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Updates in Diabetes & Cardiovascular Disease
Karen Selk, DOClinical Assistant Professor of Medicine
Division of Endocrinology
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Disclosures• Clinical study with funding from Regeneron
Pharmaceuticals
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Objectives• Briefly review the current ADA recommendations for
diabetes therapy in individuals with established cardiovascular disease
• Review GLP1 receptor agonist and SGLT2 inhibitor use –some old and some new
• Review the 2018 cholesterol recommendations for diabetics
• Review impact of hypertriglyceridemia on ASCVD risk • Review EPA for management of hypertriglyceridemia in
diabetics• Briefly Review newly FDA approved medications in diabetes
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Diabetes & Cardiovascular Disease
• The prevalence of diabetes continues to increase worldwide
• Anticipated that by the year 2040 more than 640 million people will be affected
• Affected individuals are at high risk for atherosclerotic disease and heart failure
Ogurtsova K et al. Diabetes Res Clin Pract 2017; 128:40-50.ADA Standards of Care 2019
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ADA Standards of Care, 2019
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Effects of GLP1 Receptor Agonists
Hinnen, D. Diabetes Spectrum 2017. 30(3): 202-210.
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GLP1 Receptor Agonists That Decrease Cardiovascular Risk:
• Injectable:– Liraglutide (Victoza®)
– Semaglutide (Ozempic®)
– Dulaglutide (Trulicity®)
• Oral– Semaglutide (Rybelsus®)
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LEADER: Liraglutide – July 2016
• 9340 patients
– A1c 7%+
– All type II DM
– 1 CV risk factor
• Lower risk of death from CV
cause, non-fatal MI, or non-
fatal stroke
– Reduced risk of MACE by 13%
– Absolute risk reduction: 1.9%
Marso SP, et al. NEJM. 2016; 375: 311-322.
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Marso SP, et al. NEJM. 2016; 375: 311-322.
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SUSTAIN 6: Semaglutide – November 2016• 3297 patients
– Type 2 diabetes– 50 yrs of age + known CV
disease, heart failure, stage III CKD
– A1c >7%• 26% less MACE with
semaglutide as compared to placebo
Marso SP, et al. NEJM 2016; 375:1834-1844
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Increased retinopathy in the semaglutide treated group vsplacebo.
Marso SP, et al. NEJM 2016; 375:1834-1844
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REWIND: Dulaglutide – July 2019• 9901 participants– Only 31.5% had CVD, the
others had risk factors– Median a1c 7.2%
• Reduced MACE by 12% compared to placebo
• Reduces CV outcomes for 5 years+
Gerstein HC, et al. Lancet. 2019; 394:P121-130.
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PIONEER 6: Oral Semaglutide – August 2019
• 3183 patients– 50 yrs + CVD or CKD– Mean A1c: 8.2%
• Adverse events:– GI side effects (nausea)– Retinopathy (7.1% vs
6.3%)
Husain M et al. NEJM. 2019;381:841-51.Resident360.nejm.org
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The New Kid on the Block:The Oral GLP1 Receptor Agonist
• PIONEER 4 study– 711 patients– Oral semaglutide vs
liraglutide vs placebo– Similar a1c reduction– Better weight loss (-4.4 kg
vs -3.1kg)– Similar side effect profile
as liraglutide– Cost?
Pratley R, et al. Lancet. 2019, 364:39-50.
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Rybelsus
Special Considerations:• Avoid in personal or family history of medullary thyroid cancer• Avoid with history of pancreatitis• Not approved for use in pregnancy• Most common side effect: nausea
Rybelsuspro.com
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GLP1: Practice Considerations• Consider Use:
– Established cardiovascular disease or at high risk for cardiovascular disease
– Overweight/Obesity• Avoid Use:
– Pancreatitis– Medullary thyroid cancer– ?Retinopathy
• Ozempic• Rybelsus
• Do not require renal adjustment
• Low risk of hypoglycemia• Can be costly
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SGLT2 inhibitors
Hattersley AT. NEJM. 2015;373:974-976.
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SGLT2 Inhibitors with CV Benefit• Empagliflozin (Jardiance®)• Canagliflozin (Invokana®)• Dapagliflozin (Farxiga®)
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EMPA-REG: Empagliflozin – November 2015
• 7028 patients– Type II DM– Age >18 – >99% had established
cardiovascular disease• Decreased risk for CV
related death, nonfatal MI, and non-fatal stroke
Zinman B, et al. NEJM. 2015;373:2117-2128.
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CANVAS: Canagliflozin – August 2017• 10,142 participants– Type 2 diabetes– High cardiovascular risk
with 65.6% with established disease
• Decreased risk for cardiovascular events
• Increased risk for amputation– Mostly toe – Lead to black box
warning
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Dapagliflozin – 2019
DECLARE-TIMI 58• 17,160 participants
– 59.4% without ASCVD
• No significant reduction in MACE
• However there was reduction in cardiovascular death and hospitalization for heart failure
Wiviott SD, et al. NEJM. 2019;380(347-357).
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Dapagliflozin – 2019DAPA-HF
• 4744 participants with NYHA class II/II/IV heart failure & EF <40%– Primary outcome:
hospitalization, IV therapy, CV death
McMurray JV et al. NEJM. 2019
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Lupsa B. Diabetologica. 2018;61:2118-2125.
