In the SUSTAIN-6 trial (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes), 3297 patients with type 2 diabetes were randomized to once weekly semaglutide SC or placebo and were followed for a median of 2.1 years. The primary composite outcome was 3-point MACE, and the majority of the patients (83%) had established cardiovascular disease or chronic kidney disease . Semaglutide was noninferior to placebo for reduction of the primary endpoint (HR 0.74, 95% CI 0.58–0.95; Table 2), with a significantly lower risk of nonfatal stroke (HR 0.61; 95% CI 0.38-0.99) and a nonsignificant trend toward fewer nonfatal MIs with semaglutide compared with placebo .
The Harmony outcomes trial (A Long-Term, Randomized, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus) randomized 9463 exclusively secondary prevention patients with type 2 diabetes to once weekly albiglutide SC or placebo . At baseline, all patients had coronary, peripheral, or cerebrovascular disease, and 20% had premorbid heart failure. Treatment with albiglutide resulted in a 22% reduction in 3-point MACE, meeting not only noninferiority for cardiovascular safety but also superiority for efficacy at a median follow-up of 1.6 years (Table 2) . Of note, the addition of SGLT-2 inhibitors was more common in the placebo group, due to lesser glucose control, and may have biased the results toward the null .
The EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering) randomized 14 752 patients with type 2 diabetes (73.1% with previous cardiovascular events) to once weekly extended-release exenatide SC or placebo to test noninferiority for safety and superiority for 3-point MACE . Exenatide was noninferior to placebo for safety but not superior for efficacy (Table 2) .
The recently published REWIND trial (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) randomized 9901 patients with type 2 diabetes to dulaglutide or placebo, with 31.5% having baseline cardiovascular disease. Dulaglutide SC was superior to placebo for a primary outcome of 3-point MACE at 5.4 years of median follow-up (HR 0.88, 95% CI 0.79–0.99) and significantly reduced nonfatal stroke (HR 0.76, 95% CI 0.61–0.95) .
Also recently published was the first cardiovascular outcomes trial of an oral GLP-1RA. The PIONEER 6 trial (Peptide Innovation for Early Diabetes Treatment) randomized 3183 patients to daily oral semaglutide or placebo. The majority (84.7%) had cardiovascular or chronic kidney disease at baseline. Oral semaglutide met noninferiority for the primary outcome of 3-point MACE (HR 0.79, 95% CI 0.57–1.11) .
Unlike other cardiovascular outcomes trials of GLP-1RAs, which studied patients with stable cardiovascular disease or elevated risk, the ELIXA trial (Evaluation of Lixisenatide in Acute Coronary Syndrome) examined the impact of lixisenatide on patients with recent acute coronary syndrome. Six thousand sixty-eight patients with type 2 diabetes and an MI or hospitalization for unstable angina in the previous 180 days were randomized to lixisenatide or placebo with a primary outcome of nonfatal MI, nonfatal stroke, cardiovascular death, or urgent revascularization (4-point MACE). The primary outcome showed noninferiority but not superiority of lixisenatide compared with placebo (Table 2) .
Prior to the publication of the above Harmony Outcomes, REWIND, and PIONEER 6 trials, a meta-analysis of cardiovascular outcomes trials of GLP-1RAs examined the overall effects of this drug class. In this meta-analysis, which included 33, 457 participants, GLP-1RA treatment significantly reduced 3-point MACE (10% RRR, HR 0.90, 0.82–0.99, P = 0.033), cardiovascular mortality (13% RRR, HR 0.87, 0.79–0.96, P = 0.007), and all-cause mortality (12% RRR, HR 0.88, 0.81–0.95, P = 0.002) when compared with placebo, without any evidence of heterogeneity across trials .
Currently approved GLP-1RAs are self-administered by SC injection, although oral formulations are being studied in ongoing trials [27,30]. Starting and target doses of approved GLP-1RAs are outlined in Table 1a and 1b. Prior to GLP-1RA initiation, baseline antiglycemic drug therapy should be examined for the presence of a DPP4i, which should be discontinued, or for background sulfonylurea or basal insulin, which should be reduced by 50 or 20%, respectively, in patients at elevated risk of hypoglycemia. To improve tolerability, especially of gastrointestinal side effects, slow up-titration from the lowest dose is recommended .
Previous glucose-lowering trials of GLP-1RAs have identified common adverse effects, such as nausea, vomiting, and diarrhea, as well as rare serious events including pancreatitis and pancreatic cancer. The cardiovascular outcomes trials described above similarly identified gastrointestinal side effects associated with GLP-1RA treatment, but there was no significant difference detected in the rates of acute pancreatitis or pancreatic cancer in LEADER, SUSTAIN-6, Harmony Outcomes, EXSCEL, REWIND, or PIONEER 6 trials [22–27].
