©2017 MFMER | slide-1
Cardiovascular Benefits of Two Classes of AntihyperglycemicMedicationsNathan Woolever, Pharm.D., Resident Pharmacist
Pharmacy Grand RoundsNovember 6th, 2018
Franciscan Healthcare– La Crosse, WI
©2017 MFMER | slide-2
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
©2017 MFMER | slide-3
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
©2017 MFMER | slide-4
Cardiovascular complications of diabetes
• Microvascular complications• Retinopathy• Nephropathy• Neuropathy
• Macrovascular complications• Stroke• Heart disease• Peripheral vascular disease
©2017 MFMER | slide-5
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
©2017 MFMER | slide-6
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
©2017 MFMER | slide-7
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
©2017 MFMER | slide-8
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
©2017 MFMER | slide-9
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
©2017 MFMER | slide-10
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
©2017 MFMER | slide-11
Glucagon-like peptide-1 agonists
©2017 MFMER | slide-12
GLP-1 Agonist class members• All members are subcutaneous injections
• Exenatide (Byetta®, Bydureon®)• Dulaglutide (Trulicity®)• Liraglutide (Victoza®)• Lixisenatide (Adlyxin®)• Semaglutide (Ozempic®)
©2017 MFMER | slide-13
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
©2017 MFMER | slide-14
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-15
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
©2017 MFMER | slide-16
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
©2017 MFMER | slide-17
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
©2017 MFMER | slide-18
• Cardiovascular death• Nonfatal myocardial infarction• Nonfatal stroke
• Expanded composite cardiovascular outcome• All cause death• Retinopathy• Neuropathy
Primary Outcome
Secondary Outcomes
Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844
MACE
MACE = Major adverse cardiovascular event
©2017 MFMER | slide-19
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
Marso SP, et al,. N Engl J Med. 2016;375(19):1834-1844
HR=Hazard ratio
©2017 MFMER | slide-20
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
©2017 MFMER | slide-21
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
©2017 MFMER | slide-22
Sodium-glucose co-transporter-2 inhibitors
©2017 MFMER | slide-23
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
©2017 MFMER | slide-24
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-25
SGLT-2 mechanism of action
SGLT-2 in proximal tubule
Reabsorption of 90% of glucose
Glucose remains in urine to be excreted
SGLT-2=Sodium-glucose co-transporter 2
SGLT-2 Inhibitor
©2017 MFMER | slide-26
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-27
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
©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
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-30
Randomized, double-blind, multi-center, placebo-controlled trial
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
©2017 MFMER | slide-31
• Cardiovascular death• Nonfatal myocardial infarction• Nonfatal stroke
• Expanded composite cardiovascular outcome• Primary outcome + hospitalization for
unstable angina
Primary Outcome
Secondary Outcomes
Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128
MACE
MACE = Major adverse cardiovascular event
©2017 MFMER | slide-32
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
Zinman B, et al., N Engl J Med. 2015;373(22):2117-2128
HF=Heart failureCV=CardiovascularHR=Hazard ratio
©2017 MFMER | slide-33
Randomized, double-blind, multi-center, placebo-controlled trial
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
©2017 MFMER | slide-34
• Cardiovascular death• Nonfatal myocardial infarction• Nonfatal stroke
• 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
©2017 MFMER | slide-35
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
©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
Ertugliflozin has definitively shown cardiovascular risk reduction as shown by the data in the VERTIS-CV trial:
• True• False
©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. SemaglutideB. Empagliflozin
C. GlipizideD. Either A or B
©2017 MFMER | slide-39
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
©2017 MFMER | slide-40
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
©2017 MFMER | slide-41
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-42
Questions & Discussion