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Case Studies in Type 2 Diabetes Mellitus: Focus on

Cardiovascular Outcomes TrialsLouis Kuritzky MD

Clinical Assistant Professor Emeritus

Department of Community Health and Family Medicine

College of Medicine

University of Florida, Gainesville

Statement of Sponsorship and Support

This CME Symposium is sponsored by

and supported by an educational grant from Janssen Pharmaceuticals, Inc., administered by Janssen Scientific Affairs, LLC.

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CME InformationThis Live activity, Case Studies on Type 2 Diabetes Mellitus: Focus on Cardiovascular Outcomes Trials, from 05/01/2018 -04/30/2019, has been reviewed and is acceptable for up to 1.00 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Faculty Disclosure StatementPrimary Care Education Consortium adheres to the conflict of interest policy

of the ACCME and the AMA. It is the policy of PCEC to ensure balance,

independence, objectivity, and scientific rigor in all of its educational

activities. All individuals in a position to control the content in our programs

are expected to disclose any relationships they may have with commercial

companies whose products or services may be mentioned so that

participants may evaluate the objectivity of the presentations. In addition,

any discussion of off-label, experimental, or investigational use of drugs or

devices will be disclosed by the faculty. Only those participants who have no

conflict of interest or who agree to an identified resolution process

prior to their participation were involved in the CME activity.

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Disclosures

Louis Kuritzky, MD, has no real or apparent conflicts of interest to report.

Gregory Scott, PharmD, RPh, Editorial Support, has no real or apparent conflicts of interest to report.

Learning ObjectivesAfter participating in this symposium, the learner will be able to:

• Characterize type 2 diabetes as a cardiovascular risk factor

• Differentiate traditional clinical outcomes trials from cardiovascular outcome trials

• Describe the results of cardiovascular outcome trials regarding cardiovascular safety

• Describe the results of cardiovascular outcome trials regarding cardiovascular benefit

• Integrate all available evidence, guideline recommendations, and approved product labeling in individualizing therapy

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In patients with type 2 diabetes mellitus, the primary treatment goal is to control/reduce:1. Blood glucose

2. Blood lipid

3. Blood pressure

4. Cardiovascular risk

?

The goal of cardiovascular safety trials is to demonstrate that the CV safety of the new therapy is

1. similar to placebo

2. similar to metformin

3. superior to placebo

4. superior to metformin

?

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Medications in which two classes have been shown to reduce the risk of cardiovascular events compared to placebo as part of standard care?

1. Sulfonylurea and DPP-4i

2. DPP-4i and SGLT-2i

3. SGLT-2i and GLP-1RA

4. GLP-1RA and meglitinide

?

Diabetes Mellitus as a Cardiovascular Risk Factor

0

5

10

15

20

25

30

35

40

45

Coronary HeartDisease

AtherothromboticBrain Infarction

IntermittentClaudication

Congestive HeartFailure

CardiovascularDeath

CardiovascularDisease

Annual age‐adjusted

 event rate per 1000

Framingham Heart Study

Women without Diabetes Women with Diabetes

Men without Diabetes Men with Diabetes

Kannel WB, McGee DL. JAMA. 1979;241:2035‐2038.

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UKPDS: 1% HbA1c Decrease and Reduced Risk of Complications

UKPDS, United Kingdom Prospective Diabetes Study

Stratton IM, et al. BMJ. 2000;321:405‐412.

43% 37% 19% 16% 14% 12%

Lower‐extremity amputation or fatal peripheral vascular 

disease(P<0.0001)

Microvascular disease(P<0.0001)

Cataract extraction(P<0.0001)

Heart failure(P<0.05)

Myocardial infarction(P<0.0001)

Stroke(P<0.05)

Cardiovascular complications

Recommended Targets for Adults with T2DM

1. American Diabetes Association. Diabetes Care. 2018;41(Suppl 1):S1‐S159.2. Garber AJ, et al. Endocr Pract. 2018;24(1):91‐120.3. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1‐87.

ADA1 AACE2,3

HbA1c < 7.0%* 6.5% (Individualize)

Pre-prandial plasma glucose 80–130 mg/dL* ≤ 100 mg/dL

Peak post-prandial glucose† < 180 mg/dL* ≤ 140 mg/dL

Blood pressure < 140/90 mm Hg < 130/80 mm Hg

LDL Cholesterol < 100 mg/dL< 100mg/dL (high risk)

< 70 mg/dL (very high risk)

Triglycerides < 150 mg/dL < 150 mg/dL

HDL Cholesterol≥ 40 mg/dL (male)

≥ 50 mg/dL (female)—

*More or less stringent glycemic goals may be appropriate for individual patients. Goals should be individualized based on duration of diabetes, age/life expectancy, comorbid conditions, known CVD or advanced microvascular complications, hypoglycemia unawareness, and individual patient considerations.†Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals. Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

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Approach to the Management of Hyperglycemia

low high

newly diagnosed long-standing

long short

absent severeFew/mild

absent severeFew/mild

highly motivated, adherent, excellent self-care capabilities

readily available limited

less motivated, nonadherent, poor self-care capabilities

A1C7%

more stringent

less stringentPatient/Disease Features

Risk of hypoglycemia/drug adverse effects

Disease Duration

Life expectancy

Important comorbidities

Established vascular complications

Patient attitude & expected treatment efforts

Resources & support system

Reproduced with permission of the American Diabetes Association. American Diabetes Association. Diabetes Care. 2018;41(Suppl 1):S55-S64. Available at: http://care.diabetesjournals.org/content/41/Supplement 1/S55.

