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Supplements Reducing the Risk of Cardiovascular Disease in Patients With Diabetes
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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
In recognition of the substantial prevalence of cardiovascular disease-related comorbidities among patients with diabetes and the potential for some agents to increase this risk, evaluation of cardiovascular outcomes is now a standard component of late-stage clinical trials involving antihyperglycemic agents. While most agents are evaluated in noninferiority trials to establish a lack of cardiovascular-related harm,
a few agents have shown significant reductions in cardiovascular-related outcomes, including mortality.
Am J Manag Care. 2018;24:-S0
Over the past decade, cardiovascular outcomes trials (CVOTs) have become an integral part of all novel antihyperglycemic drugs developed, with studies seeking, at a minimum, to establish a lack of cardiovascular-related harm and a few even showing cardiovascular-related benefits.1 This educational activity will provide an overview of the agents that have shown cardiovascular-related benefits and recent clinical trial data supporting their efficacy in reducing cardiovascular comorbidities alongside improving glycemic goals in patients with type 2 diabetes (T2D).

Background

To effectively evaluate cardiovascular benefits while ensuring that sample size and duration of follow-up remain reasonable, CVOTs require the use of composite end points comprised of major adverse cardiovascular events (MACEs), as explained in item 4 of  Table 1.2 The most common of these is the 3-point composite of major adverse cardiovascular event (3P-MACE), which can include cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke, although some studies add hospitalization for unstable angina (HUA) to the 3P-MACE (4P-MACE).2 However, the use of 4P-MACE is generally discouraged in the medical literature due to the subjectivity in ascertainment of HUA, lower prognostic relevance, and recent CVOTs indicating that antihyperglycemic agents have minimal impact on HUA.2 Because many CVOTs are noninferiority trials, using a 4P-MACE instead of 3P-MACE may shift the hazard ratio (HR) toward the null, which may be problematic.2 Therefore, most (but not all) trials will use a 3P-MACE to meet the safety standards.

Two primary classes of antihyperglycemic agents, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been shown to have beneficial cardiovascular effects on patients with T2D.3 Pertinent information, including clinical trial data and mechanisms of action of cardiovascular disease (CVD) risk reduction, for agents that have shown benefit are reviewed in the following pages.

SGLT2 Inhibitors

Inhibitors of SGLT2 work by inhibiting glucose reabsorption in the kidneys, thereby increasing urinary excretion of glucose and reducing hyperglycemia independent of insulin.4 There are

 4 FDA-approved agents for use in patients with T2D: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin; these agents may be prescribed as monotherapy or in combination with other antihyperglycemic agents.5

Mechanisms of CVD Risk Reduction in SGLT2 Inhibitors

Although the mechanisms by which SGLT2 inhibitors reduce the risk of cardiovascular events are not well understood, a few hypotheses have been outlined in the medical literature. In addition to the inhibitory effects on glucose reabsorption, downstream effects from SGLT2 inhibition include osmotic diuresis, natriuresis, lowering of body weight from calorie and fluid losses, lowering of uric acid, and lowering of blood pressure.6 One specific hypothesis suggests that SGLT2 inhibits the sodium-hydrogen exchanger, which has been shown in animal models to be highly effective at reducing myocardial injury.7 A second hypothesis speculates that SGLT2 inhibitors lead to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation to “an energy-efficient super fuel like ketone bodies,” which would account for improvements in myocardial and renal work efficiency and function.8,9 Third is the possible role of SGLT2 inhibitors on SGLT-induced toxic accumulations of sodium and calcium, which lead to cell death.7 Fourth and finally, glucagon is released by α cells in the pancreas following administration of SGLT2 inhibitors, which may be beneficial in heart failure (HF) through ionotropic effects.7 Both empagliflozin and canagliflozin have achieved superiority in reduction of 3P-MACE in recent clinical trials.10,11

EMPA-REG Trial

The EMPA-REG trial evaluated CVD morbidity and mortality in 7020 patients with T2D and at high risk for cardiovascular events who, in addition to the standard of care, were given

