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Updates in Pharmacotherapy for Diabetes

Dawn Battise, PharmD, BCACP

Jacky Olin, MS, PharmD, BCPS, CDE

October 2017

Disclosures

• DB and JO have no relevant financial or other relationships with commercial interests pertaining to the content presented in this program.

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Objectives

• Compare and contrast guideline recommendations for management of hypertension and dyslipidemia in people with diabetes

• Describe the evidence of improved cardiovascular mortality with certain antihyperglycemic agents in selected populations of people with diabetes

• Describe important differences between and counseling points for concentrated insulins

• Given a patient case scenario, formulate an evidence-based treatment plan

Mr. Jones

• Mr. Jones is a 68 year old AAM referred for diabetes management and education.

• PMH: T2DM, HTN, dyslipidemia, MI (age 66)

• SH: current smoker, Medicare Part D, retired teacher, lives with his wife

• Meds: atorvastatin 80 mg daily, aspirin 81 mg daily, lisinopril 20 mg daily, metoprolol succinate 200 mg once daily, metformin 1000 mg BID

Mr. Jones Labs

SCr 0.9

CrCl >100

GFR >59

Na 135

K 3.7

A1c 8.2%

TC 162

TG 170

HDL 51

LDL 77

ACR 30-300

Vitals

Ht 6’2”

Wt 243 lb

BMI 31

BP 142/87

HR 72

Home Blood Glucose

FBG 172 167 149 161 174 159

PPBG 202 215 230

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Mr. Jones

• What changes do you recommend to optimize therapy and potentially reduce his CV risk?

HYPERTENSION AND LIPID GUIDELINE UPDATES

Why This Matters

• ASCVD = acute coronary syndromes, MI, angina, coronary or other arterial revascularization, stroke, TIA, or PAD

–Greatest contributor to direct and indirect costs of DM

–*Leading cause of morbidity and mortality with DM*

• DM, HTN, and dyslipidemia ↑ASCVD risk

2017 ADA Standards of Care

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Hypertension – Goals in DM

• JNC 8 (2014): <140/90 regardless of age, with or without CKD

• ACC/AHA/ASH (2015): DM + CAD <140/90 (if >80 years may be <150/90)

• ADA (2017): – BP goal <140/90 (option <130/80 if high CV risk and

can reach without undue burden)

– First-line BP treatment = ACEi, ARB, dihydropyridine CCB or thiazide-like diuretic

– If pt has albumin:creatinine ratio >30, use ACEi

Lipids – 2013 ACC/AHA

Lipids – 2015 NLA

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ADA Recommendations - Lipids

Role of PCSK9 Inhibitors?

• Evolocumab (Repatha®) • Alirocumab (Praluent®) • Both agents:

– Addition to diet, maximally tolerated statin therapy – Treatment of adults with heterozygous familial

hypercholesterolemia – Treatment of clinical atherosclerotic CVD, who require

additional lowering of LDL

• Evolocumab only – Adjunct to diet and other LDL-lowering therapies (e.g.,

statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia who require additional LDL lowering

Repatha® and Praluent® PI

PCSK9 Inhibitors – CV Data

• Alirocumab - ODYSSEY Outcomes trials

• Ongoing trial for CV data in secondary prevention

• Estimated completion December 2017 (NCT01663402)

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PCSK9 Inhibitors – CV Data • Evolocumab – FOURIER trial

– 27,564 participants with ASCVD and LDL >70 on statin therapy

– Baseline characteristics

• White males ~62 years old, sick patients, generally good background therapy, LDL 92 mg/dL

• Median follow-up 2.2 years

PBO (%) Evolocumab (%) P value

CV death, MI, stroke, unstable angina hospitalization, coronary revascularization

11.3

9.8 < 0.0001

CV death alone 1.7 1.8 0.62

MI alone 4.6 3.4 <0.001

Stroke alone 1.9 1.5 0.01

↓LDL from baseline vs. PBO 59%

Ezetimibe - IMPROVE-IT trial

• 18,144 patients 50+ years with recent ACS (MI, high-risk UA)

• LDL 50-100 mg/dL if on a statin or 50-125 mg/dL if not on a statin

• ~64 years old, 76% male, 84% white, LDL 93 mg/dL, HTN (61%), DM (27%), smoker (33%), on statin before ACS (34%)

• 1 ̊ endpoint = CV death, nonfatal MI, nonfatal stroke, UA requiring hospitalization, coronary revascularization in 30 days

• Tx significantly reduced risk for: any MI, nonfatal MI, any stroke, ischemic stroke, urgent revascularization

• No significant difference in AE or withdrawal due to AE

Simva 40 mg + PBO

Simva 40 mg + Ezetimibe 10 mg

P value

1 ̊ endpoint 34.7% 32.7% 0.016

LDL at 1 year 69.9 mg/dL 53.2 mg/dL 0.001

Role of Non-Statin Treatment

• Per 2013 ACC/AHA: add non-statin if high risk (LDL >190, DM, ASCVD) and do not achieve expected LDL lowering or cannot tolerate statin

• However…new data are available

– PCSK9 inhibitor – if heterozygous or homozygous familial hypercholesterolemia OR high CV risk on max statin with insufficient LDL lowering (and can afford it)

– Ezetimibe- if a history of ACS, 50+ years old

• Max out statin dose first!