In addition, animal studies have suggested an increased risk of medullary thyroid cancers in rodent models . For this reason, patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 were excluded from the LEADER, SUSTAIN-6, Harmony Outcomes, EXSCEL, REWIND, and PIONEER 6 trials. In these trials, GLP-1RA therapy did not increase the risk of medullary thyroid cancer [22–27].
Hypoglycemia, which has been associated with an increased risk of adverse cardiovascular events [11,12], can occur with GLP-1RAs when used in combination with insulin or sulfonylureas. However, in many of the cardiovascular outcomes trials, patients randomized to GLP-1RA had a numerically lower rate of hypoglycemic episodes [22,24]. In LEADER, patients treated with liraglutide were less likely to have the addition of insulin and thus had lower rates of severe hypoglycemia . Patients treated with semaglutide in SUSTAIN-6 did experience higher rates of diabetic retinopathy (HR 1.76; 95% CI 1.11–2.78), perhaps due to marked and rapid reductions in glucose. This has not been observed in other GLP-1RA trials.
Putative mechanisms of cardiovascular benefit
GLP-1RA therapy appears to significantly reduce atherothrombotic cardiovascular events. Hypothesized mechanisms of cardiovascular benefits of GLP-1RAs include both their impact on cardiovascular risk factors, such as blood pressure, as well as direct effects via atherogenesis, inflammatory pathways, and endothelial function . In fact, the primary cardiovascular benefits of GLP-1RAs appear to be largely independent of established atherosclerotic risk factors .
GLP-1RA treatment has demonstrated a consistent reduction in weight and blood pressure . In the above cardiovascular outcomes trials, GLP-1RA treatment resulted in a small but significant impact on weight loss, ranging from 0.7 kg with lixisenatide to as much as 4.3 kg with semaglutide SC. Similarly, systolic blood pressure was reduced across the board, ranging from 1 mmHg with abiglutide to 3 mmHg with oral semaglutide [22–28].
In addition to relatively modest but favorable effects on classical cardiovascular risk factors, GLP-1 receptor expression has been identified in cardiovascular tissues, and GLP-1 peptides have been linked to reduction in reactive oxygen species in endothelial cells and cardiomyocytes . Infusion of GLP-1 and GLP-1RA in human subjects has resulted in improvements in left ventricular function, hemodynamics, and reduction in ischemic injury .
Sodium-glucose cotransporter 2 inhibitors
Mechanism of action
The sodium-glucose cotransporter 2 is responsible for proximal renal tubular reabsorption of glucose. Inhibition of SGLT2 prevents glucose resorption, promoting excretion in the urine and thereby reducing circulating blood glucose levels, with a greater effect the higher the plasma glucose concentration and relative protection against hypoglycemia .
Members of the SGLT2i class that have demonstrated cardiovascular risk reduction in randomized trials include empagliflozin and canagliflozin, both of which reduced 3-point MACE, and dapagliflozin, which was noninferior for MACE and significantly reduced a composite of cardiovascular death or heart failure hospitalization [36–38]. Prescribing details are outlined in Table 1a and 1b.
Cardiovascular outcomes trials
The first cardiovascular outcomes trial to test an SGLT2i was the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Seven thousand twenty patients with type 2 diabetes and established cardiovascular disease were randomized to empagliflozin or placebo . Treatment with empagliflozin was superior to placebo, resulting in a 14% reduction in 3-point MACE (Table 1a and 1b), driven by a 38% reduction in the risk of cardiovascular death (3.7 vs 5.9%; HR 0.62, 95% CI 0.49–0.77). The rates of heart failure were reduced by 35% in patients randomized to active empagliflozin (HR 0.65, 95% CI 0.50–0.85) , as were related endpoints including hospitalization or death from heart failure and investigator reported heart failure . These observations have been replicated in other SGLT2i trials [37,38].
While 10.1% of study population had heart failure at baseline, effects of empagliflozin on heart failure outcomes were consistent across patients with and without baseline heart failure. Similarly, baseline heart failure medication use did not modify the impact of empagliflozin on outcomes .
In the CANVAS Program (CANVAS: Canagliflozin Cardiovascular Assessment Study and CANVAS-R: A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus), a total of 10, 142 participants with type 2 diabetes were randomized to canagliflozin or placebo and followed for 3-point MACE for a median of 3.6 years . The study population included both patients with a history of atherosclerotic vascular disease (72.2%) and those at elevated risk (27.8%), and 17.5% of participants had chronic kidney disease at baseline .
