Olga S. Matlin, PhD

The past 2 decades have been marked by an increased awareness of the need for improved management of chronic pain and the aggressive marketing of new opioid formulations. This has been associated with an increased prevalence in prescribing of opioids, alongside an increase in the abuse of prescription drugs. In response, the Centers for Disease Control and Prevention (CDC) has described prescription drug abuse as the fastest-growing drug abuse problem in the United States.

Oxycontin (Purdue Pharmaceuticals, LP) is a controlled-release oxycodone first sold in 1995 and is today among the most widely prescribed opioid medications. The controlled-release formulation is expected to deter abuse, as the active ingredient is released over a specified time period, reducing the patient’s ability to seek a “high” by taking more medication than prescribed. However, prescription drug abusers can achieve an enhanced high by chewing, crushing and snorting, or liquefying the pills. To inhibit this behavior Purdue developed an abuse deterrent technology version of Oxycontin that was approved for sale by the US Food and Drug Administration (FDA) in April 2010; and in August 2010, the company began limiting sales exclusively to the abuse deterrent technology formulation.

 A 2012 survey of 2566 opioiddependent patients conducted in part to assess the impact of the abuse deterrent technology on opioid abuse behavior reported that following release of the abuse deterrent formulation, there was indeed a decline in Oxycontin as a primary drug of abuse. However, this was accompanied by increased use of hydrocodone and other oxycodone agents, as well as increased use of high-potency agents such as fentanyl, hydromorphone and heroin.

We analyzed de-identified prescription drug claims to examine the impact of abuse deterrent formulations on the utilization of opioid medications. We specifically considered the impact of the introduction of an abuse deterrent formulation of controlled-release Oxycontin on medication utilization in a cohort of prescription drug benefit plan members who were long-term users of Oxycontin at the time of the release of the abuse deterrent formulation in August 2010.

This analysis was conducted using de-identified CVS Caremark pharmacy benefit claims data. Prescription drug benefit members who had at least 1 pharmacy claim in calendar years between 2009 and 2012 for medications commonly used to treat pain were selected for analysis (

). Members with claims for antineoplastic medications were excluded to limit the analysis to members with pain not related to cancer. Our analyses were limited to opioid medications categorized as follows: Oxycontin, other oxycodones (including generic versions of Oxycontin), morphine sulfate, hydrocodone-acetaminophen combinations, and other opioid-based pain medications(eg, fentanyl, oxymorphone, tramadol).

We examined medication utilization rates among chronic and acute opioid users, measured as the number of prescriptions filled per 1000 eligible prescription drug benefit eligible members per year from 2009 to 2012. In addition, we examined utilization trends among chronic opioid users to identify changes in medication selection following introduction of abuse deterrent technology formulations in August 2010. For this second analysis we compared 2 cohorts: 1) patients who received at least a 90-day supply of Oxycontin during the 6 months before the introduction in 2010 of Oxycontin with abuse deterrent  technology; and 2) a comparison group of patients who received at least a 90-day supply of Oxycontin during the 6 months prior to August 2009. Both cohorts were limited to members for whom Oxycontin was the only pain medication used during the 6-month look-back period. The outcomes of prescription drug use in the 12-month follow-up period (August to July) were: 1) patient remained on Oxycontin only; 2) patient discontinued all prescription opioid medications; 3) patient changed to a prescription opioid medication other than Oxycontin; and 4) patient added another prescription opioid to the Oxycontin regimen. We compared thpattern of utilization in the post period between these groups using the χ

statistic. All analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).

During each year from 2009 to 2012, approximately 4 million unique members from the analytic data set fi lled at least 1 prescription for an opioid pain medication and met our inclusion and exclusion criteria. The average age of members with a prescription for pain medication was 44.7 years (standard deviation ± 18.3) and 56% of opioid users were female.

Of the total prescriptions filled for opioid medication, over 99% were fi lled at retail pharmacies, 52% were for 10 days or less, and an additional 13% were for 11 to 20 days. Hydrocodone-acetaminophen combinations were the largest category of opioids, accounting for over half of all opioids prescribed. The overall rate of opioid use decreased by 8.3% between 2009 and 2012 (

), with the even larger decreases observed in utilization of Oxycontin, morphine sulfate, and  hydrocodoneacetaminophen combinations (19%, 10.5%, and 12.9% decreases, respectively).