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Mr. Jones Labs

SCr 0.9

CrCl >100

GFR >59

Na 135

K 3.7

A1c 8.2%

TC 162

TG 170

HDL 51

LDL 77

ACR 30-300

Vitals

Ht 6’2”

Wt 243 lb

BMI 31

BP 142/87

HR 72

68 yo AAM PMH: T2DM, HTN, dyslipidemia, MI (age 66), tobacco abuse Medicare Part D

Meds: atorvastatin 80 mg daily, aspirin 81 mg daily, lisinopril 20 mg daily, metoprolol succinate 200 mg once daily, metformin 1000 mg BID

Mr. Jones

• HTN

– Very slightly above BP goal <140/90

– Evaluate BP trends and if BP was correctly measured

– If remains elevated may increase lisinopril

– ACEi appropriate given elevated ACR

Mr. Jones

• DLD

– Per ACC/AHA: No LDL goals so if he achieved appropriate lowering on atorvastatin that is sufficient

– Per NLA: LDL above goal <70. May consider non-statin agent. Consider risk vs. benefit.

– Per ADA: TG above goal <150 but may be corrected with improved BG control. HDL at goal >40.

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DM MEDICATIONS AND CV DATA

SGLT2 Inhibitors - EMPA-REG OUTCOMES

• Empagliflozin vs. PBO in 7020 patients with DM + established CVD

• ~63 years, 71% male, 72% white, A1c 8%, 57% DM >10 years, 76% CAD, 47% MI hx

• Median follow-up = 3.1 years

Endpoint Empagliflozin(%) PBO (%) P value

CV death, nonfatal MI, nonfatal stroke

10.5 12.1 0.04*

CV death alone 3.7 5.9 <0.001

MI (fatal or nonfatal) alone 4.8 5.4 0.23

Stroke (fatal or nonfatal) alone 3.5 3 0.26

HF hospitalization 2.7 4.1 0.002

SGLT2 Inhibitors - EMPA-REG OUTCOMES

• FDA label update (December 2016):

– Empagliflozin (Jardiance®) approved “to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease”

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SGLT2 Inhibitors - CANVAS trial • Canagliflozin vs. PBO in 10142 patients with DM + high CV risk

• ~63 years, 64% male, 78% white, 13.5 years DM, A1c 8.2%, 67% CVD hx

• Median follow-up = 2.4 years

• Endpoints measured as # of events per 1000 patient years

Endpoint Canaglifozin PBO HR (CI)

CV death, nonfatal MI, nonfatal stroke

26.9 31.5 0.86 (0.75–0.97) p = 0.02*

CV death alone 11.6 12.8 0.87 (0.72–1.06)

MI (fatal or nonfatal) alone 11.2 12.6 0.89 (0.73–1.09)

Stroke (fatal or nonfatal) alone 7.9 9.6 0.87 (0.69–1.09)

HF hospitalization 5.5 8.7 0.67 (0.52–0.87)

SGLT2 Inhibitors - CANVAS trial

• FDA label update (July 2017):

– Boxed Warning: “…INVOKANA has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg. Before initiating, consider factors that may increase the risk of amputation. Monitor patients receiving INVOKANA for infections or ulcers of the lower limbs, and discontinue if these occur.”

Adverse Event Canaglifozin PBO P value

Amputation 6.3 3.4 <0.001

SGLT2 Inhibitors - Dapagliflozin

• DECLARE-TIMI58

– Ongoing study in T2DM + high CV risk

– Anticipated completion April 2019

https://clinicaltrials.gov/ct2/show/NCT01730534

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SGLT2 Inhibitors - CVD-REAL

• Multinational observational study

• Matched initiation of SGLT2i vs other AHA use

• >300,000 people – ~57 years, 54% male, 13% established CVD

– 53% canagliflozin, 42% dapagliflozin, 5% empagliflozin

• 39% ↓ incidence of HF hospitalizations in SGLT2i users

• 51% ↓ all-cause death

GLP1 Agonists – LEADER Trial

• Liraglutide vs PBO in 9340 patients 50+ years with DM + high CV risk

• ~64 years, 64% male, 13 years DM, A1c 8.7% , ~81% established CVD

• Median follow-up 3.8 years

Endpoint Liraglutide (%) PBO (%) P value

Time to first occurrence CV outcome (CV death, nonfatal MI, nonfatal stroke)

