Could There Be a Current Treatment to Prevent Cardiovascular Disease?

Cardiovascular disease is the leading cause of death and disability in the United States.¹ The basis for clinical cardiovascular disease begins early in life and is influenced by modifiable risk factors, behaviors, and environmental exposures.²The major cardiovascular risk factors are dyslipidemia, hypertension, pre-diabetes, obesity, and smoking.³  Early intervention in managing cardiovascular risk factors is more important than treating the disease.  There is an urgent need to proactively treat cardiovascular risk factors.  High cholesterol, pre-diabetes, and hypertension should all be recognized and treated early.  How?

In recent years, many studies have found that a variety of anti-diabetic drugs exert significant protective action on the cardiovascular system.^4-6 The mechanism of these actions are partially independent of the hypoglycemic effects.^5-6  The sodium glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated reduced cardiovascular morbidity and mortality.^4-6 These agents reduce blood pressure (3-5 mmHg SBP); inhibit the reabsorption of sodium and glucose from the renal tubule, cause afferent arteriole dilation causing a reduction in plasma volume and a diuretic effect; suppress LDL-C while increasing HDL2-C; reduce arterial stiffness; improve endothelial function, reduce body weight (2-3 kg), and reduce inflammation and fibrosis in the myocardium.⁷  These mechanisms have resulted in significant reductions in major cardiac events.^4-5,8  Nonfatal myocardial infarction, hospitalization for heart failure, progression of albuminuria and all-cause mortality were significantly reduced.  Furthermore, the incidence of acute kidney injury was decreased.

Do the data support using these agents as preventative treatments for future cardiovascular agents? The answer appears to be yes.  In addition, combining these agents with renin-angiotensin aldosterone blockers (RAAS) and statins as an early preventative strategy to prevent cardiovascular disease and events should be considered.  RAAS blockade reduces blood pressure, left ventricular pressure and causes efferent arteriole dilation thereby acting synergistically with SGLT2 inhibitors. Statins reduce inflammation and LDL-C working in concert with SGLT2 inhibitors.  

Prior to starting this regimen, assessing patients for the risk of cardiovascular disease (primary prevention) with a biomarker prognostic series of cystatin-C, growth differentiation factor-15, and NT-proBNP would appear to be prudent.⁹ If these biomarkers are elevated, then starting SGLT2 inhibitors with RAAS blockade and statins should be started.  All other cardiovascular vasodilators and diuretics should be stopped prior to starting this regimen.  If these biomarkers are not elevated treating the patient with preventative guideline-directed medical care is suggested.

SGLT2 inhibitors are relatively well tolerated but have adverse effects that should be monitored.⁶Adverse effects include orthostatic hypotension (early in treatment), an increased risk of diabetic ketoacidosis (in type 1 DM), osmotic diuresis, bone fractures, and acute kidney injury (although controversial).  Creatinine clearance should be monitored prior to starting these agents.  Patients that are volume depleted should be rehydrated prior to starting these agents. SGLT2 inhibitors also have very few drug interactions making them easy to use.¹⁰ In the absence of a cardiovascular event or an adverse event the cocktail could be continued indefinitely.

In conclusion, cardiovascular disease is largely preventable.  We may have a category of drugs that can be used as preventative therapy in combination with RAAS inhibitors and statins for reducing cardiovascular disease and events. 

Mark A. Munger, PharmD, FCCP, FACC, is a professor of pharmacotherapy and adjunct professor of internal medicine, at the University of Utah, where he also serves as the associate dean of Academic Affairs for the College of Pharmacy.  

References:

1. Benjamin E, Muntner P, Alonso A, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics. Subcommittee.  Heart disease and stroke statistics-2019.  Circulation 2019;139:e56-e528.
2. Weintraub WS, Daniels SR, Burke LE, et al. on behalf ot he American Heart Association Advocacy Coordinating Council on Cardiovascular Disease in the Young, Council on Kidney in Cardiovascular Disease, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Clinical Cardiology, and Stroke Council.  Circulation 2011;124;967-990.
3. Chrysant SG, A new paradigm in the treatment of the cardiovascular disease continuum: focus on prevention. Hippokratia 2011;15(1):7-11.
4. Zhang X-L, Zhu Q-Q, Chen Y-H, Li X-L, Chen F, Huang J-A, Xu B. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: A systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc 2018;7:e007165. DOI: 10.1161/JAHA. 117.007165.
5. Zhang D-P, Xu L, Wang L-F, Wang J, Jiang F. Effects of antidiabetic drugs on left ventricular function/dysfunction: a systematic review and network meta-analysis. Cardiovasc Diabetol 2020;19:10  https://doi.org/10.1186/s12933-020-098-x
6. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors. JACC 2020;75(4) https://doi.org/10.1016/j.jacc.2019.11.031
7. Tentolouris A, Vlachakis P, Tzeravini E, Eleftheriadou I, Tentolouris N. SGLT2 inhibitors: A review of their antidiabetic and cardioprotective effects. Int J Enviorn Res Public Health 2019;16:2965.
8. Zelniker TA, Braunwald E. Clinical benefit of cardiorenal effects of sodium-gluvose cotransporter 2 inhibitors. JACC 2020;75(4) https://doi.org/10.1016/j.jacc.2019.11.0316 
9. Lindholm D, James SK, Gatrysch K, et al. Association of multiple biomarkers with risk of all-cause and cause-specific mortality after acute coronary syndromes.  A secondary analysis of the PLATO Biomarker Study. JAMA Cardiology 2018;3(12):1160-6.
10. What drugs can interact with SGLT2 inhibitors for diabetes. https://www.webmd.com/diabetes/qa/what-drugs-can-interact-with-sglt2-inhibitors-for-diabetes   Accessed 02/2020.