Comprehensive Management of DiabetesTreating patients with T2DM is more than

blood glucose controlThere’s also:

• Antiplatelet therapy• Blood pressure• Cholesterol• Dietary changes• Exercise changes

And let’s not forget• Smoking• Weight• Regular examination of

• Eyes• Mouth/Teeth• Feet/Skin• Kidneys

Plus• Diabetes distress

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Type 2 Diabetes Mellitus• Type 2 diabetes mellitus is a

• chronic, progressive disease

• That requires• ongoing collaboration, education, and support

• To help patients• improve self-management

• With the goal of• reducing cardiovascular risk and

improving health outcomes

Case Scenario: Rafael

• 62 yo man diagnosed with T2DM 4 months ago (HbA1c 8.6%)

• 3-y history of LDL hyperlipidemia, hypertriglyceridemia

• Lifestyle + Metformin initiated 4 mos ago

• Currently• A1c 7.5%• BMI 31.4 kg/m2

• BP 134/86 mmHg• LDL-C 114 mg/dL• Triglycerides 320 mg/dL

• Medications• Metformin 1 g BID• HCTZ 25 mg QD• Enalapril 10 mg BID• Simvastatin 20 mg QD• ASA 81 mg QD

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Was metformin monotherapy the appropriate initial treatment for Rafael’s hyperglycemia?

1. Yes

2. No

3. It depends

?

Reprinted with permission from American Association of Clinical Endocrinologists © 2018 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2018. EndocrPract.2018;24: 91‐120.

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Antihyperglycemic Therapy in Adults with T2DM

Reproduced with permission of the American Diabetes Association. American Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73-S85. Available at: http://care.diabetesjournals.org/content/41/Supplement_1/S73.

Antihyperglycemic Therapy in Adults with T2DM

Reproduced with permission of the American Diabetes Association. American Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73-S85. Available at: http://care.diabetesjournals.org/content/41/Supplement_1/S73.

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Since Rafael has a HbA1c of 7.5%, which class of medication would you add to metformin?

1. DPP-4i

2. GLP-1RA

3. SGLT-2i

4. Sulfonylurea

5. Thiazolidinedione

?

Pathophysiologic Defects and Sites of Action of

Medications for T2DM

HYPERGLYCEMIA

Liver:  Hepatic glucosesecretion

Muscle andadipose tissue: Glucose uptake

CNS: Delayed satietyNeurotransmitterdysfunction Kidney:  Glucose

reabsorptionGut: Diminished incretin effect

Altered intestinal glucose absorption

Adipose tissue:  Lipolysis

DPP‐4iGLP‐1RA

GLP‐1RA

Bromocriptine

SGLT‐2i

TZD

DPP‐4iGLP‐1RA

Metformin

InsulinSU

Meglitinide

Pancreas↓ Insulin secre on↑ Glucagon secre on

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Antihyperglycemic Agents as Add-on to Metformin: Effect on HbA1c

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

TZD

SU

SGLT‐2i

GLP‐1RA

DPP‐4i

Additional HbA1c Reduction as Add‐on Therapy to Metformin

Bolen S, et al. Agency for Healthcare Research and Quality. https://www.effectivehealthcare.ahrq.gov/ehc/products/607/2215/diabetes‐update‐2016‐report.pdf. Accessed May 11, 2017.

Which of the following do you consider to be the most important in selecting further glucose-lowering treatment for Rafael?

1. Glucose-lowering efficacy

2. Risk of hypoglycemia

3. Impact on weight

4. Cardiovascular safety/benefit

5. Barriers to adherence

?

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Impact of Pioglitazone on Macrovascular Disease: PROactive

• 5238 patients with T2DM with macrovascular disease

• Randomized to• Pioglitazone 15-45 mg/d

• Placebo

• Continue baseline therapy

• Mean follow-up 34.5 months

0%

5%

10%

15%

20%

25%

Primary Endpoint SecondaryEndpoint

Heart Failure

Pioglitazone Placebo

Primary endpoint=all‐cause mortality, nonfatal MI, stroke, acute coronary syndrome, endovascular/surgical intervention in the coronary/leg arteries, amputation above ankle

Secondary endpoint=all‐cause mortality, nonfatal MI, stroke

HR=0.90P=0.095

HR=0.84P=0.027

Dormandy JA, et al for the PROactive Investigators. Lancet. 2005;366(9493):1279‐1289.

Risk of Cardiovascular Outcomes: Meta-Analysis of 42 Randomized Controlled Trials

1.14 1.131.241.42

2.78

5.37

1.80

1.221.43

1.64

0.00

1.00

2.00

3.00

4.00

5.00

6.00

Myocardial Infarction Cardiovascular Death

Odds Ratio Comparator vs Rosiglitazone

Risk of Cardiovascular Outcomes for Rosiglitazone vs Comparator Drugs

Metformin SU Insulin Placebo Combined

P=0.03P=0.06

None of the comparisons are statistically significant except ‘Combined’ for Myocardial Infarction

Nissen SE, et al. N Engl J Med. 2007;356(24):2457‐2571.

CV Risk Favors Comparator

CV Risk Favors Rosiglitazone

At baseline:Mean age 56 yMean HbA1c 8.2%

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FDA Diabetes Mellitus Guidance- 2008

US Food and Drug Administration. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed May 10, 2017.

FDA Diabetes Mellitus Guidance- 2008 (cont)

• Provides recommendations about how to demonstrate that a new antidiabetic therapy to treat T2DM is not associated with an unacceptable increase in CV risk

• That is, the new therapy is safe (noninferior to placebo)• It is also possible to demonstrate that the new therapy offers

CV benefit

• Assess major adverse CV events• CV death, nonfatal MI, nonfatal stroke• Other events possible

• Trