The dispensing rate for generic statins is expected to rise slowly due to increased volumes of simvastatin and pravastatin sodium moderated by increased Crestor volumes.
High levels of cholesterol lead to an accretion of plaque lining the walls of blood vessels, subsequently increasing a person’s probability of suffering a heart attack or stroke. High cholesterol is most commonly associated with obesity, poor eating habits, sedentary lifestyles, and certain hereditary conditions.1 Lipid-lowering agents are commonly used for the treatment of various types of lipid disorders as well as for the primary and/or secondary prevention of various cardiovascular events.
According to the American Heart Association, approximately 106.7 million people have high blood cholesterol, recognized as blood cholesterol levels at or above 200 mg/dL. An estimated 35.7 million adults older than 20 years of age have total serum cholesterol levels at or above 240 mg/dL (extrapolated to 2006 using National Health Survey data 2003—2006), with a prevalence of 16.2%.2(p e103)
On the basis of data from the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, fewer than half of persons who qualify for any kind of lipid-modifying treatment for coronary heart disease (CHD) risk reduction are receiving it. In fact, fewer than half of even the highest risk persons (those with symptomatic CHD) are receiving lipid-lowering treatment. Only approximately 33% of treated patients are achieving their low-density lipoprotein (LDL) goal; fewer than 20% of CHD patients are at their LDL goal.2(p e104)
The analysis is a retrospective study of 23.2 million CVS Caremark members who had more than 240 million prescription claims. CVS Caremark’s computerized, de-identified database was used to study the utilization of the following lipid-lowering classes: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), intestinal cholesterol absorption inhibitors (Zetia and Vytorin), and nicotinic acids (eg, Niaspan) from January 1, 2008, through December 31, 2009. The population identifi ed for the study was a representative sample of members across a variety of plan sponsors including health plans, managed care organizations, Medicaid, unions, national and local employers, and government agencies located throughout the United States. Only clients with stable membership (±15% change in eligibility in 24 months) and prescription claims in the entire 24-month study period were included.
Gross cost included discounts, member contributions, and plan sponsor contributions. The manufacturer rebates were excluded. Gross cost per day was determined by the total gross cost divided by the total days supply for the time frame. The gross per member per month (PMPM) cost was determined by the total gross spending divided by the total member months of eligible plan participants (members). Utilization was based on days supply and number of unadjusted prescriptions PMPM.
Generic dispensing for lipid disorders primarily includes prescription claims for 3 generic statins—lovastatin (Mevacor), pravastatin sodium (Pravachol), and simvastatin Zocor), which have been available since December 2001, April 2006, and June 2006, respectively.3-5
shows the US Food and Drug Administration (FDA) indications for selected drugs in the combined class. Each of the drugs has several indications for various lipid disorders, and many are used in conjunction. Statins continue to be the gold standard for reduction of LDL cholesterol (LDL-C), or bad cholesterol, and consequently have been a top gross-spending class for several years. Additionally, statin utilization has been determined to have a myriad of benefits including prevention of CHD and a reduction in stroke incidence (Table 1).
Nicotinic acids such as Niaspan (niacin or vitamin B3) often are used in conjunction with other lipid-lowering agents. Zetia (ezetimibe) is an intestinal cholesterol absorption inhibitor that, unlike statins (which work with the liver), blocks cholesterol that would normally be absorbed from food in the intestines. Vytorin is a combination medicine containing ezetimibe and simvastatin (Zocor) that reduces absorption of ingested cholesterol as well as controlling cholesterol production in the liver.
In June 2010, Eli Lilly and Kowa Pharmaceuticals announced the availability of Livalo (pitavastatin) in pharmacies. Lilly entered into a promotion agreement with Kowa last December for the statin, which garnered FDA approval in August 2009 for the treatment of primary hyperlipidemia or mixed dyslipidemia. In several head-to-head trials against other statins, Livalo reduced LDL-C by up to 45% compared with other products.6 Livalo is indicated as adjunctive therapy to diet to reduce elevated total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and to increase high-density lipoprotein cholesterol in adult patients with primary hyperlipidemia or mixed dyslipidemia (see www.livalo.com). The new combination product Certriad (fenofibric acid and rosuvastatin) received a complete response letter from the FDA and will most likely have approval delayed until 2011.
