Cardiovascular Benefits of Two Classes of ...€¦ · ©2017 MFMER | slide-3 Diabetes epidemiology...

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Cardiovascular Benefits of Two Classes of AntihyperglycemicMedicationsNathan Woolever, Pharm.D., Resident Pharmacist

Pharmacy Grand RoundsNovember 6th, 2018

Franciscan Healthcare– La Crosse, WI


ObjectivesIdentify 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


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• 7th 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


Cardiovascular complications of diabetes

• Microvascular complications• Retinopathy• Nephropathy• Neuropathy

• Macrovascular complications• Stroke• Heart disease• Peripheral vascular disease


Causes of death for patients with diabetesDie 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 ratioCI=Confidence interval

Baena-díez JM,et., Diabetes Care. 2016;39(11):1987-1995


2018 Standards in Diabetes CarePatient without documented ASCVD

Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S3Holman RR, et al., N Engl J Med. 2008;359(15):1577-1589

Metformin: Trial for 3 months with lifestyle changes

Second agent : Any of 6 preferred classes

ASCVD= atherosclerotic cardiovascular disease


Preferred diabetes medications per American Diabetes Association

TZD=ThiazolidinedioneSGLT-2= Sodium-glucose co-transporter 2

GLP-1= Glucagon-like peptide-1

Biguanides

Sulfonylureas

DPP-4 Inhibitors

TZDsGLP-1 Agonists

SGLT-2 Inhibitors

Basal Insulin


2018 Standards in Diabetes CarePatient with documented ASCVD

Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S3

Metformin: Trial for 3 months with lifestyle changes

Second agent: agent with evidence of CV risk reduction

ASCVD= atherosclerotic cardiovascular diseaseCV=Cardiovascular


MedicationClass

WeightChange ASCVD CHF

Biguanide Neutral Potential benefit Neutral

SGLT-2Inhibitors Loss Potential

Benefit Potential Benefit

GLP-1Agonists Loss Potential

Benefit Neutral

DPP-4Inhibitors Neutral Neutral Potential risk

TZDs Gain Potentialbenefit Increased risk

Sulfonylureas Gain Neutral Neutral

CHF= Congestive heart failureASCVD= Atherosclerotic cardiovascular disease SGLT-2= Sodium-glucose co-transporter-2

GLP-1= Glucagon-like peptide-1DPP-4= Dipeptidyl peptidase 4


MedicationClass

WeightChange ASCVD CHF

Biguanide Neutral Potential benefit Neutral

SGLT-2Inhibitors Loss Potential

BenefitPotential Benefit

GLP-1Agonists Loss Potential

Benefit Neutral

DPP-4Inhibitors Neutral Neutral Potential risk

TZDs Gain Potentialbenefit Increased risk

Sulfonylureas Gain Neutral Neutral

GLP-1= Glucagon-like peptide-1DPP-4= Dipeptidyl peptidase 4

CHF= Congestive heart failureASCVD= Atherosclerotic cardiovascular disease SGLT-2= Sodium-glucose co-transporter-2


Glucagon-like peptide-1 agonists


GLP-1 Agonist class members• All members are subcutaneous injections

• Exenatide (Byetta®, Bydureon®)• Dulaglutide (Trulicity®)• Liraglutide (Victoza®)• Lixisenatide (Adlyxin®)• Semaglutide (Ozempic®)


GLP-1 Agonist mechanism of action

Improved blood glucose

Decreased hepatic glucose

productionDecreased food intake

Increased insulin

secretion

Decreased glucagon secretion

Increased satiety

Delayed gastric

emptying


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


Cardiovascular outcomes: GLP-1 Agonists

Pfeffer MA, et al., N Engl J Med. 2015;373(23):2247-2257Marso SP, et al., N Engl J Med. 2016;375(4):311-322

Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844Holman RR, et al., N Engl J Med. 2017;(13):1228-1239

LiraglutideSemaglutide

ExenatideLixisenatide


Semaglutide (Ozempic®)FDA approved December 2017

Ozempic (semaglutide). Novo Nordisk Canada Inc; September 2018

Initiation: 0.25 mg weekly X 4 weeks

Maintenance: 0.5 mg weekly ≥ 4 weeks

Maintenance: 1.0 mg weekly


Randomized, double-blind, multi-center, placebo-controlled trial

SUSTAIN-6 Design

• Patients (n=3297) with type 2 diabetes • Hemoglobin A1c >7%• Regimen ≤2 PO agents ± basal or premixed insulin

Inclusion Criteria

Semaglutide vs placeboPlus standard therapyIntervention

• DPP-4 inhibitor within 30 days• GLP-1 agonist or other insulin within 90 days• ACS or CVA within 90 days• Planned revascularization

ExclusionCriteria

Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844

DPP-4: Dipeptidyl peptidase 4GLP-1: Glucagon-like peptide-1ACS: Acute coronary syndromeCVA: cerebrovascular accident


• Cardiovascular death• Nonfatal myocardial infarction• Nonfatal stroke

• Expanded composite cardiovascular outcome• All cause death• Retinopathy• Neuropathy

Primary Outcome

Secondary Outcomes


MACE

MACE = Major adverse cardiovascular event


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


The cardiovascular risk reduction exhibited by semaglutide is primarily due to which portion of the primary outcome?

