cv implications dm - university of nebraska medical center...ó l ó l î ì í õ ð 0hglfdwlrqv...

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7/7/2019

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Cardiovascular Implications in Patients

with DiabetesJuly 11, 2019

Jayme Anderson, PharmD., BCPS

Disclosure

I have no financial relationship with any pharmaceutical companies, biomedical device manufacturers or distributors, or others whose products or services may be considered related to the content of this presentation.

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Learning objectives

1. Evaluate the cardiovascular (CV) consequences of diabetes

2. Describe the role of glucose-lowering medications in reducing the risk of CV outcomes in patients with diabetes

3. Design patient-specific treatment plans for patients with diabetes to help reduce CV risk

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CV Complications and Diabetes

Atherosclerotic cardiovascular disease (ASCVD)

– Cerebrovascular disease, coronary heart disease, peripheral artery disease

– Leading reason for yearly healthcare expenditures in diabetic patients

– Presence of co-morbidities can increase this risk further• Dyslipidemia• Hypertension• Kidney disease• Obesity

Rates of morbidity and mortality ↓– ….but still room for improvement!

4 American Diabetes Association. Dia Care 2019;42:S103-123.

CV Complications and DiabetesMicrovascular complications

– Kidney disease• Diabetes-related in up to 40% of cases• Typically develops later in type 1 vs type 2

– Neuropathy• May be asymptomatic in some patients• Goals differ based on type of diabetes

o Type 1 = prevent developmento Type 2 = slow progression

– Retinopathy• Can be as a result of dyslipidemia, hypertension or nephropathy

Microvascular complications can be prevented or reduced with glycemic control!


CV Complications and DiabetesMacrovascular complications

– Atherosclerotic• CV death• Coronary heart disease• Myocardial infarction (MI)• Stroke

– Heart failure (HF)• Preserved or reduced ejection fraction• Up to 2x ↑ hospitalizations

Overall, less impacted by glucose control– Type 1

• Intensive blood glucose control has shown sustained effects• May ↓ all-cause mortality

– Type 2• Intensive blood glucose control will not benefit all patients• Some ↓ in event rates, no clear mortality benefit


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Reducing the Complication RiskRisk calculators

– American College of Cardiology/American Heart Association (http://tools.acc.org/ASCVD-Risk-Estimator-Plus)

• Incorporates age, diabetes status, dyslipidemia, hypertension, medications, race, sex, smoking status

• Does NOT account for complications or disease length• May help inform treatment decisions

Risk factor modification– Lifestyle modification

• Diet• Exercise• Smoking cessation• Weight loss

– Management of co-morbidities• Dyslipidemia/hypertriglyceridemia• Hypertension• Insulin resistance

72019 ACC/AHA guideline on the primary prevention of CV disease. doi:10.1161/CIR.0000000000000678.AACE/ACE comprehensive type 2 diabetes management algorithm. Endocr Pract: 2019;25(10):pp 69-100

Medications and CV RiskDiabetics carry a high CV risk

– Avoid medications that ↑ CV risk– Example: rosiglitazone

• Data pointing to worsened cardiac outcomes FDA REMS program• Later removed restrictions

How do we know that diabetic medications are safe?– 2008 FDA guidance

• required Cardiovascular Outcomes Trials (CVOTs)• 3 point MACE: CV death, MI, stroke

o +/- hospitalization for acute coronary syndrome, revascularization, etc.• Study must include those with:

o ↑ CV risk, elderly patients, renal impairment– Data analysis of CVOTs

• Before approval: upper limit of two-sided 95% confidence interval <1.8• After approval: upper limit of two-sided 95% confidence interval <1.3

o Additional studies may be required

8FDA. Guidance for industry: evaluating CV risk in new antidiabetic therapies to treat T2DM (internet).

CVOT in T2DM: Where Do We Go From Here? Dia Care 2018;41:14-31.