13 14.9 0.01*

CV death alone 4.7 6 0.007

MI alone 6.3 7.3 0.046

Stroke alone 3.7 4.3 0.16

GLP1 Agonists - Liraglutide

• FDA label update (August 2017):

– Liraglutide (Victoza®) is approved “to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease”

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Other GLP1 Agonists

• SUSTAIN 6 (semaglutide)

–Awaiting FDA decision for US approval

– 3297 patients with DM + high CV risk

– ~64 years, 50% male, 83% established CVD and/or CKD, ~14 years DM, A1c 8.7%

– 1 ̊ endpoint = time to first occurrence CV outcome (CV death, nonfatal MI, nonfatal stroke) p=0.02 (superiority)

–Monitor: potentially increased retinopathy?

Other GLP1 Agonists

• No CV Benefit or Harm

– Exenatide weekly (EXSCEL)

– Lixisenatide (ELIXA)

• Ongoing Trials

–Albiglutide – HARMONY Outcomes (March 2018)

–Dulaglutide – REWIND (July 2018)

https://clinicaltrials.gov/ct2/show/NCT02465515 https://clinicaltrials.gov/ct2/show/NCT01394952

Important to Remember

• To date…all CV data in newer agents is for those with established CVD history or high CV risk

• None have proven benefit in primary prevention

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Mr. Jones Labs

SCr 0.9

CrCl >100

GFR >59

Na 135

K 3.7

A1c 8.2%

TC 162

TG 170

HDL 51

LDL 77

ACR 30-300

Vitals

Ht 6’2”

Wt 243 lb

BMI 31

BP 142/87

HR 72

68 yo AAM PMH: T2DM, HTN, dyslipidemia, MI (age 66), tobacco abuse Medicare Part D

Meds: atorvastatin 80 mg daily, aspirin 81 mg daily, lisinopril 20 mg daily, metoprolol succinate 200 mg once daily, metformin 1000 mg BID

Home Blood Glucose

FBG 172 167 149 161 174 159

PPBG 202 215 230

Mr. Jones

• What changes do you recommend to optimize DM therapy and potentially reduce his CV risk?

– GLP1 Agonist

• Consider liraglutide

• Pros: reduced CV risk (FDA approved), weight loss

• Cons: injection, cost, AE

– SGLT2 Inhibitor

• Consider class effect? Empagliflozin for FDA approval.

• Pros: oral, weight loss, slight BP lowering

• Cons: cost, AE

– Continue metformin

CONCENTRATED INSULINS

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Ms. Jones

• Ms. Jones, a 54 year old female, is being discharged from the hospital after 3 days for treatment of pneumonia.

• PMH: type 2 diabetes mellitus, stage III chronic kidney disease, hypertension, and dyslipidemia

• Prior to admission medications for glycemic control:

– Metformin 500 mg PO twice daily

– NPH insulin 90 units subcut twice daily

• A1c obtained during stay = 9.5

What are Ms. Jones’ glycemic, lipid, and hypertension goals?

What therapeutic alternatives may improve her glycemic control and outcomes?

Concentrated Insulins

• Type 2 diabetes characterized by insulin resistance and relative insulin deficiency

• Per the Centers for Disease Control and Prevention (CDC): – 7.2 % of US population with diagnosed diabetes

– People > age 18 with diagnosed diabetes: 87.5% overweight or obese

• Initiation of basal insulin recommended in individuals with symptomatic hyperglycemia and elevated A1c

• Continued need for safe and effective insulin options

• Additional concentrated insulins developed to improve absorption and minimize larger injection volumes

https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf

Basal: U-300 Insulin Glargine (Toujeo)

Safety and Efficacy

Similar rates of A1c lowering with lower rates of confirmed or severe hypoglycemia compared to U-100 insulin glargine

Duration of Action

> 24 hours

Maximum Units per Injection

80 Units

Availability 1.5 mL prefilled pen

Open in-use storage

42 days outside refrigerator

Insulin Conversions

• 1:1 conversion from U-100 insulin glargine or detemir • 20% dose reduction when switching from NPH insulin • Higher dose of U-300 may be needed compared to

U-100 glargine

Ritzel R, et al. Diabetes Obes Metab. 2015;17:859-867. Toujeo [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S., LLC; 2015.