10 mg empagliflozin daily, 25 mg empagliflozin daily, or placebo.11 After a median observation time of 3.1 years, the primary outcome of a 3P-MACE occurred in 10.5% of patients (490/4687) in the pooled empagliflozin group compared with 12.1% of patients (282/2333) in the placebo group (hazard ratio [HR], 0.86; 95.02% CI, 0.74-0.99; P < .001 for noninferiority; P = .04 for superiority). With 3P-MACE incidence reductions of 43.9 and 37.4 per 1000 patient-years for placebo and empagliflozin groups, respectively, the number needed to treat for the primary outcome would be 160 patients. Although there were no differences between groups in the rates of MI or stroke, patients in the empagliflozin group showed significantly lower rates of death from cardiovascular causes (3.7% vs 5.9%, RRR 38%), hospitalizations for HF (2.7% vs 4.1%, RRR 35%), and death from any cause (5.7% vs 8.3%, RRR 32%).11 See the Figure12 for some scenarios of statistical analysis and consequences per the FDA’s guidance document. Adverse events (AEs) were similar between groups except that patients receiving empagliflozin had more genital infections during the study.11 Although concern has been expressed about the potential adverse renal effects of SGLT2 inhibitors, fewer patients in the empagliflozin group than placebo group had acute renal failure (5.2% vs 6.6%) and acute kidney injury (1.6% vs 1.0%).11 The ground-breaking achievement in CVD risk reduction from the EMPA-REG trial earned empagliflozin an FDA-approved indication for reduction of cardiovascular death in adults with T2D and established CVD.13

CANVAS Trial

Similar to the EMPA-REG trial, the CANVAS and CANVAS-R trials evaluated cardiovascular outcomes among a total of 10,142 patients (pooled from 2 trials) with T2D at high risk for cardiovascular events.10 After a mean follow-up of 188.2 weeks, or approximately 3.7 years, the rate of the 3P-MACE primary outcome was significantly lower in patients receiving canagliflozin compared with placebo (HR, 0.86; 95% CI, 0.75-0.97; P < .001 for noninferiority, P = .02 for superiority) (see Figure).10,12 Renal effects were also evaluated, and, although these did not meet statistical significance per the prespecified hypothesis testing sequence, the results showed a potential benefit of canagliflozin in the progression of albuminuria (HR, 0.73; 95% CI, 0.67-0.79) and composite outcome of sustained 40% reduction in estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (HR, 0.60; 95% CI, 0.47-0.77).10 Despite the CVD and potential renal benefits demonstrated in the CANVAS trial, patients who received canagliflozin also showed an increased risk of foot or toe amputations (HR, 1.97; 95% CI, 1.41-2.75).10 This risk of amputation was recently acknowledged in an FDA safety announcement and, consequently, a black box warning was added to canagliflozin.14 Healthcare providers must consider factors that may predispose patients to amputation alongside the potential cardiovascular benefits when choosing whether to begin canagliflozin therapy.14 Risk factors that should be considered include a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.13 The FDA is currently reviewing the data from CANVAS and other trials for an added indication of CVD risk reduction.15

Notable Ongoing CVOTs

Ertugliflozin is currently undergoing a phase 3 CVOT (NCT01986881) in approximately 8000 individuals with established vascular disease.16 The trial, referred to as the VERTIS CV study, began in late 2013 and has an expected primary completion date of September 2019. Enrolled patients will receive one of 15 mg ertugliflozin orally once daily, 5 mg ertugliflozin orally once daily, or placebo for up to 6.1 years; the primary outcome is time to first occurrence of 3P-MACE.16 Similarly, the DECLARE-TIMI (NCT01730534) is evaluating cardiovascular outcomes (ie, time to 3P-MACE and time to first event of cardiovascular death or hospitalization) in more than 17,276 participants, representing the largest CVOT to date, receiving either 10 mg dapagliflozin orally once daily or placebo for up to 6 years.17 The DECLARE-TIMI trial started in 2012 and had an estimated primary completion of July 2018.17

GLP-1 Receptor Agonists

In healthy individuals, GLP-1 is secreted after eating and augments insulin secretion while suppressing glucagon release, both of which lower glucose concentrations in the blood.18 In a similar mechanism, the GLP-1 RAs supplement this action in patients with T2D in a glucose-dependent manner.18,19 Additionally, GLP-1 RAs have been associated with reductions in body weight, lipid levels, and blood pressure.20 There are 2 primary types of GLP-1 RAs: short-acting and long-acting; short-acting agents (eg, exenatide and lixisenatide) work through inhibition of gastric emptying, while long-acting agents (eg, liraglutide, exenatide LAR, and semaglutide) work more strongly on fasting blood glucose through insulinotropic and glucagonostatic actions.18

