New Drug Approvals: Implications for Older Adults

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1 New Drug Approvals: Implications for Older Adults Pharmacotherapy Update 2016 Tasha Woodall, PharmD, CGP, CPP Associate Director of Pharmacotherapy, Geriatrics Mountain Area Health Education Center Assistant Professor of Clinical Education UNC Eshelman School of Pharmacy

2 Disclosure I have no relevant financial relationships related to the material in this presentation.

3 Objectives Identify indications and mechanisms of action of six new drugs used for diabetes, heart failure, and hyperlipidemia. Describe considerations for use of these medications in older adults. Discuss potential roles in therapy for each of these six new drugs.

4 Table of Contents Diabetes Insulin glargine U-300 (Toujeo ) Insulin degludec (Tresiba ) Hyperlipidemia Alirocumab (Praluent ) Evolocumab (Repatha ) Heart Failure Ivabradine (Corlanor ) Sacubitril/valsartan (Entresto )

5 New Drugs for Diabetes Insulin degludec (Tresiba ) & U300 glargine (Toujeo )

Approved Toujeo: February 25, 3015 Tresiba: September 25, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Improvement of glycemic

6 Approved Toujeo: February 25, 3015 Tresiba: September 25, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Improvement of glycemic control in T1DM & T2DM Long-acting insulin analogs Once-daily SC injection Hypoglycemia, nasopharyngitis, URI Other glucose-lowering medications (esp. rosiglitazone) Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 2015.

7 Insulin glargine (Toujeo ) Pharmacokinetic Profile Soluble at acidic ph, forms microprecipitate when injected U300 creates smaller SC depot, leading to more consistent and prolonged insulin release Flatter profile, less intrapatient variability Plasma concentrations measurable at 36h post-dose vs. 28h for U100 Sutton G, Minguet J, Ferrero C, Bramlage P. U300, a novel long-acting insulin formulation. Expert Opin Biol Ther 2014;12:

8 Insulin glargine (Toujeo ) Efficacy & Safety EDITION 1 (Basal-Bolus vs. U100) Equivalent A1c lowering (-0.83%) over 6 months 36% vs. 46% w/ 1 hypoglycemic event over 6 months EDITION 2 (Basal vs. U100) Equivalent A1c lowering (-0.57%) over 6 months Less nocturnal or severe hypoglycemia w/ U300 (RR 0.77 [0.61, 0.99]) Less weight gain w/ U300 (0.08 kg vs kg, p=0.015) EDITION 3 (Basal in insulin-naïve vs. U100) Equivalent A1c lowering (-1.4%) over 6 months 17.9% vs. 23.5% w/ 1 nocturnal hypoglycemic event over 6 months Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 units/ml compared with glargine 100 units/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 2015;17: Yki-Jarvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014;37: Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/ml versus glargine 100 units/ml in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes

9 Insulin glargine (Toujeo ) Dosing Initial dose 10 units or 0.2 units/kg daily Thigh, arm, buttocks, abdomen Converting from NPH Once daily substitute unit-per-unit Twice daily use 80% of total daily dose Converting from Lantus Substitute unit-per-unit May require ~20% increase in number of units MORE units, but overall LESS fluid Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2015.

10 Insulin glargine (Toujeo ) Availability 1.5 ml SoloStar pen (300 units/ml) $135 per pen ($0.30 per unit) Lantus SoloStar $90 per pen ($0.30 per unit) Lantus $300 per vial ($0.30 per unit) PAP available? NO Insulin glargine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

11 Insulin glargine (Toujeo ) Role in Therapy Patients with nocturnal hypoglycemia on current basal insulin regimen Insulin resistant individuals who do not quite need U500 Less complex dosing vs. U500

12 Insulin degludec (Tresiba ) Pharmacokinetic Profile Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet 2014;53:

Insulin degludec Efficacy Included Excluded 18+ yoa (avg 59) GLP1 or TZD use A1c 7-10% BMI 40 Insulin naïve Significant CV, renal, hepatic or oncologic disease Recurrent hypoglycemia Proliferative

13 Insulin degludec Efficacy Included Excluded 18+ yoa (avg 59) GLP1 or TZD use A1c 7-10% BMI 40 Insulin naïve Significant CV, renal, hepatic or oncologic disease Recurrent hypoglycemia Proliferative retinopathy Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naïve patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;35:

14 Insulin degludec Efficacy Included Excluded 18+ yoa (avg 59) GLP1 or rosi use A1c 7-10% BMI 40 On insulin 3+ mo Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomized, open-label, treat-to-target non-inferiority trial. Lancet 2012;379:

Insulin degludec (Tresiba ) Efficacy Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Group 1: IGlar OD Group 2: IDeg OD Group 3: IDeg OD Flex A1c SMPG Meneghini

15 Insulin degludec (Tresiba ) Efficacy Efficacy and Safety of Insulin Degludec Given in Variable Once-Daily Dosing Intervals Group 1: IGlar OD Group 2: IDeg OD Group 3: IDeg OD Flex A1c SMPG Meneghini L, Atkin SL, Gough SC, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care 2013;36:

16 Insulin degludec (Tresiba ) Safety Study Overall Hypoglycemia Nocturnal Hypoglycemia Severe Hypoglycemia BEGIN One Long ERR 0.82 [0.64, 1.02] ERR 0.64 [0.42, 0.98] -- BEGIN Basal-Bolus Type 2 Novo Nordisk Meta- Analysis ERR 0.82 [0.69, 0.99] ERR 0.75 [0.58, 0.99] -- ERR 0.83 [0.74, 0.94] ERR 0.68 [0.57, 0.82] ERR 0.81 [0.42, 1.56] Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin degludec versus insulin glargine in insulin-naïve patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long). Diabetes Care 2012;35: Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomized, open-label, treat-to-target non-inferiority trial. Lancet 2012;379: Ratner RE, Gough SC, Mathieu C, et al. Hypoglycemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013;15:

17 Insulin degludec (Tresiba ) Dosing Initial dose 10 units daily Thigh, upper arm, abdomen Converting from other long-acting insulin: substitute unit-per-unit Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 2015.

18 Insulin degludec (Tresiba ) Availability 3 ml FlexTouch pen (100 or 200 units/ml) $107 per 100 unit/ml pen ($0.36/unit) $213 per 200 unit/ml pen ($0.36/unit) PAP available? NO Instant Savings Card caps out-of-pocket costs at $15/prescription NeedyMeds. Available at: Accessed May 10, Insulin degludec. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

19 Insulin degludec + Insulin aspart (Ryzodeg ) Availability 3 ml FlexTouch pen (100 units/ml), containing 70% degludec & 30% aspart Not yet available When converting from premix, basal-bolus, or basal monotherapy, initiate at same dose and frequency as basal insulin Insulin degludec. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

20 Insulin degludec (Tresiba ) Role in Therapy Patients who struggle with adherence More flexible dosing window Patients with nocturnal hypoglycemia on current basal insulin U200: for insulin resistant individuals who do not quite need U500 Eventual replacement for glargine and detemir?

21 Take Home Points Diabetes in Older Adults Among insulin-treated patients, those aged 80 and older are: 2.5x more likely to visit the ED, and 4.9x more likely to be subsequently hospitalized for hypoglycemia AGS recommends against use of medications other than metformin to achieve A1c <7.5% in most When using insulin, it is reasonable to opt for agents proven to attenuate risk of hypoglycemia Weigh relative benefit vs. higher cost Delgudec $0.36/unit vs. Glargine $0.30/unit (20% ) Consider dexterity Geller AI, Shehab N, Lovegrove MC, et al. National estimates of insulin-related hypoglycemia and errors leading to emergency department visits and hospitalizations. JAMA Intern Med 2014;174:

22 New Drugs for Heart Failure Ivabradine (Corlanor ) & Sacubitril/Valsartan (Entresto )

Approved April 15, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Reduce risk of hospitalization for worsening HF (LVEF 35%) Slows SA node firing,

23 Approved April 15, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Reduce risk of hospitalization for worsening HF (LVEF 35%) Slows SA node firing, reduces HR Initial: 5 mg BID (2.5 mg BID if h/o conduction defects) Max: 7.5 mg BID (titrate to achieve resting HR bpm) Bradycardia, hypertension, atrial fibrillation Drug Interactions Diltiazem, verapamil St. John s Wort QTc-prolonging agents Moderate risk: macrolides, FQs, methadone High risk: amiodarone, citalopram, escitalopram, fluoxetine, quetiapine Corlanor [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015.

Ivabradine (Corlanor ) Mechanism of Action Hyperpolarization-activated cyclic nucleotide-gated channel in SA node Na+ & K+ inflow Diastolic depolarization End of diastole HCN blockade slows

24 Ivabradine (Corlanor ) Mechanism of Action Hyperpolarization-activated cyclic nucleotide-gated channel in SA node Na+ & K+ inflow Diastolic depolarization End of diastole HCN blockade slows diastole decreases HR Image from: mobile.ashx?la=en&hash=74c7fc51994ab149f17007dd3732d61d55e Accessed April 28, 2016.