The results of our analyses comparing a cohort of members who were Oxycontin users at the time abuse deterrent technology was introduced in August 2010 to a similar cohort of users in August 2009 are presented in 

. In both cohorts,  approximately 10% discontinued use of all opioid medications during the year of follow-up. In the cohort that were chronic Oxycontin users in August 2009 (the year prior to the introduction of the abuse deterrent formulation), 2.2% of members switched to another opioid medication during the subsequent 12 months. Among members who were chronic Oxycontin users in August 2010 (when the new technology was introduced), 2.6% switched to a new opioid after the introduction of the abuse deterrent formulation. The differences between these cohorts were not statistically significant (

Discussion of Findings and Pipeline Therapies

The purpose of abuse deterrent technologies is to reduce the social and medical burden associated with prescription drug abuse. In our analyses, we found that in the years following introduction of the abuse deterrent formulation, there has been a decline in utilization of Oxycontin among acute and chronic users of the medication. However, the evidence that this might be due to the abuse deterrent formulation is far from clear. The decline in use of opioid medications across other categories, noneof which included abuse deterrent formulations, may indicate that there are other market reasons for the shift away from Oxycontin. In addition, we examined changes in prescription preference for chronic Oxycontin users who purchased their medication through their pharmacy benefit plan. There we found no evidence of a negative impact on Oxycontin use among these chronic users following introduction of the abuse deterrent technology.

Previous studies of the impact of abuse deterrent formulation on opioid abuse reported mixed results.

 It has been argued that prescription opiate abuse is a complex health problem that requires a comprehensive, multifaceted solution, and thus resists a single solution.

 Indeed, many have noted that targeting abuse deterrent technology to a single medication alone is an ineffective strategy, as an effective restriction would require that all opiate formulations employ the technology.

However, most recognize that in addition to the regulatory hurdles such a policy change would encounter, there would be substantially increased cost to individuals and global health budgets resulting from such a restriction.

We found that across all categories of opioids, the rate of prescriptions dispensed fell by 8.3% for prescription drug benefit members between 2009 and 2012. It has been reported that between 2001 and 2012 the annual number of prescriptions written for opioids in the United States increased by 33%

; however, most of this increase occurred prior to 2005.

 Since 2009 sales of hydrocodone-acetaminophen combinations and oxycodone hydrochloide have been flat nationally

 while worldwide sales of branded Oxycontin have declined.

 It should be noted that our data only include sales of opioids to prescription drug benefit members using their pharmacy benefit. There remains a very large market of cash sales that cannot be captured in our data, and therefore the trends of purchasing and utilization of opioid medications obtained via cash transactions were not examined in this analysis.

In April 2013, the FDA approved updated labeling for the reformulated, abuse deterrent version of controlled release oxycodone hydrochloride indicating continued support of regulators for abuse deterrent technologies in both generic and branded medications.

 we detail the pipeline for abuse deterrent technologies for other opioid based analgesics. The pipeline includes a wide array of technologies with functionality that would limit the ability of abusers to tamper with the drug. The medications in development include traditional opioid treatments for moderate to severe pain that incorporate agonist/antagonist, aversion, and physical or chemical barrier technologies. Remoxy, an oxycodone controlled release product, appears to be a future candidate for FDA approval; however, Pfizer has not yet invested in further development.

Abuse deterrent formulations continue to evolve and find application across a range of therapeutic classes and interest from public policy makers. Prescription drug abuse shows no signs of abating as a social problem; therefore, there is a growing need for formulary policy makers to be aware of the clinical and economic impact of abuse deterrent technologies.

Articles

The authors examined trends in the utilization of prescription opioid medication following introduction of abuse deterrent technology for Oxycontin.

The Impact of Abuse Deterrent Technologies on Prescription Opioid Trends

It is estimated that 26 million people in the United States have diabetes mellitus.

