More Pills, More Problems: The Polypill Revisited

August 3, 2011

By Jonathan Leventhal

Faculty Peer Reviewed

Polypharmacy has become an integral part of daily life for millions of chronically ill patients worldwide, and rightfully so. Evidence-based studies have repeatedly demonstrated that multiple drugs are required for optimal therapeutic management in chronic diseases including diabetes, hypertension, and heart disease. [1-4] A typical patient with cardiovascular disease will likely be on aspirin, a statin, an ACE inhibitor, a diuretic, a calcium channel- or beta-blocker, and possibly antidiabetic medications. Cardiovascular disease is only one area in which effective management is achieved through a combination of drugs. Patients with HIV/AIDS, malaria, tuberculosis, and asthma also take multiple medications. Unfortunately, the increasing complexity of drug regimens has its drawbacks.

As a third-year medical student on the Ambulatory Care rotation, interacting with chronically ill patients in the outpatient setting opened my eyes to the psychologically taxing and physically demanding effect polypharmacy has on the quality of patients’ lives. For instance, a poorly controlled diabetic with other medical comorbidities must not only remember to take numerous pills at different times of the day in relation to meals, but also to inject insulin subcutaneously. The patient must also do fingersticks to monitor blood glucose and then make further dietary or medication adjustments accordingly. The regimen is laborsome. It is no wonder that so many of my patients are noncompliant with their medications.

Nonadherence to medication is a global phenomenon that contributes to the discrepancy between physicians’ expectations and actual clinical outcomes. One study found that only 30% of patients with chronic conditions such as diabetes and heart failure are compliant with their medications. [5] The Office of the Inspector General estimated that noncompliance in patients with cardiovascular disease results in an estimated 125 000 excess deaths and several thousand hospitalizations per year. [6]

Treatment complexity is a well-recognized barrier to compliance with medications. [7,8] Patients with multiple prescriptions are more prone to misuse medications, with an increased risk of adverse reactions. Because polypharmacy is a contributing factor to medication noncompliance, there has been a growing trend toward simplifying drug regimens and combining medications into single pills. [1] Fixed-dose combinations (FDCs) of 2-3 medications in one pill are already in widespread use. Some common cardiovascular FDCs include sitagliptin/metformin (Janumet), glyburide/metformin (Glucovance), amlodipine/benazepril (Lotrel), losartan/hydrochlorothiazide (Hyzaar), and ezetimibe/simvastatin (Vytorin).

These combination pills can improve medication compliance. A meta-analysis that reviewed the use of FDCs in medical conditions including tuberculosis, HIV/AIDS, hypertension, and diabetes found that the risk of nonadherence with a medication regimen was reduced by 24-26% with FDCs compared to conventional single-drug regimens. [1] Two additional retrospective analyses demonstrated a 29% improvement in treatment adherence with FDCs in patients with hypertension [9] and 13% improvement in patients with diabetes. [10]

Taking it a step further, imagine a world in which one “magic bullet” pill could manage chronic disease and even be used in preventive care. The “polypill” was first proposed in 2003 for the prevention of cardiovascular disease. [11] The original model incorporated 6 components into a single pill: aspirin, a statin, 3 antihypertensives (diuretic, beta-blocker, ACE inhibitor), and folic acid. [11] Wald and Law postulated that administering the polypill to individuals older than 55 years of age would reduce the incidence of cardiovascular disease by more than 80%. [11] Another study on the potential impact of the polypill in US adults over age 55 projected that it would prevent 3.2 million cases of coronary artery disease and 1.7 million strokes over 10 years. [12] The numbers are captivating.

The Indian Polycap Study (TIPS) is the largest randomized trial to date to compare the efficacy of the “Polycap” with other combinations of medications. [13] The study was conducted on middle-aged adults without prior heart disease but with at least one cardiovascular risk factor (hypertension, obesity, hyperlipidemia, diabetes, or smoking). [13] The results of the trial were promising, in that the Polycap was efficacious and well tolerated, even in patients without some of the risk factors targeted by the multi-component pill. [13]

Larger phase III randomized trials with adequate long-term follow-up are needed to document the true efficacy and safety profile of the polypill. [14] The multi-component pill would be engineered with a limited selection of fixed doses. [14] This would challenge the physician’s ability to tailor specific medications and doses to individual patients. Furthermore, a patient with an adverse reaction to a single pill component (ie, gastrointestinal bleeding from aspirin) would lose the benefit of the other components.  [14] Some critics also fear that the availability of a preventive pill would result in the abandonment of therapeutic lifestyle modifications such as diet and exercise. [14] Additional trials recently begun in Europe will address some of these issues and concerns.

The notion of just one polypill a day to keep disease away is appealing for both healthcare providers and patients. In the meantime, clinicians should acknowledge the impact of complex treatment regimens on patients’ daily lives and make an effort to simplify multidrug regimens and incorporate the use of FDCs into patients’ treatment plans. By doing so, clinicians can help reduce the rates of nonadherence and improve quality of life and clinical outcomes for their patients.

By Jonathan Leventhal, 4th year medical student, NYU School of Medicine

Peer reviewed by Dr. Mitchell Charap, MD, Abraham Sunshine Associate Professor of Clinical Medicine


1. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713–719.

2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981–2997.

3. Hansson L, Zanchetti A, Carruthers SG, et al. and the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351(9118):1755–1762.

4. UK Prospective Diabetes Study Group. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonylurea-treated type 2 diabetes. Diab Care. 1998;21(1):87–92.

5. Dezii CM. Medication noncompliance: what is the problem? Manag Care. 2000;9(9 Suppl):7–12.

6. US Department of Health and Human Services. Medication regimens: causes of noncompliance.  Published June, 1990. Accessed April 21, 2011.

7. Benner JS, Chapman RH, Petrilla AA, Tang SS, Rosenberg N, Schwartz JS. Association between prescription burden and medication adherence in patients initiating antihypertensive and lipid-lowering therapy. Am J Health Syst Pharm. 2009;66(16):1471-1477.

8. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther. 2001;23(8):1296-1310.

9. Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on adherence to prescription medications. J Gen Intern Med. 2008;23(5):611–614.

10. Dickson M, Plauschinat CA. Compliance with antihypertensive therapy in the elderly: a comparison of fixed-dose combination amlodipine/benazepril versus component-based free-combination therapy. Am J Cardiovasc Drugs. 2008;8(1):45–50.

11. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326(7404):1419.

12. Muntner P, Mann D, Wildman RP, Shimbo D, Fuster V, Woodward M. Projected impact of polypill use among US adults: medication use, cardiovascular risk reduction, and side effects. Am Heart J. 2011;161(4):719-725.

13. Indian Polycap Study (TIPS). Yusuf S, Pais P, Afzal R, et al. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009; 373:1341-1351.

14. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: key concepts, current status, challenges, and future directions. Circulation. 2010;122(20):2078-2088.

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