25 Ivabradine Efficacy Double-blind RCT in patients with NYHA II, III or IV HFREF Active treatment group received ivabradine 5 mg BID (titrated to 7.5 mg BID after 14d) Included 18 yoa HR 70+ (NSR) HF admission w/i 12 mo LVEF 35% Optimized, stable doses of standard meds (4+ wk) Excluded MI w/i 12 mo CVA w/i 4 wk AV pacing 40% of the day Permanent Afib/Aflutter Symptomatic hypotension Uncontrolled HTN Cardioverted w/i 6 mo Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:

26 Ivabradine Efficacy Baseline characteristics Mean age 60, 76% male, 89% white Almost all with class II or III HF Primarily ischemic (68%) HR 80 bpm, LVEF 29% Background treatment 90% on beta blocker (26% at target dose) Primarily carvedilol (45%) or bisoprolol (25%) 80% on ACEI 14% on ARB 84% on diuretic 60% on aldosterone antagonist 22% on digoxin Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:

27 Ivabradine Efficacy Primary EP = composite [CV death + HF hospitalization] 29% HR 0.82 (0.75, 0.90) 24% NNT = 20 Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:

28 Ivabradine Efficacy Components of primary composite EP HR 0.91 (0.80, 1.03) HR 0.74 (0.66, 0.83) NNT = 20 HF hospitalization CV death Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:

29 Ivabradine Efficacy Effect of Age <53 years n= to <60 years n= to <69 years n= years n=1712 Endpoint Composite PEP <53 years 53 to <60 years 60 to <69 years 69 years CV death <53 years 53 to <60 years 60 to <69 years 69 years HF hospitalization <53 years 53 to <60 years 60 to <69 years 69 years HR (95% CI) 0.62 (0.50, 0.78) 0.82 (0.67, 1.01) 0.96 (0.80, 1.14) 0.84 (0.71, 0.99) 0.71 (0.53, 0.97) 0.96 (0.73, 1.27) 1.17 (0.92, 1.51) 0.82 (0.65, 1.03) 0.55 (0.42, 0.72) 0.70 (0.54, 0.90) 0.87 (0.70, 1.08) 0.80 (0.65, 0.98) Tavazzi L, Swedberg K, Komajda M, et al. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights of the SHIFT study. Eur J Heart Fail 2010;12:75-81.

30 Ivabradine Safety Ivabradine (n=3232) Placebo (n=3260) P value All serious AEs 1450 (44.8%) 1563 (47.9%) Bradycardia Symptomatic Asymptomatic 5.70 (4.6%) 184 (5.7%) 32 (1.0%) 48 (1.5%) < < Atrial fibrillation 306 (9.5%) 251 (7.7%) Phosphenes 89 (2.8%) 17 (<1%) < Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:

31 Ivabradine Safety Effect of Age <53 years n= to <60 years n= to <69 years n= years n= % 74% 75% 42% 44% 80% 48% 32% 5% 7% 9% 12% <53 YEARS 53 TO 59 YEARS 60 TO 68 YEARS 69 YEARS AF All AE All Serious AE Tavazzi L, Swedberg K, Komajda M, et al. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights of the SHIFT study. Eur J Heart Fail 2010;12:75-81.

32 Ivabradine (Corlanor ) Availability 5 and 7.5 mg tablets $450 per month (#60 tablets) PAP available? YES Safety Net Foundation (Amgen) Ready savings card caps out-of-pocket costs at $20/prescription NeedyMeds. Available at: Accessed May 10, Ivabradine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

33 Ivabradine (Corlanor ) Role in Therapy Not yet included in clinical practice guidelines Patients with stable systolic HF HR >70 on max tolerated dose of beta blocker With contraindication to beta blocker (e.g., uncontrolled asthma) In general, should not be considered as substitute

Approved July 7, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions ACEI Aliskiren Lithium Reduce risk of CV death & hospitalization

34 Approved July 7, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions ACEI Aliskiren Lithium Reduce risk of CV death & hospitalization in patients with HF & reduced EF Sacubitril inhibits neprilysin, increases natriuretic peptides Valsartan inhibits angiotensin receptors Target dose 97/103 mg BID Hypotension, hyperkalemia, increased SCr Entresto [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

