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June 2015 FAQs

Questions

What is the evidence to support twice-daily dosing of insulin glargine?

What is the rationale and significance of the FDA’s new guidance for abuse-deterrent opioids?

What should healthcare providers know about PCSK9 inhibitors, the new class of cholesterol-lowering medications?

Answers

What is the evidence to support twice-daily dosing of insulin glargine?

Background

Insulin glargine is a recombinant human insulin analog for subcutaneous administration that is used to achieve glycemic control in patients with diabetes. It is approved for use in both adult and pediatric patients with type 1 diabetes mellitus (DM), and also adults with type 2 DM.

Insulin glargine is approved for once-daily administration due to a long half-life that results in a 24-hour glucose lowering effect.1 It can be administered at any time of day as long as the timing is kept consistent. Similar to other insulins, the appropriate dose depends on a patient’s clinical response and degree of pancreatic insufficiency or insulin resistance. One favorable characteristic of insulin glargine is its peakless pharmacokinetic profile that theoretically results in fewer episodes of hypoglycemia, regardless of the timing of insulin administration. As a long-acting insulin formulation, insulin glargine is used as the basal component of basal-bolus regimens. This type of regimen most closely represents normal circadian changes in insulin levels. The American Diabetes Association (ADA) recommendations for the management of inpatient diabetes endorse using a basal-bolus regimen for glucose control in non-critically ill patients with a long-acting, peakless, 24-hour duration basal insulin that suppresses hepatic release of glucose during fasting and between meals throughout the day.2The ADA specifically favors insulin glargine over other long-acting insulin analogs (eg, insulin detemir, insulin neutral protamine Hagedorn [NPH]) because it exhibits a more peakless profile. Other guidelines for the management of DM also support the use of insulin glargine as a first-line long-acting insulin.3,4

After subcutaneous administration, insulin glargine is absorbed at a slow and consistent concentration over time profile, resulting in its extended effectiveness over 24 hours.1However, the manufacturer cautions that the actual duration of action may differ between patients. Inter-patient variability may be present in various subpopulations, such as those with renal or hepatic impairment, and it is recommended that these patients have careful glucose monitoring.

Given the concern over the variability in pharmacokinetics based on patient characteristics, the idea of using insulin glargine in a twice-daily manner recently has been raised. Some clinicians believe that certain patients may not achieve adequate basal coverage for a full 24 hours with the once-daily dose of insulin glargine, and may benefit from a split-dose regimen. The available evidence on the off-label twice-daily dosing of insulin glargine is summarized below.

Evidence for the use of twice-daily insulin glargine

There are few published evaluations of the safety and efficacy of twice-daily insulin glargine. Two prospective studies have evaluated this method of administration.5,6 In addition, 3 retrospective evaluations have been conducted to assess twice-daily dosing of insulin glargine.7-9 Pertinent information from these studies, including study design, population, interventions, and results, are presented in the Table below.5-9

Table. Published studies on the use of twice-daily insulin glargine.5-9

Study design and duration

Subjects

Interventions

Results

Conclusions

Ashwell 20065

R, SC, OL, crossover

8 weeks

n=20 patients with type 1 DM managed with a multiple insulin regimen

Mean age 43.4±13.7 years, mean BMI 26.7±4.5 kg/m2, mean HbA1c 8.0±0.9%

Insulin glargine once-daily at dinner

Insulin glargine BID at breakfast and dinner, in equally divided doses

All patients also received insulin aspart with meals

Crossover to the other dosing strategy occurred after 4 weeks

Daily insulin dose did not differ between dosing strategies (25±2.7 units with once-daily vs. 26±2.7 units with BID)

HbA1c at study end was the same in both groups (7.1±0.1%)

Post-breakfast (p=0.003), post-lunch (p=0.024), and pre-dinner (p=0.001) glucose values were higher with once-daily vs. BID

Mean 24-hour glucose values were lower with BID vs. once-daily (p=0.031)

Late afternoon hypoglycemia occurred in 3 patients on once-daily vs. none with BID

All patients reported at least 1 episode of hypoglycemia during each study period; all episodes of severe hypoglycemia (n=3) occurred in the once-daily group

Glucose control appears similar overall with once-daily and BID insulin glargine dosing strategies.

Limitations:

Type 1 DM only

Small study with limited power

Short duration to evaluate HbA1c changes

OL design

No DM-related complications were assessed

24-hour glucose measurements were taken in a controlled clinical setting with controlled dietary intake

Albright 20046

SC, OL

12 to 15 months

n=82 patients with type 1 DM

No information on baseline demographics was provided

Conversion from once- or twice-daily insulin NPH to once-daily insulin glargine

All patients also received insulin aspart or lispro with meals

Patients could be further titrated to insulin glargine BID for persistently elevated HbA1c or pre-dinner glucose levels with concurrent morning hypoglycemia, or persistently high afternoon glucose levels that could not be corrected with higher bolus doses

20 (24.2%) patients required BID insulin glargine

BID insulin glargine patients had an improvement in HbA1c (7.9% to 7.4%, p=0.03) over 3 to 6 months from baseline values and a significant reduction from the initiation of BID dosing to study end (8.1% to 7.4%, p=0.001)

HbA1c between insulin glargine once-daily and BID was not different at study end (p=0.8)

About one-quarter of type 1 DM patients required BID insulin glargine dosing to achieve acceptable glycemic control, but HbA1c levels at study end were similar with once-daily and BID dosing.