 Diabetes mellitus describes a number of metabolic conditions, but the most common forms are type 1 diabetes mellitus, a condition in which the body destroys insulin cells, requiring the person to receive insulin injections to properly control their blood glucose levels; and type 2 diabetes mellitus (T2DM), whereby the body is unable to either produce or respond to insulin in a manner sufficient to maintain normal blood glucose levels. Our analysis will focus on T2DM, which accounts for 90% to 95% of all cases of diabetes in the United States.

Over 1.4 million new cases of diabetes are diagnosed each year among people over the age of 40 years—virtually all are T2DM. Risk factors for T2DM include older age, obesity, and inactivity.

As the prevalence of these risk factors will increase with the aging of the baby boomer generation, the prevalence of T2DM is expected to increase dramatically as well. T2DM places a tremendous burden on the US healthcare system. People with T2DM have twice the mortality risk of people of similar age without T2DM. The Centers for Disease Control and Prevention reports that diabetes (types 1 and 2 combined) places a burden of over $174 billion annually on the US economy ($116 billion in direct medical costs and $58 billion from disability and productivity loss).

The goal of treatment for a diabetic patient is to maintain blood glucose levels at normal or near-normal levels. This is essential in the prevention of diabetic complications, as increased blood glucose levels are associated with loss of vision (retinopathy), kidney failure, and cardiovascular disease.

 The recommendations for medical management of diabetes have evolved with the introduction of new treatment options, particularly incretin-based therapies—dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

The incretin response, or activity, is reduced in adults with T2DM, resulting in excess blood glucose. DPP-4 is an enzyme that breaks down incretins and, by inhibiting DPP-4 production, incretin levels in the blood increase, resulting in the reduction of excess blood glucose.

 GLP-1 receptor agonists increase the levels of cyclic AMP inside cells by binding to GLP-1 receptors found in the pancreas which, when blood glucose concentrations are elevated, results in insulin secretion. As blood glucose concentrations decrease and approach normal levels, insulin secretion decreases.

We will examine how utilization and prescribing patterns have evolved for patients with existing diabetes and those newly diagnosed, paying particular attention to the role of GLP-1 receptor agonists and DPP-4 inhibitors in members who were historically treated with biguanides and/or sulfonylureas.

We conducted 3 related analyses using deidentified CVS Caremark pharmacy benefit claims from the funded commercial population from 2008 to 2012. For all analyses, members were required to be at least 40 years old and members with prescription fills for insulin were excluded to eliminate people with type 1 diabetes mellitus from our sample. Our first analysis was a description of members with prevalent diabetes between 2008 and 2012. The cohort used for this analysis consisted of all members who had at least 1 prescription fill for a diabetes medication between 2008 and 2012 (we refer to this as the Prevalence Cohort).

In the second analysis we examined patterns of medication use among members who were new users of diabetic medication. This cohort consisted of members using a diabetic medication between 2008 and 2012 who did not have a prescription fill for that medication in the 6 months prior to their first prescription fill between 2008 and 2012. In order to establish treatment-naïve status, we required these members to be continuously eligible for benefi ts for 6 months prior to their first fill of diabeticmedication (we refer to this as the Naïve Cohort). In the third analysis, we described trends in the use of DPP-4 inhibitors and GLP-1 receptor agonists as an adjunct treatment to biguanides and sulfonylureas. For this, we identified a cohort of members who had at least 1 prescription fill for either a biguanide or a sulfonylurea in 2011 and no prescription fills for either a DPP-4 inhibitor or GLP-1 receptor agonist that year. We required these members to be continuously eligible from 2011 to 2012, over the age of 40 years in 2011, and have no prescription fills for a DPP-4 inhibitor and/or a GLP-1 receptor agonist 6 months prior to their fi rst biguanide/sulfonylurea fill in 2011. We identified members of the 2011 cohort using biguanides and sulfonylureas who added (or switched to) a DPP-4 inhibitor or GLP-1 receptor agonist in 2012. Switching away from a sulfonylurea to a GLP-1 receptor agonist and/or a DPP-4 inhibitor was defi ned as the last fill of sulfonylurea before the first fill of either a GLP-1 receptor agonist or a DPP-4 inhibitor, allowing for a 7-day overlap. We refer to this as the Uptake Cohort.