35 Neprilysin inhibitor Angiotensin Receptor Blocker Sacubitril/Valsartan (Entresto ) Mechanism of Action Sacubitril increases [ANP] & [CNP] Sodium excretion Vasodilation Reduction in hypertrophy, fibrosis and sympathetic outflow Valsartan prevents unopposed RAAS stimulation by Ang II

36 Sacubitril/Valsartan Efficacy Double-blind RCT in patients with NYHA II, III or IV HFREF Randomized to 200 mg of combination BID or enalapril 10 mg BID Included 18 yoa LVEF 35% BNP 150 pg/ml or HF admission w/i 12 mo + BNP 100 pg/ml Stable doses of BB + ACEI for at least 4 weeks Excluded SBP <100 mmhg egfr <30 ml/min Symptomatic hypotension K >5.2 H/O angioedema on ACEI/ARB McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:

37 Sacubitril/Valsartan Efficacy Baseline characteristics Mean age 64, 78% male, 66% white Almost all with class II or III HF Primarily ischemic (60%) LVEF 29%, median BNP ~250 pg/ml Treatments at randomization 93% on beta blocker 80% on diuretic 30% on digoxin 55% on aldosterone antagonist McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:

38 Sacubitril/Valsartan Efficacy Primary EP = composite [CV death + HF hospitalization] 26.5% HR 0.80 (0.73, 0.87) 21.8% NNT = 21 McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:

39 Sacubitril/Valsartan Efficacy Components of primary composite EP CV death HR 0.80 (0.71, 0.89) NNT = 31 HF hospitalization HR 0.79 (0.71, 0.89) NNT = 36 McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:

40 Sacubitril/Valsartan Efficacy Effect of Age <55 years n= to 64 years n= to 74 years n= years n=1563 Endpoint Composite PEP <55 years 55 to 64 years 65 to 74 years 75 years CV death <55 years 55 to 64 years 65 to 74 years 75 years HF hospitalization <55 years 55 to 64 years 65 to 74 years 75 years HR (95% CI) 0.78 (0.64, 0.96) 0.76 (0.65, 0.90) 0.80 (0.68, 0.93) 0.86 (0.72, 1.04) 0.84 (0.65, 1.08) 0.79 (0.64, 0.98) 0.74 (0.60, 0.90) 0.84 (0.67, 1.06) 0.75 (0.57, 0.98) 0.74 (0.61, 0.91) 0.81 (0.68, 0.97) 0.87 (0.71, 1.07) Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (Sacubitril-valsartan) according to age: Insights from PARADIGM-HF. Eur Heart J 2015;36:

41 Sacubitril/Valsartan Efficacy Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: Insights from PARADIGM-HF. Eur Heart J 2015;36:

42 Sacubitril/Valsartan Safety Sacubitril-Valsartan (n=4187) Enalapril (n=4212) P value Symptomatic hypotension 588 (14.0%) 388 (9.2%) <0.001 SCr 2.5 mg/dl 139 (3.3%) 188 (4.5%) K >5.5 mmol/l 674 (16.1%) 727 (17.3%) 0.15 K >6.0 mmol/l 181 (4.3%) 236 (5.6%) Cough 474 (11.3%) 601 (14.3%) <0.001 Angioedema 19 (0.5%) 10 (0.2%) -- McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med 2014; 371:

43 Sacubitril/Valsartan Safety Effect of Age P>0.05 for all comparisons 17.4% 16.9% 17.7% 17.7% 15.1% 11.5% 11.7% 12.6% 12.4% 10.2% 12.5% 9.8% 4.8% 4.2% 1.2% 2.7% <55 YEARS YEARS YEARS 75 YEARS Symptomatic Hypotension SCr 2.5 K >5.5 Cough Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: Insights from PARADIGM-HF. Eur Heart J 2015;36:

44 Sacubitril/Valsartan (Entresto ) Dosing 36 hour washout Previous Therapy Previous Dose required for ACEI Entresto Starting Dose ACEI ARB Enalapril >10 mg/d Lisinopril >10 mg/d Ramipril >5 mg/d Enalapril 10 mg/d Lisinopril 10 mg/d Ramipril 5 mg/d Valsartan >160 mg/d Losartan >50 mg/d Olmesartan >10 mg/d Valsartan 160 mg/d Losartan 50 mg/d Olmesartan 10 mg/d 49/51 mg BID 24/26 mg BID 49/51 mg BID 24/26 mg BID Neither n/a 24/26 mg BID Double dose every 2-4 weeks to target 97/103 mg BID

Sacubitril/Valsartan (Entresto ) Availability Tablet strengths 24/26 mg (=40 mg valsartan) 49/51 mg (=80 mg valsartan) 97/103 mg (=160 mg valsartan) $450 per month (#60 tablets) PAP available?

