Cardiovascular Benefits of Two Classes of Antihyperglycemic Medications

Cardiovascular Benefits of Two Classes of Antihyperglycemic Medications Nathan Woolever, Pharm.D., Resident Pharmacist Pharmacy Grand Rounds November 6 th, 2018 Franciscan Healthcare La Crosse, WI 2017 MFMER slide-1

Objectives Identify new recommendations from the 2018 Standards in Diabetes Care guideline issued by the American Diabetes Association List three medications belonging to the GLP-1 receptor agonist or SGLT-2 receptor antagonist classes that have demonstrated cardiovascular benefit Outline clinical trial data examining cardiovascular benefits of the GLP-1 agonist semaglutide Outline clinical trial data examining cardiovascular benefits of the SGLT-2 antagonist ertugliflozin GLP-1= glucagon-like peptide-1 SGLT-2=sodium-glucose co-transporter-2 2017 MFMER slide-2

Diabetes epidemiology 30.3 Million Americans (9.4%) had diabetes in 2015 Most are type 2 diabetes Estimated 7.2 Million cases undiagnosed 1.5 Million new cases every year 7 th Leading cause of death in the US $327 Billion total cost of diagnosed diabetes in 2017 American Diabetes Association, http://www.diabetes.org/diabetes-basics/statistics/, accessed 10/15/18 2017 MFMER slide-3

Cardiovascular complications of diabetes Microvascular complications Retinopathy Nephropathy Neuropathy Macrovascular complications Stroke Heart disease Peripheral vascular disease 2017 MFMER slide-4

Causes of death for patients with diabetes Die at higher rates than non-diabetics, even after adjusted for competing risk factors Coronary Heart Disease HR 2.87 (95%CI 2.26-3.64) Stroke HR 2.26 (95%CI 1.61-3.18) Heart Failure HR 1.77 (95%CI 1.08-2.89) HR=Hazard ratio CI=Confidence interval Baena-díez JM,et., Diabetes Care. 2016;39(11):1987-1995 2017 MFMER slide-5

2018 Standards in Diabetes Care Patient without documented ASCVD Metformin: Trial for 3 months with lifestyle changes Second agent : Any of 6 preferred classes ASCVD= atherosclerotic cardiovascular disease Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S3 Holman RR, et al., N Engl J Med. 2008;359(15):1577-1589 2017 MFMER slide-6

Preferred diabetes medications per American Diabetes Association Biguanides Basal Insulin Sulfonylureas SGLT-2 Inhibitors DPP-4 Inhibitors GLP-1 Agonists TZDs TZD=Thiazolidinedione SGLT-2= Sodium-glucose co-transporter 2 GLP-1= Glucagon-like peptide-1 2017 MFMER slide-7

2018 Standards in Diabetes Care Patient with documented ASCVD Metformin: Trial for 3 months with lifestyle changes Second agent: agent with evidence of CV risk reduction ASCVD= atherosclerotic cardiovascular disease CV=Cardiovascular Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S3 2017 MFMER slide-8

Medication Class Biguanide SGLT-2 Inhibitors GLP-1 Agonists DPP-4 Inhibitors TZDs Weight Change Neutral Loss Loss ASCVD Potential benefit Potential Benefit Potential Benefit CHF Neutral Potential Benefit Neutral Neutral Neutral Potential risk Gain Potential benefit Increased risk Sulfonylureas Gain Neutral Neutral CHF= Congestive heart failure ASCVD= Atherosclerotic cardiovascular disease SGLT-2= Sodium-glucose co-transporter-2 GLP-1= Glucagon-like peptide-1 DPP-4= Dipeptidyl peptidase 4 2017 MFMER slide-9

