Opportunities for improving use of evidence‐based therapy in patients with type 2 diabetes and cardiovascular disease

Abstract Evidence‐based therapy that target hyperlipidemia, hypertension, smoking cessation, and weight loss have demonstrated significant benefits in reducing cardiovascular risks and related events. Although the benefit of intensively lowering blood glucose is unclear, newer antidiabetic drugs (glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors) have shown cardiovascular benefits in addition to their antihyperglycemic effect. Yet, studies suggest that recent use of evidence‐based therapy and management of cardiovascular risk among individuals with type 2 diabetes (T2D) and cardiovascular disease (CVD) remains largely suboptimal. The following narrative review first identifies barriers to translating research evidence to clinical practice at the levels of provider, health system, patient, and cost. Then it synthesizes previous implementation strategies that addressed multifaceted barriers and attempted to improve care for patients with T2D and CVD. In conclusion, team‐based care coordination, reminding systems in combination to pharmacist consultation and patient education, provider education compatible with clinical workflow, and coupled incentives between providers and patients appeared to be effective in reducing cardiovascular risks for patients with T2D and CVD, though the scalability and long‐term clinical effect of these strategies as well as the possibility of interventions involving payers and health systems remain uncertain.


| INTRODUCTION
Type 2 diabetes (T2D) and cardiovascular disease (CVD) are the leading causes of morbidity and mortality in the United States. 1 To varying extents, therapy that target major cardiovascular risk factors (dyslipidemia, hypertension, smoking, obesity, and hyperglycemia) have demonstrated benefits in improving cardiovascular outcomes over the past two decades. Cholesterol lowering, hypertension management, smoking cessation programs, and bariatric surgery have shown significant benefits in reducing cardiovascular adverse events among patients with T2D. Although conventional antihyperglycemic therapy have failed to improve long-term macrovascular outcomes, two new classes of antidiabetic medications, glucagon-like peptide-1 receptor agonists (GLP1ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), appear to exert macrovascular benefit among patients with T2D independent of their glycemic effect. 2,3 However, despite the substantial and emerging evidence of secondary preventive therapy, comprehensive cardiovascular risk reduction in patients with T2D and CVD remains suboptimal. Table 1 presents the percentages of US adults with T2D and CVD in the gaps of preventative care for five individual cardiovascular risk factors based on the National Health and Nutrition Examination Survey. 4,5 In particular, between 1999 and 2010, 78.7% of the adults with T2D and CVD did not achieve one or more guideline-recommended goals for hemoglobin A1C (A1C), blood pressure, and low-density lipoprotein cholesterol (LDL-C); when obesity was included as a poorly managed risk factor, 90.6% of the patients were in the gaps of preventative care. 5 Even in the COURAGE trial that included intensive medical therapy in both intervention arms to reduce cardiovascular risk, 56.9% of enrolled patients had more than four risk factors not at goal 1 year after randomization. 6 Table 2 presents the percentages of patients in the COURAGE trial with diabetes and stable coronary disease not at goal for seven individual cardiovascular risk factors between randomization and 1 year after. Globally, the achievement of secondary prevention measures among patients with T2D and CVD varies by region. Data from the TECOS trial between 2008 and 2012 found that those in Eastern Europe and Latin America were more likely to have suboptimal LDL-C levels (≥70 mg/dL) than those in North America. 7 Across 38 countries, 42.1% of patients with diabetes and CVD had poorly controlled blood pressure (≥140 mm Hg systolic, ≥90 mm Hg diastolic). Even though current secondary cardiovascular prevention is suboptimal, previous studies have demonstrated the possibility and benefits of intensively and simultaneously managing multiple cardiovascular risk factors. 8,9 To provide insight on bridging the care gap, this narrative review outlines barriers and existing implementation strategies at the provider, health system, and patient levels, as well as issues related to cost in the context of T2D and CVD management.