A. Non-fatal strokeB. Non-fatal myocardial infarctionC. Cardiovascular deathD. All of the above


Sodium-glucose co-transporter-2 inhibitors


SGLT-2 Inhibitor class membersAll members are oral, once-daily medications

• Canagliflozin (Invokana®)• Dapagliflozin (Farxiga®)• Empagliflozin (Jardiance®)• Ertugliflozin (Steglatro®)

SGLT-2=Sodium-glucose co-transporter 2


SGLT-2 mechanism of action

SGLT-2 in proximal tubule

Reabsorption of 90% of glucose

Glucose returns to bloodstream



SGLT-2 mechanism of action

SGLT-2 in proximal tubule

Reabsorption of 90% of glucose

Glucose remains in urine to be excreted


SGLT-2 Inhibitor


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



Cardiovascular outcomes: SGLT-2 Inhibitors

Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128Neal B, et al., N Engl J Med. 2017;377(7):644-657

EmpagliflozinCanagliflozin

DapagliflozinErtugliflozin


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



EMPA-REG Design

• Patients (n=7020) with type 2 diabetes and CVD • Hemoglobin A1c >7%• eGFR >30 mL/min/1.72m2

• BMI ≤ 45 kg/m2

Inclusion Criteria

Empagliflozin (10 mg or 25 mg) vs placeboPlus stabilized standard therapyIntervention

• eGFR <30 mL/min/1.72m2

• Uncontrolled hyperglycemia (>240 mg/dL)• Cancer• Bariatric surgery within 2 years

ExclusionCriteria

Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128

CVD=Cardiovascular Disease



• Expanded composite cardiovascular outcome• Primary outcome + hospitalization for

unstable angina

Primary Outcome

Secondary Outcomes


MACE

MACE = Major adverse cardiovascular event


Outcome Empagliflozin(n=1648)

Placebo(n=1649) HR (95% CI)

MACE 10.5% 12.1% 0.86 (0.74 – 0.99)

Hospitalizationfor 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 failureCV=CardiovascularHR=Hazard ratio



VERTIS-CV Design

• Patients (n=8246) type 2 diabetes and CVD • Hemoglobin A1c 7-10.5%• BMI ≥ 18 kg/m2

Inclusion Criteria

Ertugliflozin (5 mg or 15 mg) vs placeboPlus stabilized standard therapyIntervention

• Planned revascularization• Cardiovascular surgery within 90 days• Class IV heart failure

ExclusionCriteria

Cannon CP, et al., Am Heart J. 2018;206:11-23

CVD=Cardiovascular Disease



• First event of CV death or hospitalization for HF• CV death• Renal death, dialysis, transplant, doubling of SCr

Primary Outcome (non-inferiority)

Secondary Outcomes (superiority)

Cannon CP, et al., Am Heart J. 2018;206:11-23

MACE

MACE = Major adverse cardiovascular eventCV=CardiovascularSCr: Serum creatinine


Comparison of two SGLT-2 Inhibitors

Rosenstock J, et al., Diabetes Obes Metab. 2018;20(3):520-529Tikkanen I, et al., Diabetes Care. 2015;38(3):420-428

Rosenstock J, et al., Diabetes Care. 2014;37(7):1815-1823

Outcomemeasure

Ertugliflozin vs placebo Empagliflozin vs placebo

5 mg 15 mg 10 mg 25 mg

SBP (mmHg) -4.4 -5.2 -3.44 -4.16

DBP (mmHg) -1.6 -2.2 -1.36 -1.72

HemoglobinA1C (%) -0.7 -0.9 -0.62 -0.65

Body weight (kg) -3.0 -2.9 -2.39 -2.48

Fasting plasmaglucose (mmol/L)

-1.5 -2.2 -0.98 -1.36


Ertugliflozin has definitively shown cardiovascular risk reduction as shown by the data in the VERTIS-CV trial:

• True• False


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. SemaglutideB. Empagliflozin

C. GlipizideD. Either A or B


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;206:11-23Davies M, et al., JAMA. 2017;318(15):1460-1470

Bain SC, et al., Diabetes Obes Metab. 2018


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


Questions & Discussion

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