Medication Class Biguanide SGLT-2 Inhibitors GLP-1 Agonists DPP-4 Inhibitors TZDs Weight Change Neutral Loss Loss ASCVD Potential benefit Potential Benefit Potential Benefit CHF Neutral Potential Benefit Neutral Neutral Neutral Potential risk Gain Potential benefit Increased risk Sulfonylureas Gain Neutral Neutral CHF= Congestive heart failure ASCVD= Atherosclerotic cardiovascular disease SGLT-2= Sodium-glucose co-transporter-2 GLP-1= Glucagon-like peptide-1 DPP-4= Dipeptidyl peptidase 4 2017 MFMER slide-10

Glucagon-like peptide-1 agonists 2017 MFMER slide-11

GLP-1 Agonist class members All members are subcutaneous injections Exenatide (Byetta, Bydureon ) Dulaglutide (Trulicity ) Liraglutide (Victoza ) Lixisenatide (Adlyxin ) Semaglutide (Ozempic ) 2017 MFMER slide-12

GLP-1 Agonist mechanism of action Increased insulin secretion Decreased glucagon secretion Delayed gastric emptying Increased satiety Decreased hepatic glucose production Decreased food intake Improved blood glucose 2017 MFMER slide-13

GLP-1 agonist side effect profile Primarily gastrointestinal: nausea, vomiting, diarrhea Injection site reactions Acute pancreatitis Black box warning Medullary thyroid carcinoma Thyroid C-cell tumors 2017 MFMER slide-14

Cardiovascular outcomes: GLP-1 Agonists Liraglutide Semaglutide Exenatide Lixisenatide Pfeffer MA, et al., N Engl J Med. 2015;373(23):2247-2257 Marso SP, et al., N Engl J Med. 2016;375(4):311-322 Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844 Holman RR, et al., N Engl J Med. 2017;(13):1228-1239 2017 MFMER slide-15

Semaglutide (Ozempic ) FDA approved December 2017 Initiation: 0.25 mg weekly X 4 weeks Maintenance: 0.5 mg weekly 4 weeks Maintenance: 1.0 mg weekly Ozempic (semaglutide). Novo Nordisk Canada Inc; September 2018 2017 MFMER slide-16

SUSTAIN-6 Design Randomized, double-blind, multi-center, placebo-controlled trial Inclusion Criteria Patients (n=3297) with type 2 diabetes Hemoglobin A1c >7% Regimen 2 PO agents ± basal or premixed insulin Exclusion Criteria DPP-4 inhibitor within 30 days GLP-1 agonist or other insulin within 90 days ACS or CVA within 90 days Planned revascularization Intervention Semaglutide vs placebo Plus standard therapy DPP-4: Dipeptidyl peptidase 4 GLP-1: Glucagon-like peptide-1 ACS: Acute coronary syndrome CVA: cerebrovascular accident Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844 2017 MFMER slide-17

Primary Outcome Cardiovascular death Nonfatal myocardial infarction Nonfatal stroke MACE Secondary Outcomes Expanded composite cardiovascular outcome All cause death Retinopathy Neuropathy MACE = Major adverse cardiovascular event Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844 2017 MFMER slide-18

Outcome Semaglutide (n=1648) Placebo (n=1649) HR (95% CI) MACE 6.6% 8.9% 0.74 (0.58 0.95) Nonfatal Stroke 1.6% 2.7% 0.61 (0.38 0.99) Nephropathy 3.8% 6.1% 0.64 (0.46-0.88) Revascularization 5.0% 7.6% 0.65 (0.5-0.86) Retinopathy 3.0% 1.8% 1.76 (1.11 2.78) No significant difference in overall CV death, nonfatal MI, hospitalization for unstable angina, or hospitalization for heart failure HR=Hazard ratio Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844 2017 MFMER slide-19

The cardiovascular risk reduction exhibited by semaglutide is primarily due to which portion of the primary outcome? A. Non-fatal stroke B. Non-fatal myocardial infarction C. Cardiovascular death D. All of the above 2017 MFMER slide-20

