The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1479 Volume 56 October 12, 2015 IN THIS ISSUE SGLT2 Inhibitors: New Reports p 139 Evolocumab (Repatha) – A Second PCSK9 Inhibitor to Lower LDL-Cholesterol p 140 Daclatasvir (Daklinza) for HCV Genotype Infection p 142 Eloctate for Hemophilia A p 143 Addendum: PCV13 for Adults 65 Years and Older .p 144 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization Revised 11/10/2015: See p 144 The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1479 Volume 56 ▶ October 12, 2015 Take CME Exams ALSO IN THIS ISSUE Evolocumab (Repatha) – A Second PCSK9 Inhibitor to Lower LDL-Cholesterol p 140 Daclatasvir (Daklinza) for HCV Genotype Infection p 142 Eloctate for Hemophilia A p 143 Addendum: PCV13 for Adults 65 Years and Older .p 144 SGLT2 Inhibitors: New Reports The recent report of a reduction in cardiovascular mortality in patients with type diabetes treated with the SGLT2 inhibitor empagliflozin (Jardiance) was published soon after the FDA issued new warnings about an increased risk of fractures with canagliflozin (Invokana) SGLT2 INHIBITORS — SGLT2 (sodium-glucose co-transporter 2), a membrane protein expressed mainly in the kidney, transports filtered glucose from the proximal renal tubule into tubular epithelial cells SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, resulting in lower blood glucose levels that are independent of insulin secretion and a modest reduction in HbA1c These drugs also increase urinary sodium excretion, cause weight loss, and lower blood pressure View our detailed online table: SGLT-2 Inhibitors Adverse Effects – SGLT2 inhibitors can cause genital mycotic infections, urinary tract infections, increases in serum creatinine and decreases in eGFR, and increases in LDL cholesterol, and were recently associated with euglycemic ketoacidosis.1,2 Table Dosage and Cost of SGLT2 Inhibitors Drug Formulations Usual Dosage Canagliflozin – Invokana (Janssen) 100, 300 mg tabs 100-300 mg once/d Cost1 $363.10 Dapagliflozin – 5, 10 mg Farxiga (AstraZeneca) tabs 5-10 mg once/d 342.90 Empagliflozin – 10, 25 mg Jardiance (Boehringer tabs Ingelheim/Lilly) 10-25 mg once/d 342.80 Approximate WAC for 30 days’ treatment at the lowest usual dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly September 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy CARDIOVASCULAR OUTCOMES — In a randomized, double-blind trial, 7020 patients with type diabetes and established cardiovascular disease (prior myocardial infarction or stroke or angiographically demonstrated obstruction) took empagliflozin 10 or 25 mg/day or placebo for a median of 2.6 years The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke There were no significant differences between patients taking either dose of empagliflozin and those receiving placebo in the incidence of myocardial infarction or stroke, but patients taking the active drug had a significantly lower incidence of cardiovascular death (3.7% vs 5.9%, HR 0.62) Treatment with empagliflozin was also associated with significant reductions in hospitalization for heart failure (2.7% vs 4.1%) and death from any cause (5.7% vs 8.3%) There was no difference in the incidence of fractures.3 FRACTURE RISK — In an unpublished, double-blind trial conducted as part of an FDA postmarketing requirement, 714 patients 55-80 years old with poorly controlled type diabetes were randomized to canagliflozin 100 or 300 mg/day or placebo At years, those receiving canagliflozin 100 and 300 mg had placebo-corrected decreases in bone mineral density at the total hip of 0.9% and 1.2%, respectively, and smaller decreases at the lumbar spine, the femoral neck, and (with the 300-mg dose) the distal forearm An FDA analysis of fractures occurring in clinical trials with a mean exposure to canagliflozin of 85 weeks found incidence rates of 1.4 and 1.5 per 100 patient-years with 100 and 300 mg/day of canagliflozin, respectively, compared to 1.1 with placebo or an active comparator.4 An increased incidence of fractures was reported previously in patients with moderate renal impairment taking dapagliflozin (Farxiga), and there appears to be a theoretical rationale (increased phosphate, parathyroid hormone levels) for an adverse class effect on bone.5 139 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 57 (1479) ® CONCLUSION — A significant decrease