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Supplements Reducing the Risk of Cardiovascular Disease in Patients With Diabetes
The Burden of Cardiovascular Disease in Patients with Diabetes
Brooke Hudspeth, PharmD, CDE
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Jennifer D. Goldman, PharmD, RPh, CDE, BC-ADM, FCCP
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Economic Implications With Newer Agents to Reduce Cardiovascular Risk in Diabetes
Carrie McAdam-Marx, MSCI, PhD, RPh

Economic Implications With Newer Agents to Reduce Cardiovascular Risk in Diabetes

Carrie McAdam-Marx, MSCI, PhD, RPh
Cardiovascular disease (CVD) plays a significant role in the morbidity and mortality in type 2 diabetes (T2D). In addition to the negative impact on the health of patients, people with T2D and CVD encounter higher total healthcare costs compared with patients with T2D and without CVD. The FDA guidance of 2008 recommending cardiovascular outcomes trials (CVOTs) for T2D drug candidates prompted pharmaceutical companies to conduct such studies. Some of those drug candidates appear to have beneficial physiologic effects on cardiovascular outcomes. Pharmacoeconomic analysis can correlate observed improvements to cardiovascular outcomes to savings in healthcare spending and assist health plans in assessing the value of diabetes medications. To date, most pharmacoeconomic studies for antihyperglycemic drugs have been conducted using surrogate markers of CVD risk (eg, glycated hemoglobin, systolic blood pressure, body mass index, plasma lipid levels) and have established the economic benefit and value of diabetes drugs based on reduction in cardiovascular events. A few analyses have been conducted based on CVOT efficacy data and similarly demonstrate value in patients at high CVD risk. Combined, the pharmacoeconomic data reinforce that newer agents with CVOT benefit represent good value in general, as well as for patients with high CVD risk, and support managed care decisions regarding treatment coverage and recommendations for newer diabetes agents.
Am J Manag Care. 2018;24:-S0
Extra Healthcare Costs Associated With Cardiovascular Disease

The substantial economic impact of diabetes is difficult to overstate. For 2017, the American Diabetes Association (ADA) estimated that the total costs associated with diagnosed diabetes was $327 billion in the United States, with the distribution of indirect and direct costs generally about 30% ($90 billion) and 70% ($237 billion) respectively.1,2 Diabetes-related costs have increased 26% from 2012, which is attributed to growths in prevalence and medical costs.1 This growth trend is expected to continue, with total costs of diabetes estimated to exceed a half trillion dollars (≈$622 billion) in 2030 due in large part to increasing prevalence.2,3

Individuals with diabetes have costs that are over 2 times higher than for those without diabetes.1 These incremental costs are associated with comorbidities and diabetes complications, with the costs of comorbidities accounting for a large portion of direct medical costs of diabetes.2,4 A closer look reveals that cardiovascular disease (CVD) is a major driver of the direct medical costs of diabetes comorbidities, and these direct medical costs manifest in multiple ways. Diabetes also contributes to 16% of the total deaths due to CVD, which, in addition to the personal loss, results in $7.6 billion in lost productivity.1

A retrospective study by Mehta and colleagues provides additional insights into the role of CVD as a cost driver specifically in type 2 diabetes (T2D), which accounts for 90% to 95% of all cases of diabetes.5 Using a claims database linked with electronic medical records, Mehta et al analyzed the incremental costs of CVD in patients with T2D 18 years or older for the years 2011 to 2013.6 Patients with T2D and a history of CVD had per-patient per-month healthcare costs that were 16% ($200) higher than costs for patients without CVD history when adjusted for demographics and other comorbidities (rate ratio [RR], 1.16; 95% CI, 1.13-1.19; P < .0001).6 Similar statistically significant higher healthcare costs were also observed for outpatient visits, emergency department visits, inpatient hospital visits, and prescription drugs.6

The study also revealed greater disparities in total healthcare costs between cohorts with or without CVD based on certain demographic subgroups. When compared with people without a history of CVD, total healthcare costs increased by 56% in the cohort aged younger than 45 years, by 27% in the cohort aged 45 years to 64 years, but by just 2% in the cohort aged 65 years or older. The increase in healthcare costs in men with CVD history was 14%; in women with CVD history the increase was 19%. Furthermore, racial differences were evident as the observed increases in healthcare costs with CVD history were 5%, 11%, 22%, and 33% for Asians, whites, Hispanics, and African Americans, respectively (Table 1).6

In a broader study of adults (>17 years old) for the time period of 2002 to 2011 using the Medical Expenditure Panel Survey Household Component, Ozieh et al determined that the incremental costs associated with CVD in patients with diabetes was $3374 (95% CI, $3068-$3679; P < .01).7 In addition, patients with diabetes experienced significantly greater costs in each category of medical expenditures evaluated (total medical, hospital inpatient, prescription medical, office-based, home health, and emergency department). Compared with patients without diabetes, healthcare expenditures were more than 2 times greater for total healthcare costs, 1.9 times greater for office visit costs, 2.6 times greater for hospital inpatient costs, and 3.4 times greater for prescription drug costs compared with people without diabetes.7 The data highlight the significant economic impacts of CVD on healthcare costs associated with diabetes.

