the only GLP-1 receptor agonist to show improvement in renal outcomes in a cardiovascular outcomes trial, it may be warranted to prefer this GLP-1 receptor agonist when SGLT-2 inhibitors cannot be used. It is important to note that the SGLT-2 inhibitors cannot be used when estimated glomerular filtration rate is ≤ 30 mL/min, which could be a reason for considering one of the GLP-1 inhibitors.

Treatment of Heart Failure, Regardless of T2DM-status

Patients with HFrEF can be treated with the SGLT-2 inhibitors dapagliflozin or empagliflozin, even when the patient does not have underlying T2DM.³⁶ The DAPA-HF and EMPEROR-REDUCED trials included patients with HFrEF, but only about half of included patients also had T2DM.^26,32 The updated heart failure recommendations suggest that these SGLT-2 inhibitors can be initiated even before other guideline directed medical therapies like angiotensin-converting enzyme inhibitors or beta-blockers have been titrated to target doses.³⁶ At this point, there is no data to support the use of an SGLT-2 inhibitor for HFpEF treatment, in the absence of T2DM. 

Improved Chronic Kidney Disease Outcomes, Regardless of T2DM-status

Based on the DAPA-CKD, patients with chronic kidney disease may benefit from dapagliflozin even if they do not have concurrent T2DM.³³ The only other SGLT-2 inhibitor trial including patients with chronic kidney disease was CREDENCE; however, patients were required to have T2DM to be included in that trial.³⁰ 

Conclusion

In conclusion, cardiovascular and renal safety has been generally demonstrated for all newer medications for treatment of T2DM. In the process of validating cardiovascular safety in high risk patients, some surprising benefits have emerged. Selected GLP-1 receptor agonists provide ASCVD risk reduction in addition to glycemic control. The GLP-1 receptor agonists also appear to have a neutral effect on heart failure hospitalizations. Some SGLT-2 inhibitors provide ASCVD risk reduction, universally prevent heart failure hospitalization amongst those with T2DM and almost universally slow progression of kidney decline. Two SGLT-2 inhibitors have also been shown to be beneficial for treating HFrEF, regardless of T2DM status. National guidelines now recommend these agents be considered for patients with T2DM, often regardless of glycemic control, as a means of reducing cardiovascular and renal risk. 

ADDITIONAL RESOURCES

• Patient Handout
• Point-of-Care Reference Guide
  

References

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics – 2020 update. A report from the American Heart Association. Circulation 2020;141:e139-e596.
2. Rodriguez-Araujo G, Nakagami H. Pathophysiology of cardiovascular disease in diabetes mellitus. Cardiovasc Endocrinol Metab 2018;7:4-9.
3. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clinical Diabetes 2008;26:77-82.
4. Low Wang, CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus. Atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus – mechanisms, management, and clinical considerations. Circulation 2016;133:2459-2502.
5. Marwick TH, Ritchie R, Shaw JE, Kaye D. Implications of underlying mechanisms for the recognition and management of diabetic cardiomyopathy. J Am Coll Cardiol 2018;71:339-51.
6. American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes – 2021. Diabetes Care 2021;44(Suppl. 1):S73–S84
7. US Department of Health and Human Services. Food and Drug Administration. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Available from: https://www.fda.gov/media/71297/download. Accessed February 23, 2021.
8. White WW, Cannon CP, Heller SR, et al. Alogloptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
9. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patient with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
10. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs. placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. The CARMELINA randomized clinical trial. JAMA 2019;321:69-79.
11. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42.
12. Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observation from the SAVOR-TIMI 53 randomized trial. Circulation 2014;130:1579-88.
13. Package Insert. Bristol-Meyers Squibb Co. 2009.
14. Package Insert. Takeda Pharmaceuticals America, Inc. 2019.
15. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes – 2021. Diabetes Care 2021;44(Suppl. 1):S111–S124
16. Marso, SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
17. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
18. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019;381:841-51.
19. Hernandez AF, Green JB, Janmohamed S, et al. lbiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (HARMONY OUTCOMES): a double-blind, randomised placebo-controlled trial. Lancet 2018;392.1519-29.
20. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-30.
21. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
22. Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-39.
23. Das SR, Everett BM, Birtcher KK, et al. 2020 Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;76:1117–45.
24. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
25. Butler J, Zannad F, Fitchett D, et al. Empagliflozin improves kidney outcomes in patients with or without heart failure. Insights from the EMPA-REG OUTCOME trial. Circ Heart Fail 2019;12: e005875. DOI: 10.1161/CIRCHEARTFAILURE.118.005875
26. Packer M, Butler AJ, Filippatos G, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
27. Boehringer Ingelheim. EMPA-KIDNEY (The study of heart and kidney protection with empagliflozin). Available from: https://www.clinicaltrials.gov/ct2/show/NCT03594110. NLM Identifier NCT03594110. Accessed February 23, 2021.
28. Boehringer Ingelheim. Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction (EMPEROR-Preserved). Available from: https://clinicaltrials.gov/ct2/show/NCT03057951. NLM identifier NCT03057951. Accessed February 23, 2021.
29. Neal B, Perkovic V, Mahaffy KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
30. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.
31. Wiviott SD, Bonaca MP, Mosenzon O, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
32. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
33. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
34. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383: 1425-35.
35. Cherney DZI, McGuire DK, Charbonnel B, et al. Gradient of risk and associations with cardiovascular efficacy of ertugliflozin by measures of kidney function. Observations from VERTIS CV. Circulation 2021;143:602-5.
36. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus statement by the American association of clinical endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary. Endocr Pract 2020;26:107-39.
37. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177–232.
38. Writing Committee, Maddox TM, Januzzi JL Jr, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, Motiwala SR, Oliveros E, Patterson JH, Walsh MN, Wasserman A, Yancy CW, Youmans QR. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021 Feb 16;77(6):772-810. doi: 10.1016/j.jacc.2020.11.022. Epub 2021 Jan 11.

Back to Top