In these analyses, cost was defined as the total paid charges for the medication by combining the payer and member portions of the health plan’s allowable charges. Our statistical analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).

Among plan members 40 years and older, we found that 9.6% used diabetes medications and on average, 1.2% started diabetes therapy each year during our 5-year observation period. Between 2008 and 2012, the prevalence of diabetic medication use increased by 1.4 percentage points, from 8.7% to 10.1% (

). There was little change in incidence of diabetic medication use between 2008 and 2012, as it fluctuated between 1.0% and 1.3%. The average age in our Prevalence Cohort was 62.2 years (standard deviation [SD]: 11.8 years), and 49.1% were male. Members of our Naïve Cohort were younger than those in the Prevalence Cohort, with an average age of 58.6 years (SD 11.1), and 52.3% were male.

, we describe trends in medication use for the Prevalence Cohort. Between 2008 and 2012, utilization of biguanides as monotherapy or in combination increased by 5.3 percentage points, from 46.1% to 51.4%. During this same period, utilization of sulfonylurea as monotherapy or in combination declined by 3.9 percentage points, from 27.7% to 23.8%. Utilization of DPP-4 inhibitors as monotherapy or in combination increased from 8.3% in 2008 to 14.2% in 2012, and utilization of GLP-1 receptor agonists increased by 1.0 percentage point, from 3.5% in 2008 to 4.5% in 2012.

, we detailed the observed trends in cost of pharmaceutical treatment for people with diabetes from 2008 to 2012. Between 2008 and 2012, the average annual cost of providing pharmaceutical care for a person with T2DM increased from $667 to $741 (11.1%). During this period, the cost of the those drugs most commonly prescribed for T2DM—biguanides, sulfonylureas, and their combination&mdash;declined by over 33%, driven by a generic dispensing rate in excess of 96% for these drug classes. Conversely, the observed increase in cost of care for people with T2DM was driven by the increased annual cost of medication in less commonly prescribed drug classes: the DPP-4 inhibitors, GLP-1 receptor agonists, amylin analogue, and meglitinide agents. Of these, only the DPP-4 inhibitors and GLP-1 receptor agonists had a utilization rate in excess of 2%, and the increase in cost between 2008 and 2012 for DPP-4 inhibitors was 44% and for GLP-1 receptor agonists was 75%.

Between 2008 and 2012, approximately 85% to 90% of people naïve to diabetic medications initiated treatment on monotherapy (

). Most commonly, these people with diabetes were started on biguanide monotherapy(63.8% of utilizers during the study period). For biguanides, the utilization rate as monotherapy increased from 55.5% in 2008 to 67.0% in 2012. During the same period, utilization of sulfonylurea monotherapy decreased from 14.2% to 10.8%. Between 9.9% and 14.7% of people naïve to diabetes therapy were started on more than 1 medication over the study period, most commonly on a combination of sulfonylurea and biguanide, or a combination of sulfonylureas, biguanides, and at least 1 additional drug (

In our Uptake Cohort, we examined the addition of DPP-4 inhibitors or GLP-1 receptor agonists in people who were naïve to the use of those medications in 2011. This is illustrated in 

, where, for the sake of clarity, we have scaled our fi gure to represent a hypothetical cohort of 1000 people with T2DM. In 2012, 570 of the 1000 hypothetical cohort members (57%) were on biguanides, 130 (13%) were on sulfonylureas, and 300 (30%) were on both. Less than 1% of those who were naïve to DPP-4 inhibitor or GLP-1 receptor agonist therapy in 2011 were changed to one of these medications as their primary therapy in 2012. Among those on biguanide monotherapy, 5.4% had a DPP-4 inhibitor added to their regimen and 1.6% had a GLP-1receptor agonist added in 2012. For those on sulfonylurea monotherapy, 6.0% had a DPP-4 inhibitor added and 1.2% had a GLP-1 receptor agonist added in 2012. Among the 300 (30%) who were on a combination of biguanide or sulfonylurea in 2012, 28 (9.3% of the subgroup members) had a DPP-4 inhibitor added, 8 (1.9% of the subgroup) had a GLP-1 receptor agonist added, and <1 (0.3% of the subgroup) added both. In this subgroup, there were also 5 members (less than 1.3%) who had their sulfonylurea replaced with DPP-4 inhibitors, GLP-1 receptor agonists, or both. It should be noted that of our 1000 hypothetical cohort members, 914 remained only on biguanides, sulfonylureas, or a combination of those 2 medications—fewer than 95 (or <9.5%) of patients naïve to the use of DPP-4 inhibitors or GLP-1 receptor agonists started therapy on one of those medications during the year.

