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Supplements Reducing the Risk of Cardiovascular Disease in Patients With Diabetes
The Burden of Cardiovascular Disease in Patients with Diabetes
Brooke Hudspeth, PharmD, CDE
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Antihyperglycemic Medications for Cardiovascular Disease Risk Reduction
Jennifer D. Goldman, PharmD, RPh, CDE, BC-ADM, FCCP
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Antihyperglycemic Medications for Cardiovascular Disease Risk Reduction

Jennifer D. Goldman, PharmD, RPh, CDE, BC-ADM, FCCP
The LEADER trial evaluated a primary outcome of 3P-MACE in 9340 patients with T2D who were also at high risk of cardiovascular events.22 After a median follow-up of 3.8 years, the primary outcome occurred in 13% of patients (608/4668) receiving liraglutide compared with 14.9% in the placebo group (HR, 0.87; 95% CI, 0.78-0.97; P < .001 for noninferiority, P = .01 for superiority).22 Death from cardiovascular-related causes was also lower in the liraglutide group compared with placebo (HR, 0.78; 95% CI, 0.66-0.93; = .007), as was death from any cause (HR, 0.85; 95% CI, 0.74-0.97; P = .02) (see Figure).12,22 Additionally, the incidence of a composite outcome of renal or retinal microvascular events was lower in patients receiving liraglutide compared with placebo (HR, 0.84; 95% CI, 0.73-0.97; P = .02).22 AEs that occurred significantly more often in patients receiving liraglutide were predominantly related to gastrointestinal (GI) issues and included severe hypoglycemia (P = .02), acute gallstone disease (P < .001), injection-site reaction (P = .002), nausea (< .001), vomiting (P < .001), diarrhea (P < .001), abdominal pain (= .03), decreased appetite (P = .01), and abdominal discomfort (P = .002).22 The number of patients needed to treat over a 3-year period to prevent one 3P-MACE was 66, with 98 required to prevent a death from any cause.22 The results of the LEADER trial earned liraglutide an FDA-approved indication for reduction of major cardiovascular AEs in patients with T2D and established CVD.23 

In addition to CVD risk reduction, secondary outcome results from the LEADER trial have shown liraglutide offers renoprotective effects.24 The renal outcome was defined as a composite of new-onset persistent microalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease.24 After the median follow-up of 3.8 years, the renal outcome occurred in significantly fewer patients given liraglutide than those given placebo (HR, 0.78; 95% CI, 0.67-0.92; P = .003), with similar rates of renal AEs between the groups.24


The SUSTAIN-6 trial evaluated the cardiovascular risk of 2 doses of once-weekly semaglutide (0.5 mg and 1.0 mg) compared with placebo in 3297 patients with T2D; 83% of trial participants had established CVD, chronic kidney disease, or both at baseline.25 After a median follow-up of 2.1 years, the primary outcome of 3P-MACE occurred in 6.6% of patients (108/1648) receiving semaglutide and 8.9% of patients (146/1649) receiving placebo (HR, 0.74; 95% CI, 0.58-0.95; P < .001 for noninferiority, P = .02 for superiority). Although deaths from cardiovascular causes were similar between groups, nonfatal stroke occurred in significantly fewer patients in the semaglutide group compared with placebo (HR, 0.61; 95% CI, 0.38-0.99; P = .04), as did new or worsening nephropathy (HR, 0.64; 95% CI, 0.46-0.88; P = .005) (see Figure).12 Despite these benefits, retinopathy complications were found to be significantly higher (HR, 1.76; 95% CI, 1.11-2.78; P = .02).25 The authors concluded that over a period of 24 months, according to Kaplan-Meier estimates, 45 patients would need to be treated to prevent one 3P-MACE outcome.25 AEs were generally similar between groups; however, semaglutide was associated with an increased incidence of GI issues, which led to more study discontinuations in this group.25 


Thiazolidinediones (TZDs) are the only antihyperglycemic agents to directly reduce insulin resistance, but their use is often limited by serious adverse events (SAEs), including weight gain, increased bone fracture risk in postmenopausal women and elderly men, and elevated risk for chronic edema or HF.20 Additionally, these agents have been associated with an increased risk of bladder cancer; however, other studies have found a statistically significant increase in risk lacking.20,26

A meta-analysis conducted by Lincoff et al in 2007 evaluated the cardiovascular outcomes in 16,390 patients receiving either pioglitazone or control therapy across 19 clinical trials ranging in duration from 4 months to 3.5 years.27 Researchers found the primary outcome of 3P-MACE occurred in 4.4% of patients (375/8554) taking pioglitazone and 5.7% of patients (450/7836) taking control therapy (HR, 0.82; 95% CI, 0.72-0.94, P = .005); however, pioglitazone was also associated with an increased risk of serious HF (HR, 1.41; 95% CI, 1.14-176; P = .002), albeit without an increased risk of mortality.27 Despite potential benefits to CVD risk reduction, AEs, such as HF, limit the use of pioglitazone in patients with T2D.20