Limitations:

Type 1 DM only

Small study with limited power

OL design, non-randomized

No DM-related complications were assessed

Short duration to evaluate HbA1c changes

Housel 20107

SC, retrospective

n=18 patients with type 2 DM who received BID insulin glargine and n=17 subjects matched for initial HbA1c and change in insulin glargine dose

97% male, mean age 65 years, mean BMI 34 kg/m2, mean duration of DM 12 years, mean HbA1C 8.5%

Secondary analysis to determine predictors for switching among all patients who received insulin glargine during the study period

· n=28 BID group

· n=117 once-daily control group

Once-daily insulin glargine

BID insulin glargine

Conversion from once-daily to BID resulted in a mean decrease in HbA1C of 0.52±0.12% (p=0.14)

Once-daily and BID resulted in a similar HbA1c decrease (relative decrease of 0.53±0.11%, p=0.16)

Conversion to BID significantly increased the total mean daily dose of insulin glargine from 90 to 132 units (difference of 42±13 units, p=0.014)

Need for larger doses of insulin was a significant predictor of BID administration

Patients with BMI >30 kg/m2 had an unadjusted OR for receiving BID administration of 1.7 (95% CI 0.7 to 4.2)

BID administration of insulin glargine may be a good strategy for patients who require larger insulin doses and are within 0.5% of their HbA1C goal.

Limitations:

Type 2 DM only

Small study with limited power

Retrospective

No DM-related complications were assessed

McCord 20058

SC, retrospective

n=30 patients who received BID insulin glargine and n=30 age-matched controls who received once-daily insulin glargine

Mean age 54±9.6 years

Once-daily insulin glargine

BID insulin glargine

No differences between groups in mean change from baseline in fasting blood glucose, HbA1c, HDL, triglycerides, or weight

All patients had a significant reduction in HbA1c, fasting blood glucose, and triglycerides from baseline (no specific results provided)

Greater reduction in LDL for BID group (‑9.25±24.35 mg/dL vs. -26.06±42.8 mg/dL; p=0.039)

Longer duration of insulin therapy and higher insulin dose requirements were significant predictors of BID use

Insulin glargine administered BID had similar clinical efficacy as insulin glargine once-daily.

Limitations:

Small study with limited power

Retrospective

Type of DM (1 or 2) was not specified

Abstract included few specific numbers for baseline characteristics or outcome results

Garg 20049

SC, retrospective

n=292 patients with type 1 DM receiving ≥4 injections per day and using insulin glargine as their only basal insulin for 6 months

Mean age 32±10 years, mean duration of DM 15.9±10.3 years, mean duration of glargine treatment 13.1± 4.5 months

Morning insulin glargine (n=63)

Evening insulin glargine (n=126)

BID insulin glargine (n=104)

All patients also received insulin aspart or lispro before meals

Final mean daily long-acting insulin doses were higher in the BID group than the once-daily groups (p<0.01)

HbA1c values improved from baseline with BID and evening dosing, respectively (7.9% to 7.6%, p<0.01; 8.1% to 7.8%, p<0.01)

There were no differences in the final HbA1c values between groups

Only the BID dosing group had significant weight gain from baseline (mean 77.9 kg to 79.4 kg, p<0.01)

Number of severe hypoglycemic episodes was not different between groups at baseline or study end

BID insulin glargine administration did not offer any advantages in glycemic control vs. once-daily dosing.

Limitations:

Type 1 DM only

Small study with limited power

Retrospective

 Abbreviations: BID=twice daily; BMI=body mass index; CI=confidence interval; DM=diabetes mellitus; HbA1c=glycosylated hemoglobin; HDL=high density lipoprotein; LDL=low density lipoprotein; NPH=neutral protamine Hagedorn; OL=open-label; OR=odds ratio; R=randomized; SC=single-center.

A pharmacokinetic study showed that insulin and glucose exposure in 10 patients with type 1 DM did not differ between once- and twice-daily insulin glargine dosing in the final 4 hours of a 24-hour evaluation.10 Another study that crossed-over 7 patients with uncontrolled type 1 DM from once-daily to twice-daily insulin glargine administration did not find any differences in mean glucose concentration between the 2 regimens during a 72-hour continuous subcutaneous glucose monitoring assessment.11 Patients on the twice-daily regimen had a lower risk of pre-breakfast hypoglycemia compared to once-daily dosing (135 ± 43.96 mg/dL vs. 107.33 ± 44.36 mg/dL, p=0.043). Overall, pharmacokinetic evaluations do not strongly support the use of twice-daily insulin glargine over traditional once-daily administration.

Comparative efficacy of peakless long-acting insulins for twice-daily administration

While many clinicians prefer insulin glargine because of its peakless activity and guideline recommendations endorsing its preferred use, insulin detemir is a frequently used alternative long-acting basal insulin.12 Unlike insulin glargine, insulin detemir has a small but noticeable pharmacologic peak which is normally seen 6 to 8 hours after administration. Furthermore, the duration of action is dose-dependent; lower doses normally result in a shorter duration of action, while larger doses (≥0.8 units/kg) result in an extended duration of action averaging 22 to 23 hours.

One pharmacokinetic and pharmacodynamic study concluded that insulin detemir and insulin glargine have similar glucose-lowering effects during the initial 12-hour period after administration, but effects of insulin detemir are lower during the 12- to 24-hour period after administration, supporting its twice-daily administration.13 Unlike glargine, insulin detemir is FDA-approved for both once- and twice-daily dosing. Other evaluations comparing the 2 insulins have shown no significant difference between the treatments in mean glucose levels when both were dosed twice-daily.14 A review of 7 randomized controlled trials suggests that, on average, a 38% higher total daily insulin detemir dose (including both once- and twice-daily administration) is required to achieve glucose control that is similar to that achieved with insulin glargine.15 Due to conflicting results regarding which insulin is more effective when dosed twice-daily, and the limited studies evaluating twice-daily insulin glargine, the choice of twice-daily long-acting insulin will likely be based on other factors including insurance coverage and the clinician’s comfort in using an off-label insulin glargine dosing strategy.

Another peakless long-acting insulin product recently entered the US market: insulin glargine 300 units/mL (Toujeo®).16 The manufacturer describes the product as an ultralong-acting insulin since the higher concentration is designed to release from the site of administration more gradually compared to the 100 units/mL products. Toujeo has not been compared to insulin glargine 100 units/mL administered twice-daily, so the comparative efficacy and safety of these products are unknown.

Conclusion

Insulin glargine is one of several available insulins that are used as the long-acting basal insulin component of a basal-bolus regimen. Insulin glargine has a peakless profile and long duration of action that allows for once-daily dosing in most patients. Clinical studies evaluating the efficacy and safety of twice-daily insulin glargine dosing are limited. There is a need for larger, randomized controlled trials comparing the safety and efficacy of the twice-daily administration of insulin glargine compared with the traditional once-daily administration of insulin glargine, twice-daily insulin detemir, and the 300 units/mL insulin glargine product. Based on the currently available evidence, twice-daily administration of insulin glargine seems safe and is not associated with more episodes of hypoglycemia. From the trials available, populations that may benefit most from further evaluation of twice-daily insulin glargine include patients who require large daily basal insulin doses, or patients with pre-dose hyperglycemia who cannot tolerate higher basal insulin doses due to hypoglycemia.

References

1. Lantus [package insert]. Bridgewater, NJ: Sanofi-Aventis Pharmaceuticals; 2015.

2. Magaji V, Johnston JM. Inpatient management of hyperglycemia and diabetes. Clin Diabetes. 2011;29(1):3-9.

3. American Diabetes Association. Approaches to glycemic treatment; Standards of Medical Care in Diabetes. Diabetes Care. 2015;38(Suppl 1):S41-48.

4. Garber AJ, Abrahamson MJ, Barzilay JI, et al; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract.2013;19(2):327-336.

5. Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart. Diabet Med. 2006;23(8);879-886.

6. Albright ES, Desmond R, Bell DS. Efficacy of conversion from bedtime NPH insulin injection to once- or twice-daily injections of insulin glargine in type 1 diabetic patients using basal/bolus therapy. Diabetes Care. 2004;27(2):632-633.

7. Housel AK, Shaw RF, Waterbury NV. Glucose control in patients with type 2 diabetes based on frequency of insulin glargine administration. Diabetes Res Clin Pract. 2010; 88(2):e17-e19.

8. McCord AD, Kiel PJ, Duerloo D, et al. Insulin glargine: clinical efficacy and predictors of twice daily dosing [abstract 99]. Pharmacotherapy. 2005;25(10):1451.

9. Garg SK, Gottlieb PA, Hisatomi ME, et al. Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning, evening, or split dose insulin glargine. Diabetes Res Clin Pract. 2004;66(1):49-56.

10. Burge MR, Schroeder ER, Mitchell S. Assessing insulin effectiveness at the end of the day: once-daily versus twice-daily insulin glargine injection. J Diabetes Mellit. 2012;2(2):203-207.

11. Gomez-Peralta F, Santos-Mazo E, Payeras-Mas F, et al. Conversion from once- or twice-daily injections of insulin glargine in DM1 patients: a comparison by means of a continuous glucose subcutaneous monitoring (CGMS) [abstract 846]. Diabetologia. 2004;47(suppl 1):A305.

12. Levemir [package insert]. Plainsboro, NJ: Novo Nordisk; 2015.

13. Porcellati F, Rossetti P, Busciantella NR, et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care. 2007;30(10):2447-2452.

14. Tsujino D, Nishimura R, Morimoto A, Tajima N, Utsunomiya K. A crossover comparison of glycemic variations in Japanese patients with type 1 diabetes receiving insulin glargine versus insulin detemir twice daily using continuous glucose monitoring (CGM). Diabetes Technol Ther. 2012;14(7):596-601.

15. Wallace JP, Wallace JL, McFarland MS. Comparing dosing of basal insulin analogues detemir and glargine: is it really unit-per-unit and dose-per-dose? Ann Pharmacother.2014;48(3):361-368.

16. Toujeo [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2015.

Prepared by: 
Farnaz Foolad, PharmD 
PGY1 Pharmacy Practice Resident 
June 2015

The information presented is current as of the month and year stated in the document. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the rationale and significance of the FDA’s new guidance for abuse-deterrent opioids?

Introduction

The U.S. Food and Drug Administration (FDA) has recognized the need to provide industry with recommendations on study design in order to demonstrate a specific opioid formulation has abuse-deterrent properties.1 To address this issue, the FDA published the final guidance document “Abuse-Deterrent Opioids: Evaluation and Labeling” on April 1, 2015. This guidance provides the structure and context for the data required to support abuse-deterrent labeling in opioid products. Physicians, pharmacists, nurses, and other members of the health care team will need to understand what evidence, technology, and data support an abuse-deterrent opioid.

Background

The National Institute on Drug Abuse defines prescription drug abuse as “use of a medication without a prescription, in a way other than as prescribed, or for the experience or feelings elicited.”2 Opioid abusers may manipulate extended-release (ER) formulations to achieve a more rapid euphoria. 1,3 The ER design of the product may be broken to be injected or inhaled to deliver the dose more rapidly.3 According to a 2012 survey by the Substance Abuse and Mental Health Services Administration, 4.9 million Americans 12 years and older (1.9% of the population) reported nonmedical use of pain relievers in the past month.4 In 2012, 2.9 million Americans 12 years and older reported any illicit drug use for the first time; 17.0% of these new users reported initial use with pain relievers. The survey identified over 2.1 million Americans with past-year abuse or dependence of pain relievers. The problem of prescription opioid abuse has worsened over the last decade, with grave consequences.5From 1999 to 2010, deaths from prescription painkiller overdoses increased 415% for females and 265% for males.

Appropriate access to opioid products, including non-abuse deterrent formulations in certain circumstances, is critical to deliver quality patient care. 1 A 2011 report from The Institute of Medicine estimated that over 100 million Americans experienced chronic pain.6 In a 2013 statement, the American Academy of Pain Medicine recognized the need for pain management treatment plans that balance the clinical benefits of opioids with their disadvantages.7 Opioid products serve as an important cornerstone in treating chronic pain when alternate options are unsuccessful. 8 Despite the risk for abuse and toxicity, it is not feasible to avoid use of opioid products without taking away a powerful clinical tool.

FDA Guidance

The FDA guidance on abuse-deterrent opioids directs the pharmaceutical industry to develop opioid products with properties that discourage abuse. 1 The guidance provides clarity, structure, and significance behind opioid labeling by defining the pre- and post-market studies each product must achieve to earn abuse-deterrent claims in its labeling. Additionally, the guidance defines abuse-deterrent properties as “properties shown to meaningfully deter abuse, even if they do not fully prevent abuse.” The FDA recognizes that these properties may not deter abusers from swallowing multiple tablets or capsules, the most common form of opioid abuse. Development of abuse-deterrent opioids that meet FDA expectations has become an important concern for the pharmaceutical industry. When the FDA reviews the results of studies evaluating the abuse-deterrent capabilities of any opioid product, all of the available evidence will be considered. The FDA states that future similar opioid products will need to be compared to approved, abuse-deterrent formulations, if available.

The FDA has classified abuse-deterrent properties into the following categories: physical and chemical barriers, agonist and antagonist combinations, aversion, delivery system, and new molecular entities/prodrugs.1 Additionally, the FDA recognizes the opportunity to combine these properties or even develop new approaches. Physical and chemical barriers hinder extraction or rapid release of the active ingredient through the use of crush-resistant structures or gelling agents. Agonist and antagonist combinations deter abuse by reducing the euphoria associated with opioid abuse. In these combinations, antagonists are clinically inactive until the product has been tampered with, and therefore, do not interfere with the intended use. Aversion formulations contain added substances that provoke an unpleasant effect if the product is tampered. Novel delivery systems, such as depot injections and implants, can make it more difficult to manipulate or extract the opioid. New molecular entities or prodrugs could deter abuse by requiring in vitro conversions to the active opioid or changes to the receptor binding profile.

Abuse-deterrent opioid formulations

There are prescription opioid products currently on the market that have abuse-deterrent properties.8 Suboxone (buprenorphine and naloxone) and Embeda (morphine and naltrexone) utilize an agonist/antagonist combination effect in order to deter abuse. If administered parenterally, agonist/antagonist products block euphoria and may cause the unpleasant symptoms of withdrawal in opioid-dependent patients.8-10 Additionally, Embeda contains talc, an aversive excipient to deter against parenteral abuse.9 Opana ER (oxymorphone extended release), OxyContin (oxycodone), and Hysingla (hydrocodone extended release) all utilize gel-forming technology that makes them more difficult to inject.8,11-14 OxyContin, Exalgo (hydromorphone), and Hysingla have crush-resistant technology to make it more difficult to defeat the ER mechanism of the product.8,12-15 The reformulation of OxyContin in 2010 led to a reduction in past-month abuse rates, but just over a quarter of patients at drug treatment programs still reported abusing the reformulated product.16 Zohydro ER (hydrocodone extended release) and Oxaydo (oxycodone, formerly known as Oxecta) both utilize excipients that form a thick gel, making it difficult to extract the active ingredient; Oxaydo also contains a nasal irritant to deter intranasal abuse.13,17,18 Targiniq (oxycodone and naloxone), a product approved with abuse-deterrent properties in 2014 but no longer available, also used an opioid agonist/antagonist combination and aversive excipients to deter abuse.19 Four of these products – Embeda, OxyContin, Oxaydo, and Hysingla – have FDA-approved abuse deterrent labeling.9,12,14,18

Guidance for study design

The guidance describes 3 categories of premarket studies related to the abuse-deterrent properties of any opioid product: (1) lab-based in vitro manipulation and extraction studies, (2) pharmacokinetic studies, and (3) clinical abuse potential studies; additional post-marketing studies were listed as a fourth category (Table 1).1 Any development program for an abuse-deterrent opioid should plan to include data from these 3 premarket categories and develop a post-market analysis program. These categories also aim to detect new methods of abuse. Creating abuse-deterrent formulations may cause abusers to shift and utilize other routes of administration. For instance, if a product is typically abused through a non-parenteral route, but the abuse-deterrent property shifts abuse to a parenteral route, then the overall risk may be increased. Therefore, these studies should anticipate potential shifts in route of abuse, and also evaluate these routes.

Table 1. Pre- and post-marketing study types for abuse-deterrent properties.1

Category

Description

Category 1

Laboratory manipulation and extraction studies

· Evaluate ease of property being overcome by abusers

· Assess physical manipulation: ability to crush or grind

· Evaluate chemical manipulation: ability to melt or extract opioid

Category 2 Pharmacokinetic studies

· Compare pharmacokinetic profile of manipulated and unmodified formulations

· Assess pharmacokinetic profiles versus comparator products

· Evaluate various routes of administration and respective maximum concentration, time to maximum concentration, and half-life

· Determine serum opioid levels in drug-food interactions, drug-alcohol interactions, and adverse events associated with abuse

Category 3

Clinical abuse potential studies

· Measure clinical potential for abuse, preferably determined by a randomized, double-blind, placebo-controlled, positive controlled crossover study conducted in the recreational drug user population

· Outcomes should include liking of the product by users, and frequency and severity of abuse

Category 4

Post-marketing studies

· Post-marketing analysis to measure and determine if there is any significant reduction in abuse

Conclusion

The FDA has provided guidance to the pharmaceutical industry in an effort to address the growing public health problem of opioid abuse.1 While prescription opioids are a major source of abuse, they are essential to deliver appropriate patient care. Technology is advancing, and some opioid products have received labeling for abuse-deterrent properties after demonstrating their value in deterring abuse in premarket studies.1,13 Future opioid formulations will be compared against currently available opioid products in an effort to determine their superiority in preventing potential abuse. 1 The science and technology behind abuse-deterrent formulations will need to continue to evolve to combat the opioid abuse epidemic. Ultimately, the FDA guidance provides clarity, structure, and significance to products granted abuse-deterrent labeling.

References

1. Abuse-deterrent opioids – evaluation and labeling: guidance for industry. Food and Drug Administration website.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m334743.pdf . Published April 1, 2015. Accessed April 6, 2015.

2. What is prescription drug abuse? National Institute on Drug Abuse website.http://www.drugabuse.gov/publications/research-reports/prescription-drugs/what-prescription-drug-abuse . Updated November 2014. Accessed April 16, 2015.

3. Passik SD. Issues in long-term opioid therapy: unmet needs, risks, and solutions. Mayo Clin Proc. 2009;84(7):593-601.

4. Results from the 2012 national survey on drug use and health: summary of national findings. Substance Abuse and Mental Health Services Administration website.http://www.samhsa.gov/data/sites/default/files/NSDUHnationalfindingresults2012/NSDUH
nationalfindingresults2012/NSDUHresults2012.pdf . Published September 2013. Accessed April, 7, 2015.

5. Vital signs: overdoses of prescription opioid pain relievers and other drugs among women--United States, 1999-2010. MMWR Morb Mortal Wkly Rep. 2013;62(26):537-42.

6. Institute of Medicine. Committee on Advancing Pain Research, Care, and Education.Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington, D.C: The National Academies Press, 2011.http://books.nap.edu/openbook.php?record_id=13172. Accessed April 27, 2015.

7. Use of opioids for the treatment of chronic pain. American Academy of Pain Medicine.http://www.painmed.org/files/use-of-opioids-for-the-treatment-of-chronic-pain.pdf . Published Feburary 2013. Accessed April 17, 2015.

8. Moorman-li R, Motycka CA, Inge LD, Congdon JM, Hobson S, Pokropski B. A review of abuse-deterrent opioids for chronic nonmalignant pain. P T. 2012;37(7):412-418.

9. Embeda [package insert]. New York, NY: Pfizer, Inc; 2009.

10. Suboxone [package insert]. Richmond, VA: Reckitt Benckiser Pharmaceuticals Inc; 2014.

11. Opana [package insert]. Malvern, PA: Endo Pharmaceuticals, Inc; 2014.

12. OxyContin [package insert]. Stamford, CT: Purdue Pharma L.P.; 2014.

13. Fudin, J. Abuse-deterrent opioid formulations: purpose, practicality, and paradigms. Pharmacy Times website. http://www.pharmacytimes.com/contributor/jeffrey-fudin/2015/01/abuse-deterrent-opioid-formulations-purpose-practicality-and-paradigms . Published January 27, 2015. Accessed April 27, 2015.