Utilization was based on the change in average days supply and the unadjusted number of prescription claims compared year over year (YOY). All metrics increased, including the total number of scripts, and the volume based on total days supply in 2009 compared with 2008 (
Change in Days Supply
Generic Zocor (simvastatin) experienced continued double-digit growth in the class, with a YOY days supply increase of 23.9% PMPM. It was followed by Crestor (rosuvastatin), which gained a higher percentage (+32.0% PMPM). Pravastatin also had significant utilization growth, whereas Vytorin and Zetia volumes significantly declined. Overall, generic days supply PMPM increased while brand-name days supply PMPM declined, acting to moderate gross costs. Monthly simvastatin days supply figures now outnumber those of Lipitor, most likely propelling it to the number one market shareholder in the class for 2010. In 2009, Lipitor continued to have a decline in both claims and total days supply.
Change in Claims
Crestor claims PMPM rose 29.5% YOY, replacing many Vytorin and Zetia prescriptions, likely due to efficacy concerns with both drugs. Additionally, simvastatin (+22.9%) and pravastatin (+15.3%) had substantial claim volume (PMPM) increases, increasing the generic dispensing rate (GDR) to 43.9%. Overall, generic claims increased 17.9%, whereas claims for brand-name drugs decreased 6.7% PMPM.
This analysis included the primary lipid-lowering classes, which had the greatest impact on class trend and accounted for 7.8% of total gross spending. The average gross cost per day decreased from $2.37 in 2008 to $2.30 in 2009, and the average gross cost per days supply decreased 2.6%. Both declines were largely due to increased utilization of lower-priced generic statins including simvastatin, pravastatin, and lovastatin (
In 2009, brand-name drug gross cost per day increased 6.3%. Of the drugs that held significant market share in 2009, Crestor had average cost per day of $3.34 compared with generic simvastatin at $0.96 (
). Pravastatin had the largest decline in gross cost per day at −$0.24. Lovastatin continued to have the lowest gross cost per day in the class at $0.87. Although the market share of Niaspan was lower, it had the highest gross cost per day in 2009 at $3.65 and had an increase of $0.14 in the cost per day of therapy compared with 2008.
In 2009, Lipitor and simvastatin dominated the lipid-lowering drug market, holding a combined 60.5% share. Simvastatin achieved a YOY market share increase of 4.8%, pravastatin gained 0.7%, and Crestor gained 2.3%. Simcor and Niaspan gained 0.3% and 0.1%, respectively. Livalo did not have any claims in 2009 (Figure 2).
Market share declined −3.3% for Lipitor, −3.1% for Vytorin, and −1.2% for Zetia. In 2010, the market share for generics is expected to increase. Crestor market penetration is expected to increase, primarily taking share from Vytorin and Zetia.
ANALYSIS AND DISCUSSION
Generic prescription growth rates (claims PMPM) significantly outpaced brand growth rates YOY (+17.9% vs −6.7%), primarily due to a substantial increase (22.9%) in simvastatin claims and subsequent decreases in claims for the brand-name drugs Lipitor (−8.4%), Vytorin (−33.6%), and Zetia (−15.9%). Crestor was the only branded statin to have growth in days supply: +32.0% PMPM. The reduction in branded claims combined with the increase in generic claims resulted in a gross cost per day trend of −2.6%, a utilization trend of 3.5%, and a gross trend of 0.8%.
Further, generic pricing declined YOY while brand-name drugs had price increases. The GDR increased 5.7% YOY to 43.9%, accounting for 17.4% of overall costs in the class. The combined class of lipid-lowering drugs currently retains a 99.0% generic substitution rate (GSR); therefore, the increase in generic utilization will come from initial prescriptions written for a generic or the conversion of a single-source brand to a generic alternative.
In October 2009, the FDA approved Crestor for use in children aged 10 to 17 years with heterozygous familial hypercholesterolemia. The pediatric market for cholesterol-reducing drugs is not a large one, and the approval is not likely to be a material utilization driver. AstraZeneca said it would not actively promote use for this indication.7 In February 2010, the FDA approved wider use of Crestor in certain patients without evidence of heart disease. The FDA’s approval broadens the indication for Crestor as a preventive treatment for cardiovascular disease, clearing the way to market the drug to certain patients who have normal or slightly elevated cholesterol levels, a group previously considered at low risk of developing cardiovascular disease. The FDA said Crestor could now be used to reduce the risk of heart attack and stroke in people above a certain age—50 years in men and 60 ears in women—who have high levels of a measure of inflammation called C-reactive protein (CRP) in their blood and at least 1 other risk factor for heart disease such as a smoking habit or high blood pressure.
