Updates in Diabetes & Cardiovascular Disease

Karen Selk, DOClinical Assistant Professor of Medicine

Division of Endocrinology

Disclosures• Clinical study with funding from Regeneron

Pharmaceuticals

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

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

ADA Standards of Care, 2019

Effects of GLP1 Receptor Agonists

Hinnen, D. Diabetes Spectrum 2017. 30(3): 202-210.

GLP1 Receptor Agonists That Decrease Cardiovascular Risk:

• Injectable:– Liraglutide (Victoza®)

– Semaglutide (Ozempic®)

– Dulaglutide (Trulicity®)

• Oral– Semaglutide (Rybelsus®)

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.

Marso SP, et al. NEJM. 2016; 375: 311-322.

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

Increased retinopathy in the semaglutide treated group vsplacebo.

Marso SP, et al. NEJM 2016; 375:1834-1844

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.

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

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.

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

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

SGLT2 inhibitors

Hattersley AT. NEJM. 2015;373:974-976.

SGLT2 Inhibitors with CV Benefit• Empagliflozin (Jardiance®)• Canagliflozin (Invokana®)• Dapagliflozin (Farxiga®)

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.

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

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).

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

Lupsa B. Diabetologica. 2018;61:2118-2125.

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

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.

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.

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.

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)

Grundy S et al. Circulation. 2019;139:e1082-e1143.

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.

Langsted A et al. J Intern Med. 2011; 270(1):66-75

Increasing triglyceride levels are associated with increased risk for MI and mortality.

Triglyceride-Rich Lipoproteins Are Atherogenic

Goldberg, IJ et al. Aterioscler Thromb Vasc Biol. 2011;31(8):1716-1725.

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.

REDUCE-IT25% lower risk of primary endpoint in the EPA treated group

Bhatt DP et al. NEJM. 2019;380:11-22.

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

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

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

Gvoke• FDA approval 9/2019• Glucagon in a prefilled

syringe or auto-injector

Baqsimi• FDA approval 7/2019• Glucagon nasal powder

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

Thank You!