14. Hysingla [package insert]. Stamford, CT: Purdue Pharma L.P.; 2014.

15. Exalgo [package insert]. Hazelwood, MO: Mallinckrodt Brand Pharmaceuticals, Inc; 2014.

16. Cicero TJ, Ellis MS. Abuse-deterrent formulations and the prescription opioid abuse epidemic in the United States: lessons learned from OxyContin [published online ahead of print March 11, 2015]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.3043.

17. Zohydro ER [package insert]. San Diego, CA: Zogenix, Inc; 2015.

18. Oxaydo [package insert]. Palatine, IL: Acura Pharmaceuticals; 2014.

19. Targiniq ER [package insert]. Stamford, CT: Purdue Pharma L.P; 2014.

Prepared by: 
Ricky Li 
PharmD Candidate, 2015 
College of Pharmacy 
University of Illinois at Chicago 
April 2015

The information presented is current as of the month and year stated in the document. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What should healthcare providers know about PCSK9 inhibitors, the new class of cholesterol-lowering medications?

Introduction

Cardiovascular disease is currently the leading cause of death in the world and may lead to myocardial infarction, stroke, or peripheral vascular disease. 1 According to the American Heart Association, from 2009 to 2012, more than 100 million adults in the United States had total cholesterol levels >200 mg/dL and 31 million had levels >240 mg/dL. These numbers are important because in 2011 cardiovascular disease accounted for 31.3% of all deaths in the United States and was associated with an estimated annual cost of $320.1 billion. Raised cholesterol alone, defined as total cholesterol >190 mg/dL, is estimated to be the cause of 2.6 million deaths yearly.

While most of the population has high cholesterol due to poor diet and exercise habits, there is a subset of the population who develop significant elevations in cholesterol due to a genetic disorder called familial hypercholesterolemia (FH).2 The genetic disorder is most often attributed to mutations in the low density lipoprotein (LDL) receptor (85% of FH cases), but may also be due to mutations in the gene encoding apoliprotein B or the enzyme proprotein convertase subtilisin-like kexin type 9 (PCSK9). Heterozygous FH, the most common type of FH, occurs in 1 in 300 to 500 patients while homozygous FH is a very rare form of the disease, occurring in 1 in 1 million people. Patients with FH often present with LDL levels >190 mg/dL by the age of 20 years and are at a significantly increased risk for premature cardiovascular disease.

The current gold standard of pharmacologic treatment of hypercholesterolemia is the use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins.3 Statin drugs inhibit the rate-limiting enzyme in the synthesis of cholesterol. Use of statins reduces mortality and myocardial infarction in adults with coronary heart disease and reduces cardiovascular disease and stroke in patients with diabetes or elevated cardiovascular disease risk. In 2013 the American Heart Association and American College of Cardiology updated their guidelines on treatment of blood cholesterol to emphasize cardiovascular risk rather than LDL cholesterol goals. These guidelines identified 4 major patient groups that benefit from statin therapy:

· Patients with clinical atherosclerotic cardiovascular disease

· Patients with LDL ≥190 mg/dL

· Patients ages 40 to 75 years with diabetes and LDL 70 to 189 mg/dL

· Patients ages 40 to 75 years without diabetes and LDL 70 to 189 mg/dL with an estimated 10-year risk of atherosclerotic cardiovascular disease of ≥7.5%

It is recommended that patients who fit into these categories receive moderate- to high-dose statin therapy.3 In 2013, as these guidelines were being written and published, there was no evidence for an alternative or additional agent to reduce cardiovascular risk.

Ezetimibe, niacin, and fenofibrate derivatives are other agents that may be used in the treatment of hypercholesterolemia .2 These medications have not been found to reduce cardiovascular morbidity or mortality but are used in combination with statins or in patients unable to tolerate statin therapy. Of these medications options, ezetimibe is a common additional therapy to statins with best evidence for use in patients with FH reducing LDL levels by 20% to 70%.

Why is new therapy needed?

While statin therapy reduces morbidity and mortality, acute coronary syndromes remain the leading cause of death and disability.4 Risk for cardiovascular events may still remain even when a patient is on a high-dose statin. Despite less emphasis by the guidelines to focus on specific LDL target goals when treating hypercholesterolemia, LDL-lowering is still a consideration in clinical practice, and a way to measure a patient’s response to statin therapy. Patients on statin therapy may not experience satisfactory LDL reductions, or they may not be able to tolerate statin therapy due to myopathies or abnormal liver function tests. A class of drugs that works differently from statins to reduce further cholesterol could be of benefit to many patients who have hypercholesterolemia.

PCSK9 inhibitors

The enzyme proprotein convertase subtilisin-like kexin type 9 (PCSK9) is the target of a new drug class aimed to treat hypercholesterolemia.5 The enzyme PCSK9 is present naturally in the body and decreases the metabolism of LDL by binding to the LDL receptor, mainly found in the liver. This causes receptor degradation and thus less endocytosis of LDL via the LDL receptor, ultimately reducing clearance of LDL. Statins induce expression of PCSK9 through depletion of cholesterol, which limits their ability to decrease LDL after a certain point.

There is no Food and Drug Administration (FDA)-approved therapy aimed at the PCSK9 enzyme currently.5 Two PCSK9 inhibitors, evolocumab and alirocumab, are currently in Phase III trials. Both are human monoclonal antibodies administered by subcutaneous injection. The monoclonal antibodies work by binding PCSK9 in the blood and inhibiting the enzyme’s effect on degradation of LDL receptors. Ultimately more LDL receptors are present on the surface of the liver and thus more LDL can be removed from circulation. This mechanism of action for cholesterol-lowering is synergistic to the mechanism of action by which statins lower cholesterol.

These 2 PCSK9 inhibitors have been studied in patients 13 to 80 years of age, with and without statin therapy, in heterogeneous and homogeneous familial hypercholesterolemia, and patients with all ranges of cardiovascular risks.6-14 They have commonly been compared to both ezetimibe and placebo, assessing outcomes of LDL reduction and cardiovascular events. The medications have proven to be well-tolerated in clinical trials thus far.

Table. PSCK9 inhibitors expected to be approved by the Food and Drug Administration in 2015. 5,15

Generic Name

Evolocumab

Alirocumab

Trade Name

Repatha

Praluent

Manufacturer

Amgen

Sanofi and Regeneron Pharmaceuticals

Dosing

140 mg subcutaneously every 2 weeks

OR

420 mg subcutaneously every 4 weeks

75 mg subcutaneously every 2 weeks

OR

150 mg subcutaneously every 2 weeks

Adverse Drug Events

Nasopharyngitis, upper respiratory infection, headache, diarrhea,

myalgia, back pain, injection site reactions

Evolocumab phase III trials

In patients with dyslipidemia or heterozygous familial hypercholesterolemia and baseline LDL levels averaging from 90 to 160 mg/dL, evolocumab has been found to decrease LDL by 49% to 76% in the LAPLACE-2, MENDEL-2, DESCARTES, and RUTHERFORD-2 trials.6,7,9,10These effects were seen in patients with and without concomitant statin and/or ezetimibe therapy. There was no difference found administering evolocumab 140 mg every 2 weeks or 420 mg every 4 weeks. Full benefit in LDL reduction was seen in 12 weeks and the DESCARTES trial found efficacy was sustained over 52 weeks.10

Evolocumab has also been studied in patients unable to tolerate statins in the GAUSS-2 study, where it decreased LDL by 53 to 56% from average baseline levels of 190 mg/dL and led to a 37% to 39% greater reduction when compared to ezetimibe therapy (p<0.001).8

The TESLA trial is the only current trial studying the effect of PCSK9 inhibitors therapy in patients with homozygous familial hypercholesterolemia.12 The trial included 49 patients and found evolocumab to decrease LDL by 23.1% after 12 weeks of treatment versus a 7.9% increase in patients receiving placebo. This resulted in a reduction difference of 30.9% (95% confidence interval [CI], -43.9% to -18.0%, p<0.0001).

Ongoing trials include the GLAGOV trial, which is studying the effect of evolocumab on coronary atherosclerosis in patients undergoing cardiac catheterization (expected completion July 2015), and the TAUSSIG trial, which is assessing the safety and efficacy of evolocumab in patients with severe homozygous or heterozygous familial hypercholesterolemia, (expected completion January 2020).5,16 These trials may help identify new populations to qualify for PCSK9 therapy.

Alirocumab phase III trials

Alirocumab effectively lowers LDL in patients with dyslipidemia, high cardiovascular risk, and heterozygous familial hypercholesterolemia. 5,13,14 Therapy with alirocumab was found to decrease LDL by 48.7% to 61% from baseline levels between 108 and 122 mg/dL in the ODYSSEY COMBO II, ODYSSEY LONG TERM, ODYSSEY FH I, and ODYSSEY FH II trials.13,14,17 A majority of patients were found to have these decreases despite being continued on maximum statin and/or ezetimibe doses.

Alirocumab is currently being studied in high risk cardiovascular disease in the ODYSSEY OPTIONS and ODYSSEY COMBO I trial; statin-intolerant patients in the ODYSSEY ALTERNATIVE trial; heterozygous familial hypercholesterolemia patients with LDL >160 mg/dL in the ODYSSEY HIGH FH trial; as monotherapy in the ODYSSEY MONO trial, and for use following acute coronary syndromes in the ODYSSEY OUTCOMES trial.5,15

Effect of PCSK9 inhibitors on cardiovascular events

A combined data pool from OSLER and OSLER-2 trials evaluated the incidence of death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure in 4,465 patients receiving evolocumab in addition to standard of care.18 Investigators found cardiovascular events were decreased from 2.18% to 0.95% after 1 year when evolocumab was added to standard therapy (p=0.003). The FOURIER trial began January 2013 to evaluate evolocumab with atorvastatin therapy in 22,500 patients with high-risk cardiovascular disease for 5 years.15 This is a randomized, placebo-controlled trial with a primary composite outcome of time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or coronary revascularization. The study will be completed February 2018.

The ODYSSEY LONG TERM trial evaluated alirocumab 150 mg subcutaneous injection every 2 weeks in 2,341 high-risk cardiovascular patients on maximum tolerated statin therapy.13 A post-hoc analysis found a reduction in cardiovascular events of 3.3% in patients treated with alirocumab versus 1.7% with placebo (hazard ratio, 0.52; 95% CI, 0.31 to 0.90, p=0.02). Specifically, alirocumab was associated with a decrease in death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. The ODYSSEY OUTCOMES trial is currently underway to assess alirocumab in addition to background lipid lowering therapy in 18,000 patients over 5 years.5The trial was designed to assess cardiovascular benefit with a primary outcome of time to first occurrence of ischemic heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. The study will be completed March 2018.