Physicians’ opinions are divided over the question of whether healthy people with low cholesterol should take a statin to lower their cholesterol even more in an effort to prevent heart problems. A June 2010 analysis publishedin the Archives of Internal Medicine questions researchthat led the FDA to approve a broader heart disease prevention claim for AstraZeneca’s Crestor. The earlier study found that Crestor cut the risk of certain heart problems in half for the middle-aged and older men and women in the study who had normal levels of LDL-C (<130 mg/dL) and high levels of CRP. That study suggested not only a new use for Crestor, but a new blood test for CRP. Critics suggested the dramatic results might be exaggerated because the experiment was stopped after 2 years instead of the planned 5 years. They questioned why the authors didn’t report the rates of death from heart attack and stroke, which when teased out of the data turned out to be unaffected by Crestor. The new analysis raises those questions again, finding no justification from the earlier results for using a CRP test to make treatment decisions. A third article, an analysis of 11 published studies including the 2008 study, found no evidence that statins help high-risk people without heart disease live longer. If the AstraZeneca findings were incorporated into treatment guidelines, roughly 6 million more people could be put on statins at a cost of $9 billion a year.8
Results presented in July 2010 from 2 related trials (Prospective Evaluation of Proteinuria and Renal Function in Diabetic [and Nondiabetic] Patients With Progressive Renal Disease [PLANET I and II]) investigating the effects of statins on urinary protein excretion and kidney function could significantly affect how statin drugs are prescribed to diabetic patients and others with impaired kidney function. The studies found Lipitor to be renal protective and Crestor nonprotective (and possibly harmful) in diabetic and nondiabetic patients. Researchers reported that high-dose Lipitor significantly reduced proteinuria and did not affect renal function, whereas Crestor was associated with a significant decline in function and had no effect on proteinuria. In diabetic and nondiabetic patients, proteinuria is a risk factor for further loss of kidney function and progression to end-stage renal disease, even when angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers are used to lower blood pressure. Experimental results have suggested that statins reduce proteinuria and preserve kidney function, but clinical studies have produced mixed results.9
After many trials and many years of statin use, cardiologists have largely concluded that most of the lipid effects they see with statins are a class effect and not necessarily unique to any particular agent. However, researchers have suggested that the PLANET I and II results indicate that these effects are not necessarily universal, at least for the parameters studied in these 2 trials.9 Other studies like the ongoing Study of Heart and Renal Protection (SHARP) trial with simvastatin and ezetimibe aim to further test this hypothesis. Data collection is scheduled to be completed in late summer 2010.
In the past few years, adverse trial results have impacted utilization and market share of the lipid-lowering agents. For the second time in as many years, results from a large clinical trial presented in November 2009 found that the nonstatin Zetia provides little or no benefit in preventing heart disease compared with extendedrelease niacin. Zetia, which blocks the absorption of cholesterol in the intestines, is sold alone or in combination with simvastatin under the brand name Vytorin. The study found that niacin caused the regression of carotid intima-media thickness, a surrogate marker for atherosclerosis progression, whereas Zetia caused no significant change. In addition, fewer adverse cardiovascular events developed with niacin than with Zetia during 14 months of follow-up. Perhaps most important, researchers found an unexpected paradoxical relationship of a greater degree of atherosclerosis progression in patients with larger Zetia-induced reductions in LDL-C levels. The study was terminated early in July when investigators concluded there was a clear difference between the 2 groups.10
Study results published in 2008 showed that Vytorin reduced blood levels of LDL-C by 58% compared with a 41% reduction using simvastatin alone; however, plaque levels actually grew slightly more in the patients taking Vytorin. Thicker plaque increases the risk of plaque breaking off and producing clots that lead to heart attacks. Since then, prescriptions for Zetia have fallen from nearly 16.5 million in 2007 to less than 13 million in 2008, and those for Vytorin fell from 22 million to 16.5 million.10
Clinical trials on Abbott Laboratories’ cholesterol drug Niaspan may have contributed to the increase in prescription share after a clinical trial highlighted its potential for reducing plaque as part of combination therapy. The study (ARBITER 6-HALTS) looked at the effects of treatment with Niaspan plus a statin on reducing plaque buildup or atherosclerosis. Niaspan, an extended-release form of niacin, is indicated to raise high-density lipoprotein cholesterol and lower LDL-C and triglycerides, but it is not approved to promote regression of atherosclerosis in combination with a statin.
