Lipid Luminations: Polypill: Concept Becomes Reality

Atherosclerotic cardiovascular disease (ASCVD) is a major cause of death and disability worldwide. More than 80% of the global burden of ASCVD occurs in low- and middle-income countries.(1) As a means of attenuating this global epidemic, the concept of a polypill was first suggested in 2003 by Wald and Law. The term “polypill” is rather generic, intended to describe one “pill” that contains multiple ingredients commonly used separately to reduce ASCVD risk. Their initial concept was a polypill that contained aspirin, statin, B-blocker, ACE inhibitor, diuretic and folic acid. They postulated that this polypill would reduce ASCVD risk by 80% when taken by all individuals over 55, or those with known heart disease. They further suggested this polypill could be used without the need for monitoring risk-factor levels or biochemical parameters.(2)

This concept was modified over many years and turned into reality by Cadila Pharmaceuticals of India.(3) Cadila markets a polypill that contains hydrochlorothiazide 25mg, atenolol 100mg, Ramipril 10 mg and simvastatin 40mg. They conducted The International Polycap Study (TIPS). (4) This trial demonstrated improved adherence with the polypill. In follow-up, Cadila instituted TIPS-3, an ongoing cardiovascular outcomes trial with 5,713 subjects that is fully enrolled and will complete this summer. The primary outcome will be a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), heart failure, resuscitated cardiac arrest, or revascularization with evidence of ischemia.

“There now are nine versions of the polypill in use worldwide.”

trial with a version of a polypill is The Heart Outcomes Prevention Trial (HOPE-3).(5) This multinational trial involved 12,705 subjects without known CV disease in men >55 and women >65 years old. The subjects were considered to be at intermediate risk with at least one of the following: HDL-C <39 mg/dl for men and <50 mg/dl for women, smoking, pre-diabetes, diet-controlled diabetes, family history of first-degree relative with premature coronary artery disease (CAD), or renal dysfunction.

In HOPE-3, their iteration of the polypill contained rosuvastatin 10mg, candesartan 16mg, and hydrochlorothiazide 25mg. This combination was chosen because the population-attributable risk for MI is estimated to be 66% derived from abnormal lipids and hypertension alone, as demonstrated in the INTERHEART Trial.(6) The primary outcome was a composite of CV death, nonfatal MI or stroke. With a mean duration of 5-6 years, this multinational 2x2 factorial placebo-controlled trial demonstrated a

29% reduction of the primary composite endpoint. It should be noted that the event reductions when separated into the lipid-only arm vs. the blood pressure arm, primarily were attributed to the reductions in lipids, accounting for 24% of the reductions in events. The blood pressure arm was only significant if the starting systolic blood pressure was 143 or greater.

Most recently, a meta-analysis including 3,140 multinational subjects – mean age 62, 75% male and 76% with a prior CV event – examined the ability of a polypill to achieve 2016 European Society of Cardiology (ESC) guideline targets for blood pressure, low-density lipoprotein cholesterol (LDL-C), and antiplatelet therapy.(7) The polypill used included simvastatin 40mg, aspirin 75mg, Lisinopril 10mg, and either atenolol 50mg or hydrochlorothiazide 12.5mg. The study authors concluded that, over 12 months, polypill therapy significantly improved the achievement of all three ESC targets compared with usual care. This effect was most prominent in those undertreated at baseline.

This brief article does not permit a more detailed analysis but was presented to demonstrate the ongoing and future efforts in this arena to provide low-cost, effective cardiovascular protections to large populations worldwide with a minimum of medical intervention. There now are nine versions of the polypill in use worldwide. Hopefully, ongoing trials will further refine the contributions this concept can provide to large-scale prevention of CV events.

Disclosure statement: Dr. Lillo received honoraria from Amarin.