The term “polypharmacy” has evolved over time and has been defined in different ways, ranging from numerical definitions based on the number of medications taken concomitantly, to numerical definitions incorporating the duration of therapy, to descriptive definitions that consider the appropriateness of the drugs used (1,2). However, polypharmacy is still most commonly referred to as the use of five or more medications and has historically carried a negative connotation (3). Polypharmacy has been associated with increased health care costs, decreased medication-taking behavior, and increased morbidity due to adverse drug events (3–6). In individuals with type 2 diabetes, a higher number of prescribed drugs has been associated with worse glucose management, hypoglycemia events, and increased risk of incident falls, fractures, syncope, and hospitalization (7,8). However, previous studies did not ascertain the types and clinical appropriateness of prescribed medications. Due to the progressive nature of type 2 diabetes, the diversity of its complications, and the unique benefits of an increasingly diverse cadre of available treatment options, many individuals may require multiple therapies to achieve multifaceted health goals. As such, there is a pressing need for studies of these broader dimensions of polypharmacy and how they might have changed over time.
The aim of the study of Johansson et al. (9), published in this issue of Diabetes Care, was to describe changes in medication usage and polypharmacy, as defined according to concurrent treatment with ≥5 or ≥10 medications, from 2000 to 2020 among 461,849 Danish adults with type 2 diabetes. Associations among polypharmacy, demographic shifts, and the number of diseases was examined. Overall, polypharmacy increased from 53% in 2000 to 76% in 2020. Nearly 90% of people used ≥5 medications at some point during the study period and nearly half (47%) used ≥10 medications. This increase in medication usage was observed in all major demographic groups, though usage was higher among male patients and patients with greater multimorbidity, Danish ethnicity, lower educational attainment, and lower household income. Interestingly, the increase in polypharmacy prevalence was more pronounced among individuals with two or fewer chronic diseases. Further, the overall ratio of the average number of medications used to the average number of comorbidities decreased over the study period. Importantly, preventive medications to reduce cardiovascular risk, such as antihypertensive medications, statins, and antithrombotic medications, were the main contributors to the increase in polypharmacy. In particular, the use of statins increased from 12% in 2000 to 67% in 2020, while use of angiotensin II receptor blockers rose from 9% to 34% over the study period (9).
Overall, the study authors should be congratulated for a timely and rigorous study exploring the evolution of real-world usage of medications in individuals with type 2 diabetes, focusing simultaneously on the quantity and types of medications prescribed. The analysis is set against the backdrop of changes in evidence and guidelines surrounding the use of medications that confer cardiovascular disease (CVD), kidney, and metabolic benefits in this population (10–12). During the study period, national and international guidelines were updated to recommend statin therapy for all individuals with diabetes aged ≥40 years, independent of additional CVD risk factors (13,14). Hence, the observed increase in statin use aligns with current standards of care for type 2 diabetes management. Similarly, evidence emerged for stricter blood pressure targets for people with type 2 diabetes, which may explain the increase in antihypertensive medications over time (15,16). Further research efforts are needed to ascertain whether the trends observed in this analysis are generalizable to other global regions and health care ecosystems.
These findings raise important and previously underexplored questions in diabetes care: What is considered “polypharmacy” in the care of people with type 2 diabetes? Is it defined by the number of medications or the use of medications outside of current evidence-based guidelines? Is polypharmacy a cause for concern, or does its absence indicate underprescribing and potential gaps in care? Findings of previous studies have suggested that inappropriate medication use might be lower among individuals with type 2 diabetes with polypharmacy than among the general population (17,18). The average person aged ≥40 years with type 2 diabetes may require multiple glucose-lowering agents, including a statin, based on the current standards of care (10). Moreover, considering that up to three in four adults with type 2 diabetes also have hypertension, most will require one or more antihypertensive medications (19). If there are other cardiovascular risk factors, established CVD, or coexisting kidney disease, additional therapies that have been shown to improve clinical outcomes may also be indicated (e.g., sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, antithrombotic therapies, nonstatin lipid-lowering agents) (12). This implies that the average person with type 2 diabetes would meet the most commonly used numerical definition of polypharmacy despite using evidence-based, recommended therapies to reduce multimorbidity. As such, one could argue that polypharmacy in type 2 diabetes is appropriate and concordant with guidelines, and the absence of polypharmacy may signify missed opportunities for risk reduction and multimorbidity prevention.