Niaspan, which is indicated to slow atherosclerosis in combination with an older class of lipid medications known as bile acid—binding resins, also is a component of Abbott’s Simcor, which combines extended-release niacin with simvastatin.11 Several analysts have criticized the ARBITER 6-HALTS study design, including its small size, premature termination, and use of the carotid artery intima media thickness surrogate marker, which some say is not a reliable indicator of outcomes.12
Statin therapy appears to consistently have the poorest compliance among cardiovascular therapies, which is likely because of the demographics of the statin-treated population. These often-elderly patients may have lower incomes, thereby making the therapies less affordable. The asymptomatic nature of high cholesterol also may be a factor. A recent study found that improving the compliance rate by 50% in those already prescribed statins would prevent far more heart attacks and strokes than prescribing them for a larger group of patients.13
2010 AND BEYOND
A highly anticipated generic version of Lipitor is currently slated for launch in the fourth quarter of 2011. If launch occurs as projected, class costs will decline significantly in 2012 and leave only a single brand-name drug (Crestor) with significant market share. Additionally, the remaining single-source brands in the class do not retain enough market share (and subsequent potential for price inflation) to offset the momentum of generic utilization driving gross trend downward. Overall class utilization is projected to increase because of increased screening and treatment of members, expanded indications, or serendipitous benefits for the use of statins.
In February 2010, Crestor received supplemental FDA approval for reducing the risk of stroke, heart attack, and arterial revascularization procedures in persons who do not show evidence of CHD. The expanded approval could substantially boost sales of Crestor, because up to 6 million additional patients could qualify for treatment. However, some analysts caution that Crestor sales might not grow as much as expected if doctors view the new Crestor benefits as something that a cheaper generic statin also could deliver.14
The expanded approval for Crestor has rekindled the debate about the merits of a prescription-to-nonprescription statin switch. Experts say the continued recognition that statins could more widely benefit a broader treatment population represents a positive development in the quest for approval of a nonprescription statin. However, previous applications for a switch to nonprescription status for Mevacor (lovastatin) and Pravachol (pravastatin) have been rejected by the FDA, partly on the basis of the agency’s concern about the inability of the general public to assess their eligibility for statin therapy. Challenges in self-selection and consumer awareness of asymptomatic conditions remain obstacles to FDA approval of an nonprescription statin switch. Consumers often are aware of their cholesterol but are unlikely to know whether they have an elevated high-sensitivity CRP level, which is arisk factor covered by Crestor’s new indication.15
There is interest in a large study that found that people who were taking statin drugs when they caught seasonal flu and had to be hospitalized were twice as likely to survive as those who were not on such medicines. This doesn’t prove that statins can cure flu, or that starting on them after catching the flu would help. Doctors are optimistic, however, because previous studies also found that statins may improve survival from infectious diseases. A new study sponsored by the Centers for Disease Control and Prevention is the first large domestic study to look at statins for flu. It involved 2800 people hospitalized with lab-confirmed seasonal flu in 10 states during 2007-2008. Medical records showed that 801 patients received statins in the hospital. More than 3% of those not taking statins died in the hospital or in the following month. The mortality rate was half that among statin users, even though they were more likely to have underlying health problems like heart disease. Researchers took other factors such as age into account and still saw the same benefit from statin use. Should statins ultimately show a benefit in treating the flu, it would be yet another reason for expanded use of these drugs.16 Depending on the results of the study, utilization may be impacted.
The generic dispensing rate is expected to rise due to increased volumes of simvastatin and pravastatin moderated by increased Crestor volumes. Crestor’s recent supplemental approval for risk reduction of stroke and heart attack in patients without evidence of CHD has strong potential to increase utilization of the drug. Despite the issues of compliance with statin therapy due to the apparent asymptomatic nature of lipid disorders in the average patient, lipid-lowering drugs will likely continue to have higher utilization rates due to the aging population and direct-to-consumer awareness and adherence programs. The total drug cost trend will be offset by the average gross cost per day decline due to greater generic utilization and market launch of a generic version of Lipitor late in 2011.