In addition to TZDs, the quick-release (QR) formulation of bromocriptine, a dopamine-2 agonist, has demonstrated cardiovascular benefits in patients with T2D.28,29 In the Cycloset Safety Trial, cardiovascular outcomes were evaluated in 3095 patients with T2D randomized to receive bromocriptine or placebo; the study’s primary all-cause safety end point was the occurrence of any SAEs.28 The occurrence of CVD events was defined as a composite of MI, stroke, coronary revascularization, and hospitalization for angina or congestive heart failure.28 After 52 weeks, the bromocriptine-QR group demonstrated significantly fewer CVD end points compared with placebo (HR, 0.60; 95% 2-sided CI, 0.35-0.96), with similar SAEs between the groups (HR, 1.02; 95% 1-sided CI, 1.27).28 In the follow-up analysis evaluating CVD outcomes, researchers found a 55% CVD hazard risk reduction associated with bromocriptine-QR versus placebo (HR, 0.45; 95% CI, 0.23-0.88; P = .028).29 Among patients with poor glycemic control at baseline (defined as glycated hemoglobin [A1C] ≥ 7.5%), bromocriptine-QR demonstrated significantly improved efficacy compared with placebo in reduction of A1C (< .001) and achievement of goal less than or equal to 7% (30% vs 3%, P = .003).29 Despite these benefits, along with an unlikelihood of causing hypoglycemia, the use of bromocriptine is often limited in practice due to it being less efficacious than other agents, such as metformin, and having an unfavorable GI AE profile.30

Comparison of Agents and 2018 Clinical Guidelines

While multiple CVOTs have successfully demonstrated noninferiority, the CVOTs reviewed in this activity focus primarily on SGLT2 inhibitors and GLP-1 RAs, as these agents have been shown to provide cardiovascular benefits, renal benefits, and acceptable safety profiles, as summarized in Table 2.3,10 In addition to reductions in the 3P-MACE outcome, liraglutide and empagliflozin have been shown to reduce all-cause mortality, and semaglutide has been shown to reduce the risk of nonfatal stroke.3

The 2018 clinical practice guidelines published by the American Association of Clinical Endocrinologists and American College of Endocrinology provide a treatment algorithm for the progression of T2D based on entry A1C levels and symptoms to determine whether monotherapy, dual therapy, or triple therapy should be initiated.20 Both SGLT2 inhibitors and GLP-1 RAs are recommended in stages of monotherapy, dual therapy, and triple therapy; TZDs are recommended with caution.20 Specifically, if a patient has a history of atherosclerotic CVD, the guidelines recommend that initiation of dual therapy include empagliflozin or liraglutide.31

Although healthcare providers must bear in mind specific warnings and precautions that may discourage a particular agent’s use, the guidelines do not make any specific recommendations between SGLT2 inhibitors and GLP-1 RAs.20 To evaluate comparative efficacy between these agents and dipeptidyl-peptidase-4 (DPP-4) inhibitors against either placebo or no treatment, Zheng et al conducted a meta-analysis using mortality and cardiovascular end points.32 The meta-analysis covered 236 trials for a total of 176,310 patients, with a primary outcome of all-cause mortality and secondary outcomes that included CVD mortality, HF, MI, unstable angina, stroke, and safety end points (AEs and hypoglycemia).32 Researchers found that SGLT2 inhibitors (HR, 0.80; 95% CI, 0.71-0.89) and GLP-1 RAs (HR, 0.88; 95% CI, 0.81-0.94), but not DPP-4 inhibitors (HR, 1.02; 95% CI, 0.94-1.11), were associated with significantly reduced all-cause mortality in patients with T2D.32 Additionally, SGLT2 inhibitors were associated with significantly lower rates of cardiovascular mortality (HR, 0.79; 95% CI, 0.69-0.91), HF events (HR, 0.62; 95% CI, 0.54-0.72), and MI (HR, 0.86; 95% CI, 0.77-0.97); GLP-1 RAs were associated with lower rates of cardiovascular mortality (HR, 0.85; 95% CI, 0.77-0.94) but increased risk of AEs leading to study discontinuation (vs SGLT2 inhibitors, HR, 1.80; 95% CI, 1.44-2.25; vs DPP-4 inhibitors, HR 1.93; 95% CI, 1.59-2.35).32 These results indicate that either SGLT2 inhibitors or GLP-1 RAs would be effective at improving mortality outcomes among patients with T2D; however, SGLT2 inhibitors may yield fewer AEs and therefore be better tolerated by patients.

Ironically, despite the better tolerability compared with other agents, SGLT2 inhibitors have had several FDA warnings issued over the past 3 years, including increased risk of bone fracture and decreased bone mineral density (canagliflozin), ketoacidosis and serious urinary tract infections (all agents), increased risk of leg and foot amputations (canagliflozin), and acute kidney injury (canagliflozin and dapagliflozin).33


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