Compared with placebo, significantly fewer participants on canagliflozin reached the primary outcome of cardiovascular death, nonfatal MI, or nonfatal stroke (Table 1a and 1b). There was also a significant reduction in the risk for hospitalization for heart failure (HR 0.67; 95% CI 0.52–0.87).
In the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) Trial, 17, 160 patients with type 2 diabetes were randomized to dapagliflozin or placebo and were assessed for primary efficacy outcomes of 3-point MACE and a composite of cardiovascular death or heart failure hospitalization at a median follow-up of 4.2 years . The study population included patients with established, clinically evident atherosclerotic vascular disease (40.6%) and those at elevated risk (59.4%). At baseline, 10% of enrolled patients had a history of heart failure .
Dapagliflozin met noninferiority for 3-point MACE (Table 1a and 1b) and reduced the primary efficacy composite endpoint, yielding a 17% decrease in the rate of cardiovascular death or heart failure hospitalization (4.9 vs 5.8%; P = 0.005) driven by a reduction in heart failure hospitalization (HR 0.73, 0.61–0.88) . This benefit for heart failure hospitalization was observed in patients both with (7.8 vs 9.3%, HR 0.83, 0.71–0.98) and without established atherosclerotic cardiovascular disease (2.8 vs 3.4%, HR 0.84, 0.67–1.04; P = 0.99 for interaction).
SGLT2is are oral daily medications that can be initiated with limited monitoring. Doses of the individual agents described above are outlined in Table 1a and 1b. In patients with well controlled HbA1c or a history of frequent hypoglycemia, recommended medication adjustments include a 50% reduction in sulfonylurea dose and a 20% reduction in basal insulin dose at the time of SGLT2i initiation . If the patient is taking a DPP4i, the prescribing physician may decide to discontinue that medication first before starting the SGLT2i.
Because the mechanism of SGLT2i may induce some osmotic diuresis via glucosuria, consideration should be given to reduce doses of thiazide or loop diuretics at the time of SGLT2i initiation to avoid excessive diuresis and volume depletion .
Due to their effect of increased urinary glucose excretion, SGLT2is are known to increase the risk of genital mycotic infections. In the EMPA-REG trial, genital infections and urosepsis were rare but more frequently reported in the empagliflozin group . Similarly, in DECLARE-TIMI 58, treatment with dapagliflozin was associated with an increased risk of diabetic ketoacidosis (0.3 vs 0.1%, P = 0.02) and of genital infections leading to drug discontinuation (0.9 vs 0.1%, P < 0.001) .
Unique to CANVAS, canagliflozin was associated with an increased risk of amputation (HR 1.97; 95% CI 1.41–2.75), a safety signal not found in other SGLT2i trials to date and the basis of an FDA black box warning [37,40]. Similarly, fractures were more common with canagliflozin in the CANVAS trial; whereas, there was no increase in the rate of fracture with empagliflozin or dapagliflozin [36,38]. However, the CREDENCE trial, a recently published trial of canagliflozin in 4,401 patients with type 2 diabetes and chronic kidney disease did not show an increased risk of amputation or fractures .
Putative mechanisms of cardiovascular benefit
In contrast to GLP-1RAs, where the clinical benefits appear to be driven predominantly by a reduction in atherothrombotic endpoints, drugs in the SGLT2i class have demonstrated a prominent impact on heart failure in study populations where the majority of patients did not carry a heart failure diagnosis at baseline.
Several possible mechanisms underlying the benefits of SGLT2is on heart failure have been hypothesized, including direct effect on circulating volume through osmotic diuresis, reduction in typical risk factors including body weight and systolic blood pressure, and via proposed impacts on cardiovascular metabolism. Data from the EMPA-REG trial suggest that markers of plasma volume, specifically hematocrit and hemoglobin, not markers of glycemia, are the most important factors in determining the benefit of empagliflozin .
In DECLARE-TIMI 58, dapagliflozin mitigated multiple cardiovascular risk factors in addition to HbA1c, including incremental lowering of weight (1.8 kg), systolic blood pressure (3 mmHg), and diastolic blood pressure (<1 mmHg) , findings similar to those demonstrated with empagliflozin and canagliflozin [36,37].
Beyond inducing diuresis and generating modest reductions in weight and blood pressure, several direct mechanisms have been proposed for the reduction in risk of heart failure . SGLT2is may alter myocardial metabolism and improve myocardial efficiency .
Primary vs secondary atherosclerotic cardiovascular disease prevention
The majority of patients included in the existing cardiovascular outcomes trials of GLP-1RA and SGLT2i therapies had existing ASCVD at baseline, so data for patients without established ASCVD, or ‘primary prevention’, are scarce (Table 2). Absolute cardiovascular event rates in that population are lower, further limiting the ability to estimate the effects of GLP-1RAs and SGLT2is in patients without ASCVD. However, a recent meta-analysis that included data from the LEADER, SUSTAIN-6, Harmony Outcomes, EXSCEL, and ELIXA trials, suggested evidence of treatment heterogeneity. GLP-1RA treatment reduced MACE by 13% (HR 0.87, 95% CI 0.82–0.92) in patients with established ASCVD, whereas there was no benefit observed in patients without ASCVD at baseline (HR 1.03, 95% CI 0.87–1.23; P-interaction = 0.028) . Similarly, in a meta-analysis that included data from the EMPA-REG, CANVAS, CANVAS-R, and DECLARE-TIMI 58 trials, SGLT2i reduced MACE by 14% in patients with baseline ASCVD (HR 0.86, 95% CI 0.80–0.93), but no benefit was observed in patients without ASCVD at baseline (HR 1.00, 95% CI 0.87–1.16; P-interaction = 0.0501) .
By contrast, SGLT2i reduced the risk of cardiovascular death or heart failure hospitalization by 23% (0.77, 95% CI 0.71–0.84), a benefit that was consistent regardless of the presence or absence of ASCVD or heart failure at baseline . GLP-1RA treatment did not reduce the risk of heart failure hospitalization .
Chronic kidney disease
Chronic kidney disease (CKD) is a common complication of diabetes and a prevalent comorbidity in the cardiology clinic. Patients with CKD have elevated rates of MACE, including MI, stroke, heart failure, and cardiovascular death . Patients with significant renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 of body surface area, were excluded from all of the above SGLT2i cardiovascular outcomes trials, with a more stringent cutoff of eGFR greater than 60 in the DECLARE-TIMI 58 Trial. By contrast, patients with eGFR less than 30 mg/min/1.73 m2 were eligible for LEADER, SUSTAIN-6, REWIND, and PIONEER 6 [22,23,26,27]. Although a minority of patients enrolled had a reduced eGFR, liraglutide was at least as effective, if not more so, among those with baseline renal dysfunction . Similar observations have been seen with the SGLT2i efficacy for MACE .
Beyond their effects on cardiovascular endpoints, GLP-1RA and SGLT2i therapies have been implicated in renal protection. All three major SGLT2i cardiovascular outcomes trials have demonstrated significant reductions in hard renal endpoints. In a meta-analysis, treatment with SGLT2i reduced a composite of reduction in renal function, progression to end-stage kidney disease, or renal death by 45% (HR 0.55, 95% CI 0.48–0.64) .
The recently published CREDENCE trial randomized patients with type 2 diabetes and albuminuric CKD on background renin–angiotensin system blockade to canagliflozin or placebo. The trial was stopped early for efficacy of canagliflozin, with a 30% lower risk of the composite primary outcome of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular cause . Similarly, the risk of end-stage kidney disease, defined as dialysis, transplantation, or a sustained eGFR<15, was reduced by 32%. This trial also recapitulated results from the CANVAS Program, demonstrating a 20% reduction in 3-point MACE and a 39% reduction in heart failure hospitalization .
GLP-1RAs have also demonstrated renal protection, though primarily via a reduction in intermediate endpoints such as albuminuria. In a prespecified secondary analysis of the LEADER trial, fewer participants in the liraglutide group met a composite outcome of new onset macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or renal death (HR 0.78; 95% CI 0.67–0.92), driven by new onset persistent macroalbuminuria (HR 0.74; 95% CI 0.60–0.91) . SUSTAIN-6 yielded similar findings .
Dose adjustments and contraindications based on eGFR are outlined in Table 1.
Use in combination
At this time, there are no trials examining the impact of combination therapy with both a GLP-1RA and an SGLT2i on cardiovascular outcomes. The DURATION-8 trial randomized 695 patients to exenatide plus dapagliflozin, exenatide plus placebo, or placebo plus dapagliflozin for 28 weeks . Combination therapy with exenatide and dapagliflozin was superior to either alone for the primary endpoint of change in HbA1c as well as several secondary endpoints including weight loss and reduction in systolic blood pressure, with no significant increase in adverse events with combination therapy . These findings suggest that GLP-1RA and SGLT2i therapy may have complementary action not only in glycemic control but potentially in pathways that yield cardiovascular benefit. Combination therapy is endorsed in the current American and European recommendations for approach to glucose management in type 2 diabetes .