CVOT Timeline

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ELIXA, EMPA-REG OUTCOME,

EXAMINE, SAVOR-TIMI 53, TECOS

ACE, CANVAS, CARMELINA, DEVOTE,

EXSCEL, FREEDOM-CVO, IRIS,

LEADER, SUSTAIN-6

PIONEER 6, HARMONY OUTCOMES, REWIND, VERTIS CV, Dapa-HF,

CAROLINA, DECLARE-TIMI 58, CREDENCE, EMPEROR-

Preserved, EMPEROR-Reduced, Dapa-CKD

2013-2015 2016-20172018-

Present


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Medications for Diabetes

Pharmacology and Cardiovascular Outcome Data

Metformin

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Medication Class:– Biguanide

Mechanism of action:– Effects on glucose =

• ↓ production (liver)• ↓ absorption (intestine)• ↑ uptake + utilization (improving insulin sensitivity)

Cardiovascular safety: exempted from mandatory trials, no consistent significance reported

Pearls– Ok to use in stable HF– Lactic acidosis – keep risk factors in mind– Renal dosing

• Cautious dose titration with eGFR < 60o eGFR 45-60 (consider max 2 grams/day)o eGFR 30-45 (consider max 1 gram/day)

• Contraindicated with eGFR <30 mL/min/1.73 m2

1st line therapy for Type 2 diabetes

2019 ACC/AHA guideline on the primary prevention of CV disease. doi:10.1161/CIR.0000000000000678.Lexi-Drugs®, Hudson, Ohio:; July 3, 2019.

Dipeptidyl peptidase 4 (DPP-4) inhibitors

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Mechanism of action:– ↑ incretin hormones

• ↓ glucagon– Effects on glucose = ↓ production (liver)

Warnings/precautions:– Pancreatitis– HF – alogliptin, saxagliptin not recommended

Pearls– Linagliptin – no renal adjustment– Evidence showing benefit for inpatient use as well

Lexi-Drugs®, Hudson, Ohio:; July 3, 2019.

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DPP-4 CVOTs

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Trial Name DPP-4 inhibitor MACE Outcome Notes

CAROLINA linagliptin Non-inferiority Initial resultsActive comparator

CARMELINA linagliptin Non-inferiority + kidney outcome (NS)

TECOS sitagliptin Non-inferiority Ø superiority

SAVOR-TIMI saxagliptin Non-inferiority HR 1.27, p=0.007 (HF)

EXAMINE alogliptin Non-inferiority Included ACS within 90 daysHR 1.19 (HF)

Boehringer Ingelheim. CAROLINA®. Accessed July 2, 2019.CVOT in T2DM: Where Do We Go From Here? Dia Care 2018;41:14-31.

CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79.

Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RA)

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Mechanism of action:– Incretin hormone, GLP-1

• ↓ glucagon– ↑ gastric transit time– ↑ B-cell growth– Effects on glucose = ↓ production (liver)

Dosage form: subcutaneous injection

Warnings/precautions:– ↑ heart rate noted in several studies– Boxed warning for C-cell thyroid malignancy

Pearls– VERY high incidence of gastrointestinal side effects

• Improve with time– Pharmacokinetic factors differ and should be considered– Can aid in blood pressure control, weight loss

CVOT in T2DM: Where Do We Go From Here? Dia Care 2018;41:14-31.Lexi-Drugs®, Hudson, Ohio:; July 3, 2019.

GLP-1 RA CVOTs

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Trial Name GLP-1 RA MACE Outcome Notes

REWIND dulaglutide Non-inferiority <1/3 patients w/CV disease

HARMONYOutcomes

albiglutide* Non-inferiority Superiority (↓ MI)

PIONEER 6 semaglutide Non-inferiority ORAL semaglutide

EXSCEL ER exenatide Non-inferiority “usual care setting”43% discontinuation

SUSTAIN-6 semaglutide Non-inferiority No superiority testing in protocol

LEADER liraglutide Non-inferiority Superiority (↓ CV death, all-cause

mortality)

ELIXA lixisenatide Non-inferiority 4 point MACE

*Not currently available in U.S.CVOT in T2DM: Where Do We Go From Here? Dia Care 2018;41:14-31.

REWIND. Lancet. [e-pub ahead of print June 10, 2019].Andrikou E et al. doi:10.1016/j.hjc.2018.11.008.