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SGLT2 Inhibitor Practice Considerations• Avoid canagliflozin with osteoporosis, peripheral
vascular disease, neuropathy• Avoid use in individuals with recurrent UTI• Consider testing for possible autoimmune diabetes
before use– Given risk for DKA
• Consider use in individuals with history of heart failure and cardiovascular disease– With ASCVD, dapagliflozin would not be preferred agent
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Who is considered very high risk for ASCVD:
2 major events or 1 major with 2+ high risk
Major Events• Recent ACS
– Within last 12 months
• History of ischemic stroke
• History of MI
• Symptomatic PAD – Claudication with ABI <0.85
– Amputation or previous revascularization
High Risk Conditions• Age >= 65 years
• Heterozygous familial hypercholesterolemia
• History of CABG or PCI
• Diabetes mellitus• Hypertension
• CKD (eGFR 15-59 mL/min/1.732)
• Current smoking
• LDL-C >= 100 despite maximum statin + ezetimibe
• History of heart failure
Grundy S et al. Circulation. 2019;139:e1082-e1143.
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ACC/AHA 2018 Cholesterol Guidelines
• “In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10 year ASCVD risk, moderate intensity statin therapy is indicated” (IA)– For type I and type 2– Not based on lipid values– For those age >75, we should continue statin therapy
if tolerate (high risk)
Grundy S et al. Circulation. 2019;139:e1082-e1143.
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What About the Diabetics Who are 20-30 Years of Age?
• ASCVD rates increase with duration of DM• The risk of ASCVD is low in those who are <30 years • However, if with early type 2 diabetes there can be
significant ASCVD by their 30s• Consider starting if DM2 for 10+ years and DM1 for 20+
years • Consider if 1 CV risk factor or microvascular disease
Grundy S et al. Circulation. 2019;139:e1082-e1143.
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ACC/AHA 2018 Cholesterol Guidelines• “In adults 40 to 75 years of age with diabetes
mellitus and an LDL-C level of 70-189 mg/dL, it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific PCE to help stratify ASCVD risk” (IIB)
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Grundy S et al. Circulation. 2019;139:e1082-e1143.
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Clinical Considerations: Statin
• All diabetics >40 yrs should be on moderate
intensity statin therapy
– Exception ESRD
• Start statin therapy younger if duration of DM
10+ years in type 2 and 20+ in type I
• If ASCVD is known, LDL-C target is <70 mg/dL
Grundy S et al. Circulation. 2019;139:e1082-e1143.
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Langsted A et al. J Intern Med. 2011; 270(1):66-75
Increasing triglyceride levels are associated with increased risk for MI and mortality.
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Triglyceride-Rich Lipoproteins Are Atherogenic
Goldberg, IJ et al. Aterioscler Thromb Vasc Biol. 2011;31(8):1716-1725.
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REDUCE-IT: January 2019• Icosapent Ethyl (Vascepa ®)• 8179 participants– With established CVD (70.7% or with risk factors)– On statin therapy, LDL-C 40-100 mg/dL– TG level 135-499 mg/dL– Started on 2g icosapent ethyl twice daily vs placebo– Primary endpoint: CV death, non fatal MI, nonfatal
stroke, coronary revascularization, unstable angina
Bhatt DP et al. NEJM. 2019;380:11-22.
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REDUCE-IT25% lower risk of primary endpoint in the EPA treated group
Bhatt DP et al. NEJM. 2019;380:11-22.
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NLA Recommendation for Icosapent Ethyl:• For diabetics:
– If “50 years of age or older with type 2 diabetes requiring medication and 1 additional risk factor, and fasting triglycerides 135-499 mg/dl on maximally tolerated statin, with or without ezetimibe, treatment with icosapent ethyl is recommended for ASCVD risk reduction”
Risk factors:• Men 55yrs, women 65yrs• Smoking• Hypertension• HDL <40 for men or <50 for
women• Hs-CRP >3.0 mg/dL• eGFR <60 mL/min• Retinopathy• Micro- or macro-albuminuria• ABI <0.9 without symptoms or
intermittent claudicationLipid.org
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Icosapent Ethyl Considerations:• First in class• minimal ezetimibe and without PCSK9 inhibitor
use• Increased bleeding risk• Increased risk for atrial fibrillation• Cost – insurance coverage?• Over-the-counter preparations are not effective
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Don’t Forget The Power of Lifestyle Change and Diabetes Education
• Improves a1c – 1-1.9% in type 1
– 0.3-2% in type 2
• Improves quality of life
• Improving coping
ADA Standards of Care, 2019
Dependablelock.com
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Gvoke• FDA approval 9/2019• Glucagon in a prefilled
syringe or auto-injector
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Baqsimi• FDA approval 7/2019• Glucagon nasal powder
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Objectives• Briefly review the current ADA recommendations for
diabetes therapy in individuals with established cardiovascular disease
• Review GLP1 receptor agonist and SGLT2 inhibitor use –some old and some new
• Review the 2018 cholesterol recommendations for diabetics
• Review impact of hypertriglyceridemia on ASCVD risk • Review EPA for management of hypertriglyceridemia in
diabetics • Briefly Review newly FDA approved medications in diabetes
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Thank You!