Generic atorvastatin led to an increase in generic dispensing rate and a reduction in the cost of treatment for patients requiring cholesterol-lowering treatment. The upcoming introduction of the PCSK9 inhibitor may change this trend.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Major risk factors for CVD include hypertension, dyslipidemia, age, obesity, tobacco use, lack of physical activity, family history, and diabetes. Among these, dyslipidemia, a complex disease caused by the interplay of genetic, dietary, and physiologic factors, is a major modifiable risk factor for CVD. Low-density lipoprotein cholesterol (LDL-C), a component of cholesterol, accounts for approximately 60% to 70% of total serum cholesterol and is considered to be the element most strongly associated with increased risk of CVD. Risk factors for elevated LDL-C include a diet high in saturated fat or cholesterol, an inactive lifestyle, tobacco use, and a family history of heart disease and diabetes.1-3 The most common genetic cause of dyslipidemia is familial hypercholesterolemia, which affects 1 in 500 people and results in abnormally high levels of serum cholesterol due to impaired LDL receptor function in the liver.4
The World Health Organization estimates that dyslipidemia is associated with more than half of the global cases of heart disease and more than 4 million deaths per year.5 It is estimated that more than 63 million people in the United States (nearly 40% of US adults) have elevated LDL-C, and 12 million of these are not at goal.2,6 Due to its association with CVD, dyslipidemia places a financial burden on individuals and the healthcare system that is estimated to be in excess of $400 billion annually.7
The goal of treatment for dyslipidemia is to decrease levels of LDL-C, leading to reduced risk of major cardiovascular events and comorbidities.1,8 The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines recommend an LDL-C goal for all patients of less than 100 mg/dL.9 However, if the patient is at high risk of cardiac events, the recommended LDL-C goal is less than 70 mg/dL. Reduction in serum LDL-C has been shown to reduce the risk of heart disease by an average of 30%.10
Lifestyle change and statin drug therapy are the treatments of choice for LDL-C reduction. However, even with statin treatment, many patients fail to reach their recommended treatment targets. This is seen in patients with genetic abnormalities, those with extremely elevated levels of LDL-C (>400 mg/dL), and patients with difficulty tolerating high-dose statins. The proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme prevents recycling of the LDL receptors and increases the rate of their degradation, restricting the ability of the receptors to remove circulating LDL-C and leading to elevated serum LDL-C. PCSK9 inhibitors regulate the degradation of LDL receptors and have been shown to signifi cantly reduce LDL-C. Interestingly, statins have been found to
stimulate the production of PCSK9, limiting the statin’s own ability to lower serum cholesterol levels beyond a certain point. Inhibiting the PCSK9 pathway therefore represents an exciting and novel mechanism for increased lowering of LDL-C, and one that has shown promise in several phase 2 trials when used with statins or as monotherapy.11-13
While PCSK9 inhibitors are likely to result in increased pharmacy costs due to patent protection and route of administration (PCSK9 requires injection every 2 to 4 weeks), the argument can be made that this cost will be offset by a decrease in expensive cardiovascular events and associated disability. In this paper we will describe the trends in expenditure on cholesterol-lowering agents, examine the use of low- versus high-dose statin formulations, and consider the implications of introduction of the PCSK9 inhibitor in the market for cholesterol-lowering agents.
This descriptive analysis was conducted using deidentified CVS Caremark pharmacy claims data. Members who had a claim in calendar year 2011 or 2012 were selected from the claims database, and those with a claim for a statin medication were considered. The specific statin medications identified were lovastatin, rosuvastatin, fluvastatin, atorvastatin, pitavastatin, pravastatin, and simvastatin. We classifed a member as being on “high-dose” therapy if their dosage was higher than defined in
Member pharmacy claims were analyzed for 2011 and 2012, during which time atorvastatin (the generic version of Lipitor) was introduced (November 2011). We also identified members as having diabetes or cardiovascular comorbidities (ie, hypertension, coronary artery disease, or congestive heart failure) based upon their prescribed medications. We report the generic dispensing rate (GDR) and cost per utilizer per day. For this purpose, cost is defined as the total paid charges for the medication by a third-party payer. The member’s age was that noted from the earliest claim.
Our descriptive analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).
We identified 574,909 members in our sample that filled a prescription for statin medications, indicating a prevalence of statin use in this sample of 10.1%. The average age was 59.0 years (standard deviation [SD] 14.2). The sample was 51% male and 73% were prescribed medication for diabetes, a cardiovascular comorbidity, or both. Of the cardiovascular comorbidities being treated, the most common was hypertension. Of the statin users, 88% were on a low-dose regimen (see
). Members on the high-dose regimen were more likely to have comorbidities than those on the low-dose regimen (83% vs 72%, P <.0001). In
we detail the specific comorbidities identified for each group. On average, members on a high-dose regimen were more likely to have diabetes or a cardiovascular comorbidity.
The introduction of generic atorvastatin in November 2011 was followed by an increase in GDR from 64%= to 81% (
). The increase in GDR was similar for members who were on low-dose (66% to 83%) and highdose (55% to 70%) regimens. This increase led to a 19% decline in the cost per day per utilizer, from $1.76 in 2011 to $1.42 in 2012 (see
). The decline was larger in the low-dose regimen members ($1.70 to $1.33, or 22%) than that seen among members on high-dose therapy ($2.21 to $2.02, or 9%).
Impact of Pipeline Therapies
The introduction of atorvastatin led to a substantial increase in the generic dispensing rate and an accompanying decline in the daily cost of treatment. We would expect the loss of patent protection by rosuvastatin (Crestor) in 2016 to have similar impact, but not as substantial due to the smaller market share enjoyed by that medication. The commercialization of the PCSK9 inhibitors is likely to reverse this trend toward a lower cost of treatment of dyslipidemia on a per utilizer basis.
We conducted a preliminary analysis to estimate the consequence of introduction of a PCSK9 inhibitor. In our descriptive analyses, we found that 10.1% of members were on cholesterol-lowering medication. Of these, 12% were on a high-dose regimen. We considered 2 scenarios for use: (1) the PCSK9 inhibitor prescribed as an ancillary therapy in addition to a statin prescribed first line; and (2) the PCSK9 inhibitor prescribed as a replacement for the statin prescribed first line. We also tested 2 assumptions concerning the ultimate indication for use of the PCSK9 inhibitor: (1) A narrow indication with only patients with comorbidities currently on high-dose statin therapy considered medically appropriate use—based upon our analyses, we estimate this would be a maximum of 9% of current statin users; and (2) A broad indication where diabetics who would benefit from aggressive cholesterollowering targets would be considered medically appropriate use—we estimate that this would be a maximum of 26% of current statin users. The results of our analyses are provided in
We estimated that the incremental per member per year (PMPY) could range from $4.43 based on our most restrictive assumptions concerning indication, uptake, and costs to $393.90 based on aggressive assumptions. Even under conservative utilization and low drug-cost assumptions, the PCSK9 inhibitor would represent one of the more expensive specialty drug programs on the market.14 This disproportionate fi nancial impact is due to the prevalence of dyslipidemia, one of the most common chronic diseases, in contrast to other specialty pharmacy programs that target relatively rare diseases.
Market analysts have recognized that PCSK9 inhibitors have the potential to reach blockbuster status with billions of dollars in annual sales—a view reflected in the substantial investments being made by major pharmaceutical companies toward development of a PCSK9 inhibitor (See
15-24). The team of Sanofi and Regeneron Pharmaceuticals, Inc, is closest to market with their PCSK9 inhibitor, REGN727. They have completed phase 2 trials and have begun recruiting for phase 3. They are conducting a series of 10 separate clinical trials, collectively referred to as ODYSSEY, to evaluate 22,000 participants over 6 years with the goal of proving safety and efficacy of REGN727 as a monotherapy and in combination with other lipid-lowering agents. The largest of these, ODYSSEY Outcomes, will enroll 18,000 participants who recently suffered acute coronary syndrome.15-17 If this reflects the indication ultimately sought for REGN727, the market for PCSK9 inhibitors would be at the conservative end of our estimates in Table 3.
If PCSK9 inhibitors ultimately obtain US Food and Drug Administration approval, they will likely obtain well-defined, “add-on” use indications within current treatment parameters and are expected to have significant associated costs.25 Pharmacy benefit managers will likely seek to control costs in this large patient segment by implementing clinically robust guidelines for treatment. We would expect that these guidelines will ensure that the use of PCSK9 inhibitors is limited to patients with hypercholesterolemia who are intolerant to, or unable to meet LDL-C goals with, currently approved, less-costly statin medications. According to the Metabolic and Atherosclerosis Research Center of Cincinnati, this subpopulation is estimated to represent 10% to 20% of patients with high cholesterol26 and would result in a PMPY in the mid-range of our estimates in Table 3.
Dyslipidemia is one of the most common chronic conditions experienced by people in the United States. Treatment of high cholesterol is primarily addressed through the use of generic, once-daily oral medications with a high level of tolerability. That paradigm will likely be challenged by the inclusion of PCSK9 inhibitors as addon agents to aid patients who cannot achieve cholesterol treatment targets on statins alone. Clinical trials such as ODYSSEY represent large investments by pharmaceutical manufacturers and indicate their belief in the potential of these medications to gain broad acceptance due to improved clinical outcomes. Even if PCSK9 inhibitors gain the acceptance anticipated by manufacturers, statins will likely retain their well established role as first-line therapy due to their low cost and the overwhelming clinical evidence supporting their use.