Impact of New Agents and Pipeline Therapies

In these analyses, we found a prevalence of diabetic medication use of 9.6% among our plan members over the age of 40 years, with an additional 1.2% initiating therapy on diabetic medication each year. At least 70% of these members were on a biguanide, sulfonylurea, or a combination that includes these medications. We estimate that the annual cost of medication for these members was $741 in 2012, a sum that has been increasing at an average rate of 2.7% per year since 2008 despite a reduction in cost of biguanides and sufonylureas.

The new incretin-based therapies—DPP-4 inhibitors and GLP-1 receptor agonists&mdash;represent an important option to augment fi rst-line therapies for people with T2DM. Prior to the availability of these medications, first- and second-line treatment options for T2DM were primarily biguanides, sulfonylureas, basal insulin, and thiazolidinediones.

 These new therapies are considered to offer comparable glycemic management with fewer side effects than traditional therapies, including hypoglycemia, weight gain, and edema.

 Incretin mimetics have also been reported to improve β-cell function and reduce cardiovascular risk factors.

Recent guidelines from the American Association of Clinical Endocrinologists/ American College of Endocrinology and  American Diabetes Association/European Association for the Study of Diabetes support incretin-based therapies as a fundamental treatment option, suggesting that DPP-4 inhibitors and GLP-1 receptor agonists are helpful in treatment of patients with T2DM who are on other glucose-lowering medications and those naïve to therapy. The guidelines also suggest GLP-1 receptor agonists are preferred over the DPP-4 inhibitors because of their superior impact on glycated hemoglobin (A1C) levels.

 An additional benefit that has been reported for the GLP-1 receptor agonists is modest weight loss for people with diabetes.

It should be noted, however, that incretin-based therapies have signifi cant shortcomings. GLP-1 receptor agonists require subcutaneous administration, which can be a challenge for elderly diabetics. There is also the concern of a potential link between people being treated with GLP-1 receptor agonists or DPP-4 inhibitors and pancreatitis and pancreatic cancer.

 It must also be recognized that the enhanced efficacy of the incretin based therapies comes at a higher fi nancial cost. The cost of pharmaceutical treatment of people with diabetes has been rising since 2008 in spite of a decline in the cost of biguanides and sulfonylureas. This has been largely due to the adoption of incretin-based therapies that have a higher cost than these first-line therapies. We estimate that in 2012, the cost of incretin-based medications added $282 per utilizer per year to the cost of treatment for the average person with T2DM. Extrapolating this to the total population of people with T2DM in the United States,this represents an annual burden of $6.6 billion to the US healthcare system. Given the trend toward increased use of these medications, we would expect to see the economic burden increasing by over $2.9 billion annually over the next few years. However, at least a portion of the increased costs for medication may be offset by lower healthcare expenditures for diabetics who benefi t from improved glycemic control and fewer side effects. Pharmaceutical manufacturers have continued to invest heavily in the development of incretin-based therapies. In 2013, 3 new medications were approved for the US market: Nesina (alogliptin), Kazano (alogliptin/metformin), and Oseni (alogliptin/pioglitazone) by Takeda Pharmaceutical.