While the current findings are promising, these are post-hoc analyses and the results of the FOURIER and OUTCOMES trials are needed to evaluate if PCSK9 inhibition significantly decreases cardiac events.

When will these products be available?

Amgen submitted a biologics license application (BLA) for evolocumab to the FDA on August 27, 2014, based on data collected from 6,800 patients in clinical trials.19 The FDA accepted the application for review November 2014 and the current FDA target review date is set for August 27th, 2015. Currently PROFICIO, or Program to Reduce LDL-D and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations, is collecting a comprehensive data set of all 22 evolocumab clinical trials.

Sanofi submitted their BLA for alirocumab to the FDA in 2014 based on data from over 5,000 patients in 10 ODYSSEY phase 3 clinical trials.20 Alirocumab was approved for priority review January 26, 2015. Sanofi and Regeneron Pharmaceuticals bought a priority review voucher from BioMarin Pharmaceutical, Inc. for $67.5 million and thus has an expedited 6-month review rather than the standard 10-month review.21 The current set FDA target action date is July 24, 2015 and if all goes as planned, alirocumab will be the first PCSK9 to the US market.

Unanswered questions

Even with the numerous phase III trials, there are still questions that remain unanswered. What will PCSK9 inhibitors cost? Can patients self-inject the medications? Will the PCSK9 inhibitors have to be filled at specialty pharmacies? Are the medications safe and effective in patients with liver or kidney dysfunction?

Where will this new drug class apply in therapy?

For years statins have been the gold standard of hypercholesterolemia treatment because they have shown to decrease cardiovascular events.4 Clinical trials on PCSK9 inhibitors have shown promising decreases in LDL between 23% to 76% in all populations studied and both drugs are relatively well-tolerated. In theory, decreasing LDL would lower rates of cardiovascular events; however, this has not always proven to be the case.22 Emerging evidence now suggests both evolocumab and alirocumab also decrease cardiovascular events and death when used in combination with standard care, but these findings came from an open-label trial and a post-hoc analysis. Manufacturers of both PCSK9 inhibitors have ongoing large randomized, controlled trials to attempt to confirm these findings. If found to decrease cardiovascular events, the leading cause of death in the world, PCSK9 inhibitors may become common practice in the treatment of hypercholesterolemia.

References:

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: A report from the American Heart Association. Circulation. 2015;131(4):e29-322.

2. Robinson JG. Management of familial hypercholesterolemia: A review of the recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Manag Care Pharm. 2013;19(2):139-149.

3. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adultsJ Am Coll Cardiol.2014;63(25 Pt B):2889-2934.

4. Sahebkar A, Watts GF. New LDL-cholesterol lowering rherapies: Pharmacology, clinical trials, and relevance to acute coronary syndromes. Clin Ther. 2013;35(8):1082-1098.

5. Desai NR, Sabatine MS. PCSK9 inhibition in patients with hypercholesterolemia [published online ahead of print February 11, 2015]. Trends Cardiovasc Med. doi: 10.1016/j.tcm.2015.01.009.

6. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA.2014;311(18):1870-1883.

7. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331-340.

8. Stroes E, Colguhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol.2014;63(23):2541-2548.

9. Koren MJ, Lundgvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531-2540.

10. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809-1819.

11. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial.Circulation. 2014;129(2):234-243.

12. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341-350.

13. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499.

14. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186-1194.

15. Cicero AF, Tartagni E, Ertek S. Safety and tolerability of injectable lipid-lowering drugs: a review of available clinical data. Expert Opin Drug Saf. 2014;13(8):1023-1030.

16. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol.2014;11(10):563-575.

17. Sanofi and Regeneron present detailed positive results from four pivotal alirocumab trials at ESC Congress 2014. Sanofi website.http://en.sanofi.com/Images/37129_20140831_AlirocumabESCDataRelease_en.pdf . Updated August 31, 2014. Accessed April 21, 2015.

18. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events [published online ahead of print March 15, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1500858.

19. FDA accepts Amgen's biologics license application for LDL cholesterol-lowering medication evolocumab. Amgen website. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2014&releaseID=1987861. Accessed April 12, 2015.

20. Sanofi and Regeneron announce Praluent™ (alirocumab) biologics license application has been accepted for priority review by US FDA. Sanofi website.http://en.sanofi.com/Images/38242_20150226_alirocumabbla_en.pdf. Updated January 26, 2015. Accessed April 17, 2015.

21. Sanofi and Regeneron announce plan to use priority review voucher for alirocumab U.S. FDA submission. Sanofi website.http://en.sanofi.com/Images/36951_20140730_sano_rege_en.pdf. Updated July 30, 2014. Accessed April 17, 2015.

22. Verdoia M, Schaffer A, Suryapranata H, De Luca G. Effects of HDL-modifiers on cardiovascular outcomes: a meta-analysis of randomized trials. Nutr Metab Cardiovasc Dis.2015;25(1):9-23.

Prepared by: 
Amy Hilliard, PharmD 
PGY1 Pharmacy Practice Resident 
College of Pharmacy 
University of Illinois at Chicago 
June 2015

The information presented is current as of the month and year stated in the document. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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