Use without background metformin therapy
The benefits of empagliflozin and liraglutide were not modified by baseline medication use, although there was a high rate of background metformin therapy in both trials [22,36]. The American Diabetes Association and European Association for the Study of Diabetes consensus recommendations identify metformin as first-line therapy, after which the addition of cardioprotective therapy with a GLP-1RA or SGLT2i can be considered . However, the cardiovascular benefits of GLP-1RA and SGLT2i therapy may be independent of baseline antihyperglycemic medication use.
Use in patients with type I diabetes mellitus
Although these therapies can be used in combination with insulin, neither the GLP-1RA nor SGLT2i classes have been approved for use in patients with Type I diabetes.
Use in patients without diabetes mellitus
Given the notable reductions in heart failure-related outcomes, there is growing interest in the use of SGLT2is in heart failure patients without diabetes, especially as many proposed mechanisms of benefit do not rely on antihyperglycemic effects. To date, SGLT2is are not yet approved for patients without diabetes. However, there are several ongoing trials to evaluate the benefits of SGLT2i drugs in nondiabetic patients with heart failure. These include EMPEROR-PRESERVED and EMPEROR-REDUCED, which evaluate the impact of empagliflozin on a composite of cardiovascular death or heart failure hospitalization in patients with heart failure with a preserved and reduced ejection fraction, respectively, without a requirement for type 2 diabetes (NCT03057951, NCT03057977); and the DAPA-HF trial, which investigates the impact of dapagliflozin on a composite primary outcome of cardiovascular death, heart failure hospitalization, or urgent heart failure visit in patients with reduced ejection fraction, with or without type 2 diabetes (NCT03036124).
There are multiple ongoing or recently completed trials in these cardioprotective drug classes. In the GLP-1RA class, these include the SELECT trial, which will test the effects of semaglutide on CV outcomes in overweight and obese patients without diabetes (NCT03574597). Multiple SLGT2i trials are also underway, including the VERTIS-CV trial evaluating ertugliflozin in adults with type 2 diabetes and established cardiovascular disease ; the SCORED trial evaluating sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, in patients with type 2 diabetes, cardiovascular risk factors, and moderate renal impairment (NCT03315143); and SOLOIST-WHF, which examines sotagliflozin in patients with type 2 diabetes with ejection fraction less than 50% after a heart failure hospitalization (NCT03521934).
Drugs under investigation
There are several drugs under investigation that may further expand the scope of cardioprotective drugs, including recent interest in ‘dual incretin’ therapies of both GLP-1 and glucose-dependent insulinotropic (GIP) hormone. A recently published human phase 2 trial randomized 108 adults with type 2 diabetes to a combined GIP/GLP-1 receptor agonist, open label liraglutide, or placebo for 12 weeks. The dual agonist resulted in significantly better glycemia, more weight loss, and lower total cholesterol . A second phase 2 trial randomized 555 participants with type 2 diabetes to a dual GIP/GLP-1 receptor agonist, dulaglutide, or placebo for 26 weeks. The dual agonist resulted in significantly greater glycemic control and weight loss than dulaglutide . These novel diabetic therapies, which build on existing GLP-1RA therapy, may also have promise for cardioprotection, though this has yet to be studied.
Approved drugs in the GLP-1RA and SGLT2i classes have demonstrated consistent and significant benefits in reducing adverse cardiovascular outcomes – including MI, stroke, heart failure, and cardiovascular death. Figure 1 outlines a simple clinical algorithm, so that these agents may be more frequently incorporated into usual cardiovascular practice for the benefit of patients. As cardiologists have long focused on attentive management of lipids, blood pressure, antiplatelets, smoking, weight, and physical activity, they now have additional tools to incorporate into the comprehensive care of patients with diabetes at high cardiovascular risk.
Conflicts of interest
B.M.E. reports grant support from the Novartis and the NHLBI, and consulting income from Roche Diagnostics, Amgen, Novartis, the NIDDK, and the FDA. J.M.B.is supported by a T32 postdoctoral training grant fromthe National Heart, Lung, and Blood Institute (T32HL007604).
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Keywords:© 2019Wolters Kluwer Health Lippincott Williams Wilkins
diabetes; atherosclerotic cardiovascular disease; glucagon-like peptide 1 receptor antagonists; sodium-glucose cotransporter 2 inhibitors