in cardiovascular mortality has been reported with use of the SGLT2 inhibitor empagliflozin (Jardiance) to treat patients with type diabetes who have established cardiovascular disease The mechanism of this reduction is unclear, and these results may not apply to patients with type diabetes and less advanced cardiovascular disease Whether the increase in fractures reported with canagliflozin (Invokana) could also occur with empagliflozin remains to be established All SGLT2 inhibitors are only modestly effective for treatment of diabetes ■ ▶ Evolocumab (Repatha) – A Second PCSK9 Inhibitor to Lower LDLCholesterol Evolocumab (Repatha – Amgen), a subcutaneously injected PCSK9 inhibitor, has been approved by the FDA as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol (LDL-C) It was also approved as an adjunct to diet and other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Evolocumab is the second PCSK9 inhibitor to be approved in the US; alirocumab (Praluent) was approved earlier.1 Pronunciation Key Evolocumab: e” voe lok’ ue mab Repatha: ri pa’ tha MECHANISM OF ACTION — PCSK9 (proprotein convertase subtilisin kexin type 9) binding to LDL receptors on hepatocytes promotes receptor degradation, prevents LDL-C clearance from blood, and increases serum concentrations of LDL-C Evolocumab is a human IgG2 monoclonal antibody that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C October 12, 2015 In brief: ketoacidosis with SGLT2 inhibitors Med Lett Drugs Ther 2015; 57:94 AL Peters et al Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter inhibition Diabetes Care 2015; 38:1687 B Zinman et al Empagliflozin, cardiovascular outcomes, and mortality in type diabetes N Engl J Med 2015 Sept 17 (epub) FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density Available at: www.fda.gov/Drugs/DrugSafety/ ucm461449.htm Accessed October 1, 2015 SI Taylor et al Possible adverse effects of SGLT2 inhibitors on bone Lancet Diabetes Endocrinol 2015; 3:8 Table Pharmacology Class Formulation Route Tmax Metabolism Elimination Half-life PCSK9 inhibitor 140 mg/mL preservative-free solution in single-use prefilled syringe or autoinjector Subcutaneous injection 3-4 days Probably degradation to small peptides and amino acids Low concentrations: primarily saturable binding to PCSK9 Higher concentrations: primarily nonsaturable proteolysis 11-17 days CLINICAL STUDIES — Results of some clinical trials of evolocumab are summarized in Table 3.2-6 A prespecified exploratory analysis of the OSLER-1 and -2 trials found that after one year, the KaplanMeier estimated percentages of patients having a cardiovascular event were significantly lower among those receiving evolocumab than those receiving standard treatment alone (0.95% vs 2.18%).2 A more definitive study to evaluate the effect of evolocumab on cardiovascular outcomes (FOURIER) is underway ADVERSE EFFECTS — The most common adverse effects reported in clinical trials with evolocumab included nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection-site reactions Table PCSK9 Inhibitors for Hypercholesterolemia Drug Formulations Usual Adult Dosage Cost1 Alirocumab – Praluent (Sanofi/Regeneron) 75, 150 mg/mL single-use pens, prefilled syringes Initial: 75 mg SC q2 wks Max: 150 mg SC q2 wks $13,440.00 Evolocumab – Repatha (Amgen) 140 mg/mL single-use autoinjectors, prefilled syringes Initial: 140 mg SC q2 wks or 420 mg SC once/month2 Max: 140 mg SC q2 wks or 420 mg SC once/month2 140 13,015.40 Approximate WAC for one year’s treatment at the lowest initial dose WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly September 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Dosage for patients with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic CVD Dosage for patients with homozygous familial hypercholesterolemia (HoFH) is 420 mg SC once monthly The Medical Letter ® Vol 57 (1479) October 12, 2015 Table Some Evolocumab Clinical Trials Mean LDL-C Change (placebo-corrected) Trial Population Treatment Arms OSLER-1 and -21 (n=4465) 52 weeks Patients with various degrees of high LDL-C Evolocumab 140 mg q2 wks2 Evolocumab 420 mg q4 wks2 Standard treatment alone3 -60.9%4 DESCARTES5 (n= 901) 52 weeks MENDEL-26 (n=614) 12 weeks LDL-C ≥75 mg/dL with diet alone, diet plus statin therapy, or statin therapy with or without ezetimibe Low CV risk patients with LDL-C ≥100 and