The cardiovascular risk reduction exhibited by semaglutide is primarily due to which portion of the primary outcome? A. Non-fatal stroke B. Non-fatal myocardial infarction C. Cardiovascular death D. All of the above 2017 MFMER slide-21

Sodium-glucose co-transporter-2 inhibitors 2017 MFMER slide-22

SGLT-2 Inhibitor class members All members are oral, once-daily medications Canagliflozin (Invokana ) Dapagliflozin (Farxiga ) Empagliflozin (Jardiance ) Ertugliflozin (Steglatro ) SGLT-2=Sodium-glucose co-transporter 2 2017 MFMER slide-23

SGLT-2 mechanism of action SGLT-2 in proximal tubule Reabsorption of 90% of glucose Glucose returns to bloodstream SGLT-2=Sodium-glucose co-transporter 2 2017 MFMER slide-24

SGLT-2 mechanism of action SGLT-2 in proximal tubule SGLT-2 Inhibitor Reabsorption of 90% of glucose Glucose remains in urine to be excreted SGLT-2=Sodium-glucose co-transporter 2 2017 MFMER slide-25

SGLT-2 inhibitor side effect profile Genital fungal infections Urinary tract infections Fournier s gangrene Acute kidney injury Hypovolemia Bone fracture Increased rate of amputation SGLT-2=Sodium-glucose co-transporter 2 2017 MFMER slide-26

Cardiovascular outcomes: SGLT-2 Inhibitors Empagliflozin Canagliflozin Dapagliflozin Ertugliflozin Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128 Neal B, et al., N Engl J Med. 2017;377(7):644-657 2017 MFMER slide-27

Which one of the following agents has not yet shown cardiovascular risk reduction? A. Liraglutide (Victoza ) B. Semaglutide (Ozempic ) C. Empagliflozin (Jardiance ) D. Canagliflozin (Invokana ) E. All of the above have shown CV risk reduction 2017 MFMER slide-28

Which one of the following agents has not yet shown cardiovascular risk reduction? A. Liraglutide (Victoza ) B. Semaglutide (Ozempic ) C. Empagliflozin (Jardiance ) D. Canagliflozin (Invokana ) E. All of the above have shown CV risk reduction 2017 MFMER slide-29

EMPA-REG Design Randomized, double-blind, multi-center, placebo-controlled trial Inclusion Criteria Patients (n=7020) with type 2 diabetes and CVD Hemoglobin A1c >7% egfr >30 ml/min/1.72m 2 BMI 45 kg/m 2 Exclusion Criteria egfr <30 ml/min/1.72m 2 Uncontrolled hyperglycemia (>240 mg/dl) Cancer Bariatric surgery within 2 years Intervention Empagliflozin (10 mg or 25 mg) vs placebo Plus stabilized standard therapy CVD=Cardiovascular Disease Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128 2017 MFMER slide-30

Primary Outcome Cardiovascular death Nonfatal myocardial infarction Nonfatal stroke MACE Secondary Outcomes Expanded composite cardiovascular outcome Primary outcome + hospitalization for unstable angina MACE = Major adverse cardiovascular event Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128 2017 MFMER slide-31

Outcome Empagliflozin (n=1648) Placebo (n=1649) HR (95% CI) MACE 10.5% 12.1% 0.86 (0.74 0.99) Hospitalization for HF 2.7% 4.1% 0.65 (0.50 0.85) Death from CV causes 3.7% 5.9% 0.62 (0.49-0.77) No significant difference in revascularization, hospitalization for unstable angina, TIA, and fatal or nonfatal stroke HF=Heart failure CV=Cardiovascular HR=Hazard ratio Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128 2017 MFMER slide-32