Alogliptin, an active ingredient in each of these medications, is a new DPP-4 inhibitor.13 Several new incretin-based therapies are also pending US Food and Drug Administration approval or are in phase 3 clinical trials in the United States (

It is a limitation to our analysis that we excluded members  who were on insulin. We recognize that this eliminates from our analysis a substantial subgroup of people. However, we felt it to be very important that we eliminate from our analysis people with type 1 diabetes, or other non—type 2 conditions that would reduce the applicability of our results to people with T2DM. It is likely that this approach led to a very modest underestimation of the absolute prevalence and incidence of diabetic medication use (we suspect that our prevalence estimate is at most 1.5 points below the true prevalence and the incidence estimate is at most 0.2 points below the true incidence). However, comparisons between the medications would be affected only to the extent that insulin use would be associated more with one medication than another. As there is no reason to expect that to be the case, these comparisons are likely to be unbiased.

Incretin-based therapies have proved to be effective in the treatment of people with T2DM who are not responsive to fi rst-line therapy with biguanides and sulfonylureas. As medical therapies for T2DM advance, so do the complexities of recommended treatment options. The role of incretin-based therapies will likely evolve and continue to challenge formulary managers and payers weighing effectiveness and cost in management of people with T2DM.

We examined the prevalence of use and cost impact of DPP-4 inhibitors and GLP-1 receptor agonists in people with diabetes.

The Expanding Role of New Medications in the Treatment of Type 2 Diabetes Mellitus

Gout is a rheumatic disease affecting nearly 3.9% (8.3 million) of adults in the United States, with men almost 40% more likely to beafflicted than women.

 Hyperuricemia, or elevated uric acid levels greater than 6.8 mg/dL, which result in the formation of monosodium urate crystals in joint tissues, is the primary cause of gout.

 Gout initially presents as an acute episode of arthritis, most commonly beginning in the metatarsalphalangeal joint at the base of the big toe.

 Risk factors for gout include lifestyle-related behaviors such as alcohol use and consumption of purine-rich foods, in particular organ meats and oily fishes.

Medical conditions including obesity, diabetes, and renal insufficiency contribute to the risk of gout, as do medications such as diuretics and chemotherapeutic agents.

 The treatment goals for acute and chronic gout differ, as do the medications used in each setting (

The goal of treatment for an acute episode of gout is pain relief through reduction of inflammation.

 This is often achieved by the use of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), prescription corticosteroids, or colchicine. For patients with chronic gout, the goal of treatment is to reduce the frequency of painful episodes by reducing and maintaining uric acid concentrations of less than 6 mg/dL using a combination of nonpharmacological interventions (ie, dietary and lifestyle changes) and pharmacological agents.

The American College of Rheumatology (ACR) has recommended first-line pharmacologic prophylaxis with a xanthine oxidase inhibitor (XOI), such as allopurinol or febuxostat, along with low-dose colchicine or an NSAID in treatment of chronic gout.

 Probenecid, a uricosuric, is recommended as an alternative first-line agent when either allopurinol or febuxostat is contraindicated or when a patient has demonstrated intolerance to at least 1 of the first-line agents.

 The ACR further designated the combination of an XOI and a uricosuric as a second-line treatment in refractory disease. A newer therapeutic option, pegloticase, is a recombinant uricase reserved as a third-line agent in cases of refractory disease where a patient has failed or was not able to tolerate an appropriately dosed oral urate-lowering therapy. Pegloticase is administered biweekly by infusion in a healthcare setting.

Until recently the cost of medication for the treatment of chronic gout was relatively low, with the monthly cost for a single medication ranging from $18 to $100, depending on disease severity and duration.

 However, treatment of chronic gout may require multiple medications, and the combined economic burden has been estimated by some investigators to be over $200 per month.

 The cost associated with gout therapies is poised to increase dramatically due to federal policy decisions and pipeline developments. In June 2006, the US Food and Drug Administration (FDA) initiated a new drug safety proposal to remove medications, such as colchicine, from the market that previously had not been required to demonstrate safety or efficacy.12 In order to incentivize evaluation of medications impacted by this initiative, the FDA offered marketplace exclusivity to companies that conducted the necessary safety and efficacy studies.

 In 2007, URL Pharma, a maker of generic medications (since acquired by Takeda Pharmaceutical Company Limited), conducted clinical trials to examine the efficacy of colchicine and identify the smallest efficacious dose for the treatment of gout.