We propose that there is a need to rethink and redefine polypharmacy in type 2 diabetes. Rather than being confined to conventional numerical definitions (use of five or more medications), terminology should be expanded to incorporate guideline-based appropriateness. In addition to enhancing focus on treatment priorities and simultaneously capturing complementary domains of benefit and risk, reframing to “appropriate polypharmacy” and “inappropriate polypharmacy” may function to identify clinically relevant polypharmacy phenotypes (Fig. 1). Akin to other conditions (e.g., heart failure and chronic kidney disease) in which multiple pharmacotherapeutic “pillars” with additive benefits are recommended to extend healthy lifespan, appropriate polypharmacy may be necessary for people with type 2 diabetes to achieve comprehensive management goals (20). Redefining polypharmacy according to guideline-based appropriateness may also help destigmatize diabetes care. For example, patients who perceive themselves as taking “too many medications” may feel overwhelmed and burdened, while those who understand that their treatment is targeted to their unique physiology and risks may feel more empowered. Underprescribing of recommended therapies may also frequently coexist with (and be viewed as an extension of) inappropriate polypharmacy, and this improved patient-clinician alignment may enhance efforts to achieve guideline-concordant care.
Polypharmacy in type 2 diabetes: shifting to a patient-centered descriptive paradigm based on clinical appropriateness.
Polypharmacy in type 2 diabetes: shifting to a patient-centered descriptive paradigm based on clinical appropriateness.
However, even when even polypharmacy is appropriate, clinicians must recognize the potentially adverse effects of multiple medications, which may include excess out-of-pocket costs (e.g., financial toxicity), regimen complexity, and greater potential for drug-drug interactions. Importantly, this threshold may vary from patient to patient and emphasizes the need for individualized discussions around prescribing and deprescribing. It should be emphasized that deprescribing is not the sole pathway to managing polypharmacy. Indeed, excess/dysfunctional adiposity is a widespread root cause of type 2 diabetes, and effective weight reduction may diminish glucose- and blood pressure–lowering therapy requirements while also ameliorating risk of death and disability (21,22). Combination glucose-lowering therapies may also mitigate excess pill burden (23).
As the therapeutic landscape for managing type 2 diabetes increasingly accelerates toward development of new drugs that prioritize morbidity and mortality in addition to glucose control, this article highlights the widespread nature of numerical polypharmacy in type 2 diabetes, the importance of distinguishing between appropriate versus inappropriate polypharmacy in clinical care, and the need for future research exploring new polypharmacy definitions and paradigms tailored to type 2 diabetes. As the approach to type 2 diabetes management becomes increasingly multifaceted, novel and flexible health care delivery efforts are needed to optimize the balance of safety and efficacy in all populations.
See accompanying article, p. 2120.
Article Information
Acknowledgments. V.R.A. is an editor of Diabetes Care but was not involved in any of the decisions regarding review of the manuscript or its acceptance.
Funding. J.W.O. reports grant support from the National Institutes of Health (5T32HL007604-39).
Duality of Interest. V.R.A. reports research support (institutional) and/or consulting fees (institutional and/or personal) from AstraZeneca, Applied Therapeutics, Boehringer Ingelheim, Corcept Therapeutics, Fractyl Health, Mediflix, Novo Nordisk, Pfizer, Rhythm, Sanofi, Eli Lilly, and Servier. No other potential conflicts of interest relevant to this article were reported.
Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Matthew C. Riddle.