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Sodium-Glucose Cotransporter 2 inhibitors (SGLT-2)

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Mechanism of action:– Effects on glucose = ↓ reabsorption (kidneys)

• Excreted in urine• ↓ overall glucose levels

Warnings/precautions:– Fournier’s gangrene– Genital mycotic infections– Ketoacidosis

Pearls– Review concomitant medications and volume status

• Hypotension risk (BP meds, diuretics)– Contraindicated eGFR <30 mL/min/1.73 m2

• Recommendations for eGFR between 45-60 mL/min/1.73 m2 vary– Take in morning

Lexi-Drugs®, Hudson, Ohio:; July 3, 2019.

SGLT-2 CVOTs

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Trial Name SGLT-2 MACE Outcome Notes

CREDENCE canagliflozin N/A Combined renal + CV outcome; trial stopped

earlySignificant 30%

reduction

DECLARE-TIMI 58 dapagliflozin Non-inferiority ↓ CV death/ HF hospitalization

CANVAS canagliflozin Non-inferiority Long duration diabetes2- phases data

↑ LDL cholesterol

EMPA-REG empagliflozin Non-inferiority BMI ≤45Superiority (38% RR,

p<0.001)↓ CV death (p=0.001)↓ HF hospitalization

CVOT in T2DM: Where Do We Go From Here? Dia Care 2018;41:14-31.Canagliflozin and renal outcomes in T2DM and nephropathy. NEJM. 2019;380(24):2295-2306.

Dapagliflozin and CV outcomes in T2DM. NEJM. 2019;380(4):347-357.

SGLT-2: Current Trials

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Trial Name SGLT-2 Expected End Date

Dapa-CKD dapagliflozin November 2020

EMPEROR-Preserved empagliflozin November 2020

EMPEROR- Reduced empagliflozin July 2020

VERTIS CV ertugliflozin December 2019

Dapa-HF Dapagliflozin July 2019


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SGLT-2s: HF and Renal Outcomes

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HF– 3 studies- combined analysis:

• EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58

• ↓ HF hospitalization 31%(~30% with ASCVD)

• HF outcomes improved most with↓ renal function

– CREDENCE• Secondary outcome• Significantly ↓ (p<0.001)

Renal– 3 studies- combined analysis:

• EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58

o ↓ renal outcomes by 45% (p<0.0001)

o Greater impact in higher eGFR groups

• CREDENCEo ↓ renal outcome 34%

(p<0.001)o Significantly ↓ rates of

end-stage renal disease and SCr doubling p=0.002, p<0.001

respectively

Canagliflozin and renal outcomes in T2DM and nephropathy. NEJM. 2019;380(24):2295-2306.Zelniker TA et al. Lancet 2019;393:31-39.

Bottom Line– Current data is very promising– Several trials in progress

• Further define patients that will derive greatest benefit

Thiazolidinediones (TZDs)

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Mechanism of action:– ↑ insulin sensitivity

• Peroxisome proliferator-activated receptor-gamma

Warnings/precautions:– Can worsen HF symptoms (fluid retention)

• Contraindicated in advanced HF– Possible weight gain– Bone fracture (osteoporosis)– Caution with elevated liver enzymes

Cardiovascular safety: some evidence of + CV benefit; can exacerbate HF

Pearls– Affordable– Typically efficacious at lower doses


Kernan WN et al. NEJM 2016;374(14):1321-1331.

Sulfonylureas

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Mechanism of action:– ↑ insulin release

• Pancreatic islet cells• ↑ insulin sensitivity

– Effects on glucose = ↓ production (liver)

Warnings/precautions:– Hypoglycemia– Possible weight gain– Caution with hepatic or renal impairment– Contraindicated in diabetic ketoacidosis

Cardiovascular safety: conflicting CV data; used as comparator in CAROLINA

Pearls– Efficacy may wane over time– Shorter acting agents preferred in geriatric patients


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Meglitinides

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Mechanism of action:– ↑ insulin production (glucose dependent)

• Pancreatic beta cells• Targets post-prandial blood glucose

Warnings/precautions:– Hypoglycemia– Some infection risk (respiratory and other)– Caution with hepatic or renal impairment– Contraindicated in diabetic ketoacidosis

Cardiovascular safety: no evidence of CV benefit

Pearls– For use ≤ 30 minutes of eating– Efficacy may wane over time


Alpha-glucosidase inhibitors

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Mechanism of action:– Slows carbohydrate absorption and breakdown

• Small intestine• Targets post-prandial blood glucose

Warnings/precautions:– Caution with hepatic or renal impairment

• Contraindicated in cirrhotic patients• May cause elevations of hepatic enzymes

– Contraindicated with bowel disease or intestinal obstruction

Cardiovascular safety: ACE trial (acarbose) – no evidence of significant CV benefit

Pearls– Take with food– Gastrointestinal side effects improve with time


Insulin

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Mechanism of action:– Breaks down amino acids, promotes fat metabolism

• Pancreatic islet cells– ↓ protein metabolism (promotes synthesis)– Effects on glucose

• ↓ production (liver)• Promotes uptake

Warnings/precautions:– Hypoglycemia– Weight gain

Cardiovascular safety: no evidence of CV benefit

Pearls– Rotate sites to avoid lipodystrophy– Variety of products/formulations – select agent based on cost and patient needs


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Summary of CV data

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CV Benefit CV Neutral Possible Harm (HF)

canagliflozin DPP-4s (- alogliptin, saxagliptin)

alogliptin

empagliflozin insulins saxagliptin

albiglutide exenatide TZDs

liraglutide lixisenatide

semaglutide Other 2nd line agents


Selecting Treatment Based on CV Risk

Practicing Evidence-Based Medicine

Establish Care Goals

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A1c goal

Patient factors

Therapy plan


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Setting A1c Goal

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Patient history– How long has the patient had diabetes?– Does the patient have any co-morbidities that ↑ CV risk?– Are any complications of diabetes present?

Patient’s view– Age– Life expectancy– Quality of life

Personalized goal– Younger patients with earlier disease more aggressive target– Older patients with co-morbidities and complications consider higher goal

American Diabetes Association. Dia Care 2019;42:S103-123.

Selecting Optimal Medication(s)

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Patient factors– Ability to follow prescribed regimen– Co-morbidities– Cost– Support

Professional guidance– American Diabetes Association– American Association of Clinical Endocrinologists (AACE)/American College of

Endocrinology (ACE)

Medications– Best medication(s) to meet patient needs– Benefits vs risks

American Diabetes Association. Dia Care 2019;42:S103-123.

30 American Diabetes Association. Dia Care 2019;42:S90-S102

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AACE/ACE

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Co-morbidities– Separate algorithms with recommendations for dyslipidemia, hypertension,

obesity• ACEi/ARB• Statin• Additional therapies as needed

Initial therapy– Recommendations based on “entry A1c”

• Single, dual, triple therapy– DPP-4, GLP-1 RA, SGLT-2 highly recommended

Medications– Great summary table to help consider which agent is best for patient

• Color coded

AACE/ACE comprehensive type 2 diabetes management algorithm. Endocr Pract: 2019;25(10):pp 69-100

Patient Case

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D.D. is a 63 year old male with Type 2 Diabetes Mellitus. He received the diagnosis 12 years ago. D.D. is a smoker and has hypertension, hyperlipidemia and obesity (BMI 31). His current regimen includes metformin and glipizide. He takes an ACEi and statin to manage his co-morbidities, but reports that he struggles to follow his prescribed diet and exercise regimen.

– D.D. overall feels well today, but reports some recent episodes of hypoglycemia. He reports being diagnosed with heart failure in the past week. Upon chart review, his most recent A1c is 8.5%

1. What are D.D.’s ASCVD risk factors?

Patient Case

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1. What are D.D.’s ASCVD risk factors?

AgeDiabetes

Hyperlipidemia

Hypertension

Obesity

Smoking

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Patient Case

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D.D. is a 63 year old male with Type 2 Diabetes Mellitus. He received the diagnosis 12 years ago. D.D. is a smoker and has hypertension, hyperlipidemia and obesity (BMI 31). His current regimen includes metformin and glipizide. He takes an ACEi and statin to manage his co-morbidities, but reports that he struggles to follow his prescribed diet and exercise regimen.