45 Sacubitril/Valsartan (Entresto ) Availability Tablet strengths 24/26 mg (=40 mg valsartan) 49/51 mg (=80 mg valsartan) 97/103 mg (=160 mg valsartan) $450 per month (#60 tablets) PAP available? YES Entresto Central Patient Support Program (Novartis) $10 Co-Pay Card Free Trial Card (first 30 days free) NeedyMeds. Available at: Accessed May 10, Sacubitril/valsartan. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

46 Sacubitril/Valsartan (Entresto ) Role in Therapy Not yet included in US clinical practice guidelines Canadian Cardiovascular Society recommends for mild-moderate HF w/ elevated natriuretic peptide, recent hospitalization, K<5.2 and egfr >30 Untested in patients with new HF diagnosis Consider substituting for ACEI or single-agent ARB in those with: LVEF 40% Elevated BNP (or HF admission w/i 12 mo) SBP 100 mmhg egfr 30 ml/min Prior treatment w/ ACEI or ARB (for at least 4 weeks)

47 Take Home Points Heart Failure in Older Adults More than 75% of those with CHF are older than 65 Older adults are more likely to develop HF with preserved EF Older adults with HF may be under-treated with therapies that reduce mortality and morbidity Also underrepresented in clinical trials be careful applying findings from broader population! Neither ivabradine nor sacubitril/valsartan are included yet in major US guidelines, but practice is already shifting Rich MW. Congestive heart failure in older adults: Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc 1997;45:

48 New Drugs for Hyperlipidemia Alirocumab (Praluent ) & Evolocumab (Repatha )

Approved July 24, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Statin adjunct in patients with familial hypercholesterolemia or

49 Approved July 24, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Statin adjunct in patients with familial hypercholesterolemia or clinical ASCVD Inhibits PCSK9, promotes degradation of LDL receptors mg SC every 2 weeks Diarrhea, myalgia, liver enzyme disorder No clinically significant interactions Praluent [package insert]. Bridgewater, NJ: Regeneron Pharmaceuticals, Inc.; 2015.

50 PCSK9 Inhibitors Mechanism of Action PCSK9 inhibitor McKenney JM. Understanding PCSK9 and anti-pcsk9 therapies. J Clin Lipidol 2015;9:

51 Alirocumab (Praluent ) Efficacy Placebo-controlled, multinational RCT in statin-treated patients at high risk for CV events Randomized 2:1, active treatment group received alirocumab 150 mg SC every 2 weeks Included 18 yoa HeFH or established CHD or coronary risk equivalent LDL-C 70 mg/dl 4 weeks of maximally tolerated statin Excluded CV event, CVA or TIA w/i 3 mo NYHA III or IV HF BP >180/110 H/O hemorrhagic stroke Systemic CS w/i 6 weeks TG >400 egfr <30 ml/min Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Eng J Med 2015;372:

52 Alirocumab (Praluent ) Efficacy Baseline characteristics Mean age 60, 60% male, 93% white 69% with established CHD, 41% with risk equivalent 47% on high-dose statin (atorva 40, rosuva 20, or simva 80); 14% on ezetimibe Baseline levels LDL-C 122 Non-HDL 152 apob 101 TG 133 Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Eng J Med 2015;372:

53 Alirocumab (Praluent ) Efficacy Primary EP = percent change in LDL-C from baseline to week 24 Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Eng J Med 2015;372:

54 Alirocumab (Praluent ) Efficacy Post hoc analysis of major CV events Composite EP [CV death + nonfatal MI + ischemic stroke + UA requiring hospitalization] 1.7% (alirocumab) vs. 3.3% (placebo) HR 0.52 (0.31, 0.90) Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Eng J Med 2015;372:

55 Alirocumab (Praluent ) Safety Adverse Events Variable Alirocumab (n=1550) Placebo (n=788) P value Any AE 1255 (81.0%) 650 (82.5%) 0.40 Serious AE 290 (18.7%) 154 (19.5%) 0.66 Leading to D/C 111 (7.2%) 46 (5.8%) 0.26 Myalgia 84 (5.4%) 23 (2.9%) Neurocognitive AE 18 (1.2%) 4 (0.5%) 0.17 Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Eng J Med 2015;372:

56 Alirocumab (Praluent ) Dosing & Availability 75 mg SC every 2 weeks May titrate to 150 mg SC every 2 weeks after 4-8 weeks Store in refrigerator, allow to reach RT before injecting 1 ml Pen Injector (75 or 150 mg/ml) Inject in upper arm, stomach or thigh $672 per pen PAP Available? YES MyPraluent (Sanofi-Aventis) Diplomat s Co-Pay Assistance Navigator Program Patient Access Network (PAN) Foundation NeedyMeds. Available at: Accessed May 10, Alirocumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

Approved August 27, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Statin adjunct in patients with familial hypercholesterolemia

57 Approved August 27, 2015 FDA Approved Indication Mechanism of Action Dosing and Administration Notable Adverse Effects Drug Interactions Statin adjunct in patients with familial hypercholesterolemia or clinical ASCVD Inhibits PCSK9, promotes degradation of LDL receptors 140 mg SC every 2 weeks or 420 mg SC monthly Myalgia, nasopharyngitis No clinically significant interactions Repatha [package insert]. Thousand Oaks, CA: Amgen Inc.; 2016.

58 Evolocumab (Repatha ) Efficacy & Safety Adverse Events Variable Evolocumab (n=2976) Standard Tx (n=1489) Any AE 2060 (69.2%) 965 (64.8%) Serious AE 222 (7.5%) 111 (7.5%) Leading to D/C 71 (2.4%) N/A Muscle-related 190 (6.4%) 90 (6.0%) Neurocognitive 27 (0.9%) 4 (0.3%) Sabatine MS, Glugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:

59 Evolocumab (Repatha ) Efficacy & Safety Cardiovascular Events 2.18% 0.95% Sabatine MS, Glugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:

60 Evolocumab (Repatha ) Dosing & Availability 140 mg SC every 2 weeks or 420 mg SC every 4 weeks Store in refrigerator, allow to reach RT before injecting 1 ml SureClick auto-injector pen (140 mg/ml) Inject in upper arm, stomach or thigh $650 per pen PAP available? YES Patient Access Network (PAN) Foundation For those < % FPL NeedyMeds. Available at: Accessed May 10, Evolocumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: Accessed May 10, 2016.

61 PCSK9 Inhibitors Role in Therapy ACC recommends 2 nd or 3 rd line in patients intolerant of statins or who fail to achieve adequate response on statin monotherapy Use only in those with ASCVD ± baseline LDL 190 May be used first-line in patients with ASCVD and baseline LDL-C 190 if <50% reduction achieved with statin alone NOT recommended for primary prevention in patients without the above risk factors or in patients with HF May be considered as add-on or replacement Consider dexterity Lloyd-Jones DM, Morris PB, et al ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. J Am Coll Cardiol 2016 Mar 28. [Epub ahead of print]

62 Take Home Points Hyperlipidemia in Older Adults Statins remain the best studied treatment for hyperlipidemia, BUT: May be less well tolerated by older adults Some residual risk remains, even on maximized therapy Preliminary data on CV outcomes with PCSK9 inhibitors is encouraging Likely little role in the setting of life-limiting illness Consider cost to the health care system How much bang for the buck? Schulman KA, Balu S, Reed SD. Specialty pharmaceuticals for hyperlipidemia impact on insurance premiums. N Engl J Med 2015;373:

63 In summary

64 Paradigm Shift? T2DM HFREF HLD Insulin degludec offers lower risk of hypoglycemia with more flexible dosing May come to replace glargine as basal insulin of choice Sacubitril/valsartan offers greater benefit than current standard of care in the general population Be cautious when extrapolating to older adults, since benefit was less pronounced in the oldest old PCSK9 inhibitors are potent LDL lowering agents Reserve use for most higher-risk patients until prospective CV outcomes data are available

65 Tasha Woodall, PharmD, CGP, CPP Associate Director of Pharmacotherapy, Geriatrics Mountain Area Health Education Center Assistant Professor of Clinical Education UNC Eshelman School of Pharmacy

PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS: ARE YOU SURE THESE ARE REALLY CARDIAC DRUGS?

PCSK9 INHIBITORS, ARNIS, FUNNY CHANNEL INHIBITORS: ARE YOU SURE THESE ARE REALLY CARDIAC DRUGS? ALLORIE SMITH, PHARM.D. CARDIOVASCULAR UPDATE CONFERENCE FEBRUARY 9, 2012 OBJECTIVES Explain the pharmacology