| Medication nonadherence
Nonadherence to medications is a common barrier to desired clinical outcomes at the patient level. 17 Proportion of days covered (PDC) and medication possession ratio (MPR) are two valid and widely used measurements to evaluate medication adherence. 18 A meta-analysis of eight observational studies showed a 37.8% rate of poor adherence (PDC < 80%) to antihyperglycemic and cardiovascular drug therapy among adults with T2D. 19 Similarly, a meta-analysis of 19 cardiovascular prevention studies reported that 34% of patients with prior CVD adhered poorly (PDC < 75%) to five classes of guidelinerecommended medications. 20 Among adults with a prior history of CVD, the overall adherence rate to evidence-based medications was shown to improve modestly over time, though the adherence to different drug classes was highly heterogeneous, ranging between 40% and 80%. 21,22 The percentage of patients with prior myocardial infarction (MI) who fully adhered to statin, beta-blocker, and angiotensinconverting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) increased from 29.1% in 1995 to 46.4% in 2003. In contrast, limited data exist regarding the adherence to GLP1ra and SGLT2i.
The reasons for nonadherence are multifaceted. One survey of over 24 000 adults with chronic illness found that up to 70% of patients reported at least one of three unintentional adherence behaviors: forgetting to take medication, forgetting to refill prescriptions, or not taking medication at the correct times. 23 27 In addition, prescription costs can considerably affect a patient's ability to self-manage T2D and CVD.

| Cost-related issues
Out-of-pocket cost burden is one major barrier to use of evidence-based medications. Multiple studies have highlighted the association between increased prescription costs and reduced use of evidence-based medications including statins and beta-blockers among patients with T2D and/or a history of CVD. 28 However, in another randomized study of 214 patients with diabetes, coronary heart disease, or both, a goal-driven care coordination plan where nurses closely monitored patients' progress, adjusted medications accordingly, and provided motivational coaching significantly led to a between-group reduction in A1C by 0.58%, LDL-C by 6.9 mg/dL, and systolic blood pressure by 5.1 mm Hg compared to controls (P < .001). 34 Other evidence suggests that nurses or outreach coordinators can improve cardiovascular risk factor management by further reducing clinical inertia and healthcare costs. 35 Given the complexity of care for patients with T2D and known CVD, care coordination between PCPs and specialists may also be effective, although limited data are available on how it should be designed and whether it improves clinical biomarkers.

| Social integration
Social interventions such as guidance on community resources and provision of basic needs can also improve cardiovascular risk factor management. For example, the Health Leads program screened primary care patients for unmet basic needs such as food, medication, housing, and transportation; if screened positive, those patients (26% of whom had diabetes) would be connected to a patient advocate who helped patients to navigate community resources. Between preand-post intervention, and comparing to those screened negative, those screened positive had a significant reduction in systolic blood pressure (−1.6 mm Hg; 95% CI, −2.5 to −0.6 mm Hg) and LDL-C (−3.9 mg/dL; 95% CI, −7.2 to −0.6 mg/dL), but not in A1C. 38 The effect of such social interventions on secondary CVD has not been studied.

| Framework-based interventions
Since barriers to optimal T2D and CVD management are multifaceted, several interventions have adopted a theoretical framework to improve health for patients with chronic diseases. One well- Clinical decision support and framework-based interventions seem to address provider and system-level barriers to managing patients with T2D and CVD. However, their effect is unclear and future studies should focus on investigating clinical endpoints and improving workflow integration and sustainability. In contrast, care coordination programs where the nurse coordinator was able to discuss specific goals with patients, adjust medications, and closely monitor patients' progress showed success in T2D and CVD management. Social interventions can also improve disease management, but their feasibility and scalability may be a concern, particularly for patients with T2D and CVD who require more intensive healthcare resources than low cardiovascular risk patients.

| Reminders and mobile technologies
Reminding systems have been implemented to target forgetfulness and address nonadherence to cardiometabolic medications among patients with T2D or CVD. However, the effect of reminding systems has thus far been minimal. The REMIND trial investigated the effect of three low-cost reminder devices (pill bottle strip with toggles, digital timer cap, or standard pillbox) on improving medication adherence among 18 to 64-year-old adults who were taking one to three medications, yet with suboptimal adherence (MPR of 30%-80%). Optimal adherence (MPR ≥ 80%) did not differ between any groups after 12 months, including those who were taking medications for cardiovascular or non-depressive conditions. 43 The IMAGE-CHD trial examined the effect of two low-literacy reminding strategies, an illustrated schedule and a postcard refill reminder, via a 2 × 2 factorial design in patients with prior coronary heart disease. 44 There was no significant difference in medication adherence across all intervention arms compared with controls after 12 months. Finally, the HeartStrong trial randomized 1509 patients following an acute MI to an intervention that used an electronic pill bottle, lottery incentives, social support, and engagement counseling, vs usual care. 45 There was no significant difference between the intervention and usual care in clinical outcomes or medication adherence after 1 year.