– D.D. feels overall well today, but reports some recent episodes of hypoglycemia. He reports being diagnosed with heart failure in the past week. Upon chart review, his most recent A1c is 8.5%

2. What are the key aspects of the therapy plan that need to be considered?

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A1c goal

Patient factors

Therapy plan

Set personalized A1c goal– May consider less stringent goal

• Hypoglycemia• Duration of disease

Patient factors– Assess co-morbidities and complications– Address lifestyle modifications

Medications– Costs– Best medication regimen for patient needs

Patient Case

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His current regimen includes metformin and glipizide - recent episodes of hypoglycemia- recently diagnosed HF- A1c is 8.5%

Continue metformin unless patient experiences HF exacerbation, advanced HF or meets other contraindication criteria. Ensure dose is optimized.

Consider changing patient’s glipizide (sulfonylurea) to empagliflozin (SGLT-2) for improved CV and HF benefits.

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Keys to Success

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Use a multidisciplinary approach!– Diabetes education– Nutrition– Other providers/healthcare professionals

Empower the patient!– Involve them in decision making– Inform them

• Medication counseling• Side effect management• What to do if financial issues arise

– Stress importance of managing co-morbidities• Lifestyle changes (diet, exercise, smoking cessation)

– Establish support system

Re-evaluate– Lifestyle management– Medications

• If adjustments are needed, consider combination therapy• Don’t jump straight to insulin

Remember, this is a continuous process!

AACE/ACE comprehensive type 2 diabetes management algorithm. Endocr Pract: 2019;25(10):pp 69-100American Diabetes Association. Dia Care 2019;42:S103-123.

38 American Diabetes Association. Dia Care 2019;42:S34-S45

Cardiovascular Implications in Patients

with DiabetesJuly 11, 2019

Jayme Anderson, PharmD., BCPS

7/7/2019

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References

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1. American Diabetes Association – Standards of Medical Care in Diabetes – 2019. Diabetes Care 2019 Jan; 42(Supplement 1):S29-138.

2. Andrikou E, Tsioufis C, Andrikou I, et al. GLP-1 receptor agonists and cardiovascular outcome trials: An update. Hellenic Journal of Cardiology. 2018. doi:10.1016/j.hjc.2018.11.008.

3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;000:e26-28. doi:10.1161/CIR.0000000000000678.

4. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105-113. doi:10.1016/S2213-8587(17)30412-6.

5. Boehringer Ingelheim. CAROLINA®: evaluating the long-term CV safety profile of linagliptin versus glimepiride in patients with early T2D at increased CV risk. 2019. Available at https://www.carmelinatrial.com/carolina-trial.html. Accessed July 2, 2019.

6. Cefalu WT, Kaul S, Gerstein HC et al. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum. Diabetes Care 2018;41:14-31. doi:10.2337/dci17-0057.

7. Garber AJ, Abrahamson MJ, Barzilay JI et al. 2019 Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm-2019 executive summary. Endocrine Practice: January 2019;25(10:pp 69-100. doi:10.4158/CS-2018-0535.

8. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. [e-pub ahead of print June 10, 2019]. doi:10.1016/S0140-6736(19)31149-3.

9. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374(14):1321-1331. doi:10.1056/NEJMoa1506930.

10. Lexi-Comp Online® , Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; July 3, 2019.11. Li YR, Tsai SS, Chen DY, et al. Linagliptin and cardiovascular outcomes in type 2 diabetes after acute coronary

syndrome or acute ischemic stroke. Cardiovasc Diabetol. 2018;17:2. doi:10.1186/s12933-017-0655-y.12. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J

Med 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744.13. U.S. Food and Drug Administration. Guidance for industry: diabetes mellitus – evaluating cardiovascular risk in new

antidiabetic therapies to treat type 2 diabetes (internet). Available from www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed July 1, 2019.

14. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of Linaglipitin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269.

15. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389.

16. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39. doi:10.1016/S0140-6736(18)32590-X.

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