Updates in Pharmacotherapy for Diabetes in Pharmacotherapy...آ  10/2/2017 1 Updates in Pharmacotherapy

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  • 10/2/2017

    1

    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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    3

    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):

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    5

    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 3.4 190, 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!

  • 10/2/2017

    7

    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

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    8

    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

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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

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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

  • 10/2/2017

    12

    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?

    – GL