With 10 years of experience since the FDA guidance mandating evaluation of cardiovascular risk for new antihyperglycemic drugs, researchers have engaged in healthy discussions on their merits and on the merits of cardiovascular outcomes trials (CVOTs), including how to determine the costs and benefits of such large-scale trials, how to improve study design, and how to translate the knowledge gained into clinical recommendations.8-12 Through this process, researchers have demonstrated that newer diabetes agents do not impart cardiovascular risk. In fact, select sodium-glucose cotransporter 2 inhibitors (SGLT2is) (empagliflozin and canagliflozin) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (liraglutide, semaglutide) have been shown to reduce the risk of major adverse cardiovascular events (MACEs) in high-risk patients. For payers, these data should contribute to the value assessment of these newer diabetes medications.

Evaluating the Pharmacoeconomics of Antihyperglycemic Drugs

While this activity focuses on the economic implications of newer diabetes drugs vis a vis the reduction of cardiovascular events, clinicians should always be mindful of the health and economic benefits of lifestyle modifications and appropriate pharmacologic treatment of CVD risk factors, such as hypertension and dyslipidemia.13-17 However, as it is a chronic and progressive disease, patients with diabetes require pharmacologic interventions to manage hyperglycemia and reduce the risk of both CVD and microvascular complications. Evaluating the pharmacoeconomic efficacy alongside the pharmacologic efficacy is critical to support diabetes treatment decisions made by payers, providers, and patients.

Cost-Effectiveness of Diabetes Drugs: Cardiovascular Outcomes

Studies that evaluate the overall cost-effectiveness of diabetes drugs are relatively common. The question of interest here is the economic impact of diabetes drugs based on reductions in CVD risk and/or cardiovascular outcomes. Given that CVOT data are relatively new, pharmacoeconomic studies using CVOT data are limited and to date have been published for pioglitazone, which is a thiazolidinedione, and empagliflozin, an SGLT2i. Based on the prospective pioglitazone clinical trial in macrovascular events (PROactive) study, the cost-effectiveness of pioglitazone was compared with placebo. The PROactive study involved more than 5000 patients with T2D with high CVD risk in a prospective, double-blind, randomized, parallel group clinical trial that was conducted in multiple international sites and followed patients for a median of 34.5 months.18 Patients received either pioglitazone or placebo in addition to their existing diabetes treatments and were treated to a glycated hemoglobin (A1C) goal of less than 6.5%. A1C reduction from baseline was statistically significantly greater with pioglitazone than placebo groups (−0.85% and −0.3%, respectively; P < .001), although, on average, the cohorts did not achieve the less than 6.5% goal.  Although, the study did not find a significant  reduction in the risk of the primary end point (all-cause mortality plus nonfatal myocardial infarction [MI], silent MI, acute coronary syndrome, and stroke, as well as endovascular or surgical intervention in the coronary or leg arteries, amputation above the ankle) (hazard ratio [HR], 0.90; 95% CI, 0.80-1.02; P = .095) a reduction in CVD risk per the main secondary end point (all-cause mortality, nonfatal MI, and stroke) was identified (HR, 0.84; 95% CI, 0.72-0.98; P = .027).

The cost-effectiveness of pioglitazone was determined for both the United Kingdom and the United States.19,20 Both analyses, conducted from a payer perspective, were based on the PROactive study population and event rates for the components of the primary composite end point. They used a version of the IMS (now IQVIA) CORE diabetes model that was modified to incorporate observed reductions in cardiovascular events, including heart failure (HF) hospitalizations, and edema, that also retained microvascular outcomes. The model projected the incremental cost-effectiveness ratio (ICER), quality-adjusted life expectancy (QALE), and quality-adjusted life-years (QALYs). In the UK study, the cost-effectiveness was determined for 2 time frames: short-term (within-trial) and long-term (35-year horizon). For the within-trial analysis, pioglitazone increased QALE by 0.0190 QALY compared with placebo, with an increased cost of £102 ($135.01 USD) per patient, which translated to an ICER of £5396 ($7146.08 USD) per QALY.19 When modeled for a 35-year time frame, pioglitazone increased QALE by 0.152 QALYs compared with placebo, with an increased cost of £619 ($819.76 USD) per patient and a calculated ICER of £4060 ($5376.77 USD) per QALY.19 The US analysis focused on a lifetime horizon of 35 years. Like the UK study, pioglitazone increased QALE by 0.166 QALYs compared with placebo. Treatment with pioglitazone increased a patient’s lifetime total direct costs by $7305, and the ICER for pioglitazone compared with placebo was $44,105 per QALY.20 Both studies found pioglitazone to be cost-effective in the respective countries of analysis.19,20 Sensitivity analyses indicated that ICERs were most sensitive to time horizon, which reflects the long-term nature of the benefits of CVD risk reduction.19,20 Application of these findings must be used cautiously given that risk reduction per the PROactive primary end point did not reach significance.

The 2 recently published pharmacoeconomic analyses of empagliflozin were based on data from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial with Greece as the country of analysis and the US analysis data added from other published epidemiologic studies.21,22 The EMPA-REG OUTCOME trial was designed as a noninferiority study to assess the effect of empagliflozin (10 mg or 25 mg) versus placebo on the primary composite 3-point major adverse cardiovascular event (3P-MACE) outcome of death from cardiovascular causes, as well as nonfatal MI or stroke in patients at high cardiovascular risk.23 More than 7000 patients were treated in the EMPA-REG OUTCOME trial in a randomized, double-blind, placebo-controlled study that was conducted at multiple international sites and had a median follow-up time of 3 years.24 In this study, the placebo-adjusted change in A1C was modest (−0.3%) per study design. Empagliflozin-treated patients were significantly less likely to experience a MACE (HR, 0.86; 95.02% CI, 0.74-0.99; P < .001 for noninferiority; P = .04 for superiority for 3P-MACE composite outcome).

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