Mechanisms of CVD Risk Reduction in GLP-1 RAs

Incretin-based therapy with the GLP-1 RAs offers cardioprotective effects through several mechanisms not mediated through improvements in hyperglycemia, weight loss, or blood pressure reduction.21 In studies of human umbilical vein endothelial cells, liraglutide showed antioxidative, anti-inflammatory, and antiapoptotic effects, in addition to reducing hyperglycemia-induced endoplasmic reticulum stress and attenuating endothelial cell dysfunction.21 Additional vasodilatory effects have been seen on the vascular system in both GLP-1 receptor-dependent and receptor-independent mechanisms, along with protections against ischemia-reperfusion injury.21 Lastly, GLP-1 RAs have also been noted as renoprotective via reductions of proteinuria and microalbuminuria.21 Two long-acting agents, liraglutide and semaglutide, have been shown in recent clinical trials to provide cardiovascular and/or mortality benefits in patients with T2D.3

LEADER Trial

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3. Singh AK, Singh R. Recent cardiovascular outcome trials of antidiabetic drugs: a comparative analysis. Indian J Endocrinol Metab. 2017;21(1):4-10. doi: 10.4103/2230-8210.196026.
4. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diabetes Vasc Dis Res. 2015;12(2):78-89. doi: 10.1177/1479164114561992.
5. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes–2018. Diabetes Care. 2018;41(suppl 1):S73-S85. doi: 10.2337/dc18-S008.
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7. Bell RM, Yellon DM. SGLT2 inhibitors: hypotheses on the mechanism of cardiovascular protection. Lancet Diabetes Endocrinol. 2017;6(6):435-437. doi: 10.1016/S2213-8587(17)30314-5.
8. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115-1122. doi: 10.2337/dc16-0542.
9. Ferrannini E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017;26(1):27-38. doi: 10.1016/j.cmet.2017.04.011.
10. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.
11. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720.
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13. Jardiance [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2017. www.accessdata.fda.gov/drugsatfda_docs/label/2017/204629s016lbl.pdf. Accessed May 11, 2018.
14. US Food and Drug Administration. FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). FDA website. www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Published May 6, 2017. Updated July 25, 2017. Accessed May 11, 2018.
15. Helfand C. ACC: waiting on the FDA’s heart-helping verdict, J&J shares more positive CV data for Invokana. FiercePharma website. www.fiercepharma.com/pharma/acc-awaiting-fda-verdict-j-j-touts-more-positive-cv-data-for-invokana. Published March 11, 2018. Accessed May 11, 2018.
16. Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835-004). clinicaltrials.gov/ct2/show/NCT01986881. Published November 19, 2013. Updated May 17, 2018. Accessed June 3, 2018.
17. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). clinicaltrials.gov/ct2/show/record/NCT01730534. Published November 21, 2012. Updated June 25, 2018. Accessed July 3, 2018.
18. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728-742. doi: 10.1038/nrendo.2012.140.
19. Zhao TC. Glucagon-like peptide-1 (GLP-1) and protective effects in cardiovascular disease: a new therapeutic approach for myocardial protection. Cardiovasc Diabetol. 2013;12(1):90. doi: 10.1186/1475-2840-12-90.
20. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association
of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2
diabetes managmenet algorithm–2018 executive summary. Endocr Pract. 2018;24(1):91-120. doi: 10.4158/CS-2017-0153.
21. Strain WD, Smith C. Cardiovascular outcome studies in diabetes: how do we make sense of these new data? Diabetes Ther. 2016;7(2):175-185. doi: 10.1007/s13300-016-0165-z.
22. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/NEJMoa1603827.
23. Victoza [prescribing information]. Plainsboro, NJ: Novo Nordisk Inc; 2017. www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf. Accessed May 12, 2018.
24. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377(9):839-848. doi: 10.1056/NEJMoa1616011.
25. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.
26. Actos [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2017.
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27. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2007;298(10):1180-1188. doi: 10.1001/jama.298.10.1180.
28. Gaziano JM, Cincotta AH, O’Connor CM, et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care. 2010;33(7):1503-1508. doi: 10.2337/dc09-2009.
29. Chamarthi B, Ezrokhi M, Rutty D, Cincotta AH. Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin. Postgrad Med. 2016;128(8):761-769. doi: 10.1080/00325481.2016.1243003.
30. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf. 2013;12(2):153-175. doi: 10.1517/14740338.2013.752813.
31. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care. 2018;41(5):917-928. doi: 10.2337/dci18-0007.
32. Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes. JAMA. 2018;319(15):1580-1591. doi: 10.1001/jama.2018.3024.
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