| Patient education and pharmacy-based interventions
In contrast, pharmacy consultation combined with patient education has demonstrated benefits in improving adherence to cardiovascular medications and cardiovascular risk factor management, including diabetes care. The FAME trial was the first study to test the effect of a pharmacy-based program that combined patient education, medication management, and regular follow-ups with pharmacists on medication adherence and clinical outcomes among elderly patients. 46 After a 6-month run-in period, the proportion of patients with good adherence (taking greater or equal to 80% of pills prescribed) in the entire study sample increased from 5.0% to 98.7% (P < .001). Following randomization and another 6 months of follow-up, 97.4% of pills in the pharmacy-based intervention arm were taken as instructed, whereas the percentage declined to 69.1% in the usual care arm (P < .001).
Sustained adherence was associated with significant reductions in systolic blood pressure only in the intervention arm (−6.9 mm Hg; P = .001), but not in the usual care arm (−1.0 mm Hg; P = .69).
Another pharmacist-led intervention incorporated patient education, care coordination with PCPs, and reminding messages in discharged patients with acute coronary syndrome (45% of whom had diabetes). 47 Compared with usual care, the intervention led to 15% more patients to adhere (PDC ≥ 80%) to four classes of cardiovascular medications (beta-blockers, statins, antiplatelet agents, and ACEI/ARB, P = .003). However, blood pressure, LDL-C, and costs did not differ significantly between the intervention and control arms after 12 months.

| Behavioral economics
Behavioral economics was also applied to couple incentives between providers and patients in order to improve lipid management in high cardiovascular risk population. One multicenter study randomized 340 primary care physicians and their 1503 patients (34% had preexisting coronary artery disease) to a physician incentive arm (quarterly payments based on monthly reports on patients' adherence and LDL-C levels), patient incentive arm (a daily lottery), shared physicianpatient incentive arm (half of the benefits received in other two arms), or control. 48 After 12 months, only the shared physician-patient incentives group achieved a significant reduction in LDL-C (8.5 mg/dL; 95% CI, 3.8-13.3) compared with control. However, no other cardiovascular risk factors and clinical outcomes were evaluated in the study.
These patient-level intervention studies suggest that reminders plainly addressing forgetfulness are unlikely to improve medication adherence. However, support from health professionals such as pharmacists, mediated through patient education, can improve medication adherence and some clinical outcomes in patients with T2D and CVD.
Incentivized patient-provider co-management and smooth transitions between refills have also shown clinical benefits, yet whether these interventions are scalable and feasible in different health systems is unknown. in clinical outcomes such as stroke incidence, yet the magnitude of improvement may not be clinically meaningful. Optimal T2D and CVD management is unlikely to be achieved unless interventions address cost barriers along with provider, health system, or patient-level barriers. Figure 1 provides an overall visual summary of the barriers and corresponding implementation strategies to optimal management of T2D and CVD.  52 On the patient side, adherence-targeting interventions may be most effective when reminding systems are coupled with pharmacist consultation and patient education. Interactions between providers and patients appear to be also critical in improving patient adherence and cardiovascular risk factors.

| Next steps
Lastly, few implementation studies focused on the evaluation of multiple surrogate biomarkers, long-term clinical endpoints, or costeffectiveness metrics. To drive clinical changes and downstream benefit on the population level, incentives for both providers and patients as well as collective efforts from payers and health systems may be required so that payment structure will be redesigned for preventative care in patients with T2D and CVD. The scalability and sustainability of many implementation strategies are worth being further assessed. Livongo. Yumin Gao has no disclosure or grant information to report.

ACKNOWLEDGMENTS
No funding from any organization was received for this review.
F I G U R E 1 Framework of barriers to optimal management of T2D and CVD and corresponding implementation strategies. Provider and system level (orange), patient level (blue), and cost-related (red). Abbreviations: CVD, cardiovascular disease; T2D, type 2 diabetes