 A lower-dose regimen with an incidence of adverse events similar to placebo was identified and in 2009 the manufacturer was granted 3 years of marketplace exclusivity for their colchicine formulation, Colcrys.

Following this approval, the FDA mandated the removal of all unapproved single-ingredient oral colchicine products from the market resulting in an unintended increase in the cost of treatment from pennies per day to nearly $5 per day.

This report will examine the prevalence of prescription medications utilized in the treatment of gout. In addition, the influence of Colcrys on utilization and cost of treatment for gout will be analyzed. Finally, the current status and economic consequence of recently launched and pipeline medications used for the treatment of gout will be discussed.

This descriptive analysis was conducted using de-identified CVS Caremark pharmacy claims data. Adult members who had a pharmacy claim in calendar years from 2009 to 2012 for at least 1 of the medications primarily used for the treatment of gout were selected for analysis. The medications considered were: colchicine, febuxostat, pegloticase, colchicine with probenecid, and allopurinol. Age and gender were based upon that reported for the last claim for each member. The generic dispensing rate (GDR) and cost per utilizer per day were also calculated. For this analysis, “cost” is defi ned as the total paid charges for the medication (the payer and member portions combined). The descriptive analyses were conducted using SAS 9.1 (SAS Institute, Cary, North Carolina).  

 A total of 955,356 unique members were identified with a pharmacy claim for at least 1 gout medication. This reflects a prevalence of 1.5% among adult members, which remained stable over the observation period (2009-2012). The average age of members with gout was 62.8 years (standard deviation ±14.2) and 75.9% of members utilizing prescription gout medications were male. The prevalence of gout varied by payer type (Figure 1), and as would be expected due to their older age, gout was more common among members in Medicare plans than members in other plans. Members in Medicaid plans had the lowest prevalence of gout. This is likely an artifact of coverage policies for prescription medications for treatment of gout in these plans and the high prevalence of young women and children among Medicaid beneficiaries.

The prevalence of use of prescription gout medications is illustrated in Table 2. Allopurinol had the highest utilization, with nearly 80% of members taking this medication, while colchicine was taken over by 30% of members. Since the introduction of branded colchicine (Colcrys), as well as the removal of generic versions, the use of colchicine has declined over 5 points. A steady year to year increase in market share for febuxostat is seen since its introduction in February 2009. There were very few claims paid for pegloticase over the 4-year period. Given the route of administration for this medication, claims for pegloticase would most likely be paid under the member’s medical benefit rather than the pharmacy benefit, and as a consequence would not be included in the data set.

In 2009, the combined GDR for prescription gout medications was nearly 99%. With the withdrawal of generic colchicine from the market and the introduction of febuxostat, the combined GDR declined to 78% by 2012. The impact on the combined GDR of the FDA’s decision  to grant marketplace exclusivity to Colcrys is illustrated in 

. The GDR fell in 2010 and 2011 as pharmacy inventories of generic colchicine were depleted and by 2012 it had fallen to 0.3%. During this period, the cost per unit increased from $0.17 to $4.53. This was accompanied by an increase in the annual cost of treatment with colchicine on a per user per year basis from $27 to $560.

The average cost per unit of medications prescribed for the treatment of gout is summarized in 

. In addition to the dramatic increase in the cost of colchicine there was an increase in the cost of febuxostat, while the cost of the other gout medications remained constant. The extremely high cost for pegloticase is based upon a limited number of claims, but is consistent with the stated cost of the medication and dosing schedule.

 Nonetheless, the magnitude of the estimate for pegloticase provides evidence of the potential impact specialty medications may have on the cost of treatment for gout in the future.

Summary of Findings and Impact of Pipeline Medications

Gout is a relatively common rheumatic disease affecting over 8 million adults in the United States.

 Based upon the prevalence of medication utilization in this analysis we estimate that approximately 3.6 million adults in the United States are taking prescription medications for gout. Until recently, these prescription medications for the treatment of gout were relatively inexpensive. However, this has been reversed because of 2 factors: 1) the unintended consequence of policy decisions; and 2) the recent launch of additional gout therapies.