VERTIS-CV Design Randomized, double-blind, multi-center, placebo-controlled trial Inclusion Criteria Patients (n=8246) type 2 diabetes and CVD Hemoglobin A1c 7-10.5% BMI 18 kg/m 2 Exclusion Criteria Planned revascularization Cardiovascular surgery within 90 days Class IV heart failure Intervention Ertugliflozin (5 mg or 15 mg) vs placebo Plus stabilized standard therapy CVD=Cardiovascular Disease Cannon CP, et al., Am Heart J. 2018;206:11-23 2017 MFMER slide-33

Primary Outcome (non-inferiority) Cardiovascular death Nonfatal myocardial infarction Nonfatal stroke MACE Secondary Outcomes (superiority) First event of CV death or hospitalization for HF CV death Renal death, dialysis, transplant, doubling of SCr MACE = Major adverse cardiovascular event CV=Cardiovascular SCr: Serum creatinine Cannon CP, et al., Am Heart J. 2018;206:11-23 2017 MFMER slide-34

Comparison of two SGLT-2 Inhibitors Outcome measure Ertugliflozin vs placebo Empagliflozin vs placebo 5 mg 15 mg 10 mg 25 mg SBP (mmhg) DBP (mmhg) Hemoglobin A1C (%) Body weight (kg) Fasting plasma glucose (mmol/l) -4.4-5.2-3.44-4.16-1.6-2.2-1.36-1.72-0.7-0.9-0.62-0.65-3.0-2.9-2.39-2.48-1.5-2.2-0.98-1.36 Rosenstock J, et al., Diabetes Obes Metab. 2018;20(3):520-529 Tikkanen I, et al., Diabetes Care. 2015;38(3):420-428 Rosenstock J, et al., Diabetes Care. 2014;37(7):1815-1823 2017 MFMER slide-35

Ertugliflozin has definitively shown cardiovascular risk reduction as shown by the data in the VERTIS-CV trial: True False 2017 MFMER slide-36

Ertugliflozin has definitively shown cardiovascular risk reduction as shown by the data in the VERTIS-CV trial: True False 2017 MFMER slide-37

50 year old male with type 2 diabetes diagnosed approximately 6 months ago. Lab results: Hemoglobin A1C: 8.0% FPG: 180 mg/dl Current medications: Metformin XR 2000 mg daily Atorvastatin 40 mg daily Aspirin 81 mg daily Lisinopril 20 mg daily Allopurinol 200 mg daily PMH: Hypertension CAD Gout Which medication is the best choice to add to metformin for further glycemic control in this patient as recommended by the America Diabetes Association? A. Semaglutide B. Empagliflozin C. Glipizide D. Either A or B 2017 MFMER slide-38

50 year old male with type 2 diabetes diagnosed approximately 6 months ago. Lab results: Hemoglobin A1C: 8.0% FPG: 180 mg/dl Current medications: Metformin XR 2000 mg daily Atorvastatin 40 mg daily Aspirin 81 mg daily Lisinopril 20 mg daily Allopurinol 200 mg daily PMH: Hypertension CAD Gout Which medication is the best choice to add to metformin for further glycemic control in this patient as recommended by the America Diabetes Association? A. Semaglutide B. Empagliflozin C. Glipizide D. Either A or B 2017 MFMER slide-39

On the horizon Ertugliflozin (Steglatro ) Cardiovascular outcomes VERTIS-CV trial in progress Oral semaglutide Phase 2 is complete Phase 3 trials ongoing Cannon CP, et al., Am Heart J. 2018;206:11-23 Davies M, et al., JAMA. 2017;318(15):1460-1470 Bain SC, et al., Diabetes Obes Metab. 2018 2017 MFMER slide-40

Summary ADA recommends second agent with CV benefit in patients with ASCVD Members of the SGLT-2 inhibitor and GLP-1 agonist classes offer CV benefits Semaglutide shows CV benefit but largely due to reduction in nonfatal stroke Ertugliflozin has performed similarly to empagliflozin thus far, but CV benefit data is pending 2017 MFMER slide-41

Questions & Discussion 2017 MFMER slide-42