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Basal: Insulin degludec (Tresiba) Safety and Efficacy

Non-inferior A1c lowering with lower rates of hypoglycemia compared to U-100 insulin glargine in insulin-naïve and previously treated type 1 and type 2 diabetes patients Non-inferior cardiovascular risk compared to glargine

Duration of Action

42 hours

Maximum Units per Injection

160 Units for 200 units/mL pen

Availability 200 units/mL 3 mL pen (also a 100 units/mL formulation)

Open in-use storage

56 days outside refrigerator

Insulin Conversions

• 1:1

Marso SP, et al. N Engl J Med. 2017;377(8):723-732. Ratner RE, et al. Diabetes Obes Metab. 2013;15(2):175-184. Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2015.

U-500 Insulin (Humulin R): Basal and bolus characteristics

Safety and Efficacy

Similar A1c reductions with thrice-daily vs twice-daily regimens Non-severe hypoglycemia lower with thrice-daily, severe hypoglycemia and weight gain similar **Only for patients requiring > 200 units of insulin/day

Duration of Action

21 hours (range 13-24 hours)

Maximum Units per Injection

250 Units

Availability 500 units/mL, 3 mL pen; 20 mL multiple dose vial

Open in-use storage

28 days

Insulin Conversions

• A1C >8%: start total daily dose (TDD) of U-500 at 100% of U-100 TDD.

• A1C ≤8%: start TDD of U-500 at 80% of U-100 TDD

Hood RC, et al. Endocr Pract. 2015;21(7):782-793 Humulin R U-500 KwikPen [package insert]. Indianapolis, IN: Eli Lilly & Co; 2016.

Bolus: U-200 Insulin Lispro (Humalog)

Safety and Efficacy

Bioequivalence study in euglycemic patients without diabetes

Duration of Action

4-5 hours

Maximum Units per Injection

60 Units

Availability 200 units/mL 3 mL pen

Open in-use storage

28 days

Insulin Conversions

1:1

delaPena A, et al. Clin Pharmacol Drug Dev. 2016;5(1):69-75. Humalog [package insert]. Indianapolis, IN: Eli Lilly & Co; 2015.

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Ms. Jones

• Ms. Jones, a 54 year old female, is being discharged from the hospital after 3 days for treatment of pneumonia.

• PMH: type 2 diabetes mellitus, stage III chronic kidney disease, hypertension, and dyslipidemia

• Prior to admission medications for glycemic control:

– Metformin 500 mg PO twice daily

– NPH insulin 90 units subcut twice daily

• A1c obtained during stay = 9.5

What are Ms. Jones’ glycemic, lipid, and hypertension goals?

What therapeutic alternatives may improve her glycemic control and outcomes?

References – HTN and Lipids • American Diabetes Association. Standards of Medical Care in Diabetes 2017. Diabetes Care.

2017;40(Suppl.1).

• James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20.

• Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, Cannon CP, De Lemos JA, Elliott WJ, Findeiss L, Gersh BJ. Treatment of hypertension in patients with coronary artery disease. Hypertension. 2015;65(6):1372-407.

• Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PWF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129:S1-S45.

• Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1–executive summary. Journal of clinical lipidology. 2014 Oct 31;8(5):473-88.Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW, García FA, Gillman MW, Kemper AR, Krist AH, Kurth AE, Landefeld CS. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force recommendation statement. JAMA. 15;316(19):1997-2007.

• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;2017(376):1713-22.

• Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM. Ezetimibe added to statin therapy after acute coronary syndromes. New Engl J Med. 2015;372(25):2387-97.

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References - Diabetes

• Professional Resource. Diabetes Medications and Cardiovascular Impact. Pharmacist’s Letter/Prescriber’s Letter. August 2016.

• CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes [Internet]. United States National Institutes of Health. [cited 2017 Sept 7]. Available from: https://clinicaltrials.gov/ct2/show/NCT01243424.

• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.

• Jardiance [package insert]. Ridgefield,CT: Boehringer Ingelheim Pharmaceuticals, Inc.: 2016.

• Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017; 377:644-657.

• Invokana [package insert]. Titusville, NJ: Janssen Pharmaeuticals, Inc.: 2017.

• Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) [Internet]. United States National Institutes of Health. [cited 2017 Sept 13]. Available from: https://clinicaltrials.gov/ct2/show/NCT01730534.

• Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen M, Thuresson M, Arya N. Lower Risk of Heart Failure and Death in Patients Initiated on SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study. Circulation. 2017:CIRCULATIONAHA-117.

• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;2016(375):311-22.

• Victoza [package insert]. Plainsboro, NJ: Novo Nordisk, Inc.: 2017.

• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New Engl J Med. 2016;375(19):1834-44.

• Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus. United States National Institutes of Health. [cited 9 September 2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT02465515.

• Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND). United States National Institutes of Health.

[cited 9 September 2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT01394952 .