The intended result of the FDA Unapproved Drug Initiative was to provide FDA oversight, as well as guidance on indications, dosing, and drug interactions for medications that previously had not demonstrated evidence of safety and efficacy.

 However, in the case of colchicine the Initiative has had the unintended consequence of a 21-fold increase in the cost of medication (Table 3). According to the results, 28.5% of members receiving prescription medications for the treatment of gout were on colchicine in 2012 (Table 2). Extrapolating this to the national health budget would indicate that the annual burden to the US healthcare system of treatment with colchicine in 2012 is more than $540 million larger than it was in 2009. The higher cost of colchicine may have also put access to the medication beyond the reach of some members, indicated by a reduction in its use from 33.9% in 2009 to 28.5% in 2012. This would indicate that in 2012 approximately 194,000 people with gout who would otherwise have been taking colchicine either switched to an alternative gout medication or fell off of therapy—each of which represents a shift in the treatment burden to the member that should be recognized.

These data allows estimation of the increased cost for pharmacy benefit plans that has resulted from the policy change in colchicine and the introduction of febuxostat. There has been an estimated increase of $0.26 per member per month (PMPM) to cover prescription treatment of gout since 2009 (from $0.06 to $0.32 PMPM). Of this increase, $0.18 per member per month PMPM (71%) is due to the increased cost of colchicine, and $0.08 PMPM (28%) is due to the introduction of febuxostat. The cost associated with other gout treatments was relatively fl at or declined

Due to a lack of data, the role of pegloticase or forthcoming specialty medications in infl uencing the cost of care of members with gout could not be evaluated. Claims for pegloticase, similar to other infused products, are rarely part of the pharmacy benefi t. However, it is estimated that 3% of patients with gout do not respond to existing therapies and thus would benefi t from pegloticase.

 Therefore, while the impact of pegloticase was not captured in this study, its impact could be substantial.

 suggests, there continues to be a strong interest in the development of new medications for the treatment of gout. The pending medication approvals include both oral medications with existing mechanisms of action, and new mechanisms of action and an injectable medication. The oral medications lesinurad, ulodesine, and arhalofenate are being studied in patients who are unable to achieve target serum urate levels on allopurinol or febuxostat alone. Since the utilization of other medications such as diuretics can contribute to hyperuricemia, lesinurad is being studied in a population that takes these medications concurrently. Arhalofenate may offer additional benefi ts such as decreased triglycerides and blood glucose along with its urate-lowering effects. The injectable medication in the pipeline is an interleukin-1 (IL-1) inhibitor, canakinumab, which is currently approved for the treatment of children with autoinflammatory cryopyrin-associated periodic syndromes and seeking a supplemental indication for the symptomatic relief of gout fl ares refractory to other treatments.25 While the pipeline refl ects possible therapies for those with comorbidities and for refractory members, the introduction of additional branded and specialty therapies may result in a continued increase in the cost of care.

This study has demonstrated that both the decisions of policy makers and innovations in treatment will impact the cost of treatment for diseases such as gout that have traditionally been low in cost. Decisions concerning a single medication, colchicine, have resulted in a 5-fold increase in the PMPM cost for treatment of gout with prescription medications. At this point there are not enough data to quantify the impact of current or upcoming specialty medications on the cost to pharmacy or medical plans for the treatment of gout, but these medications promise to present a continuing challenge for plan administrators. Therefore, it will be more important thanever to continue to look for ways to manage the rising cost of care. Utilization management tools such as prior authorization, step therapy, or medical carve outs will help to ensure that the use of these expensive therapies is appropriate and cost-effective.

With new drugs in the pipeline and the impact of updated FDA drug safety policies on colchicine, gout may no longer be inexpensive to treat.

Trends in Medication Utilization and the Cost of Treatment for Gout

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.

 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.

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.

 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.

 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.

The goal of treatment for dyslipidemia is to decrease levels of LDL-C, leading to reduced risk of major cardiovascular events and comorbidities.

 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.

 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%.

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.

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%, 

 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%).

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&mdash;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.

 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 

). 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.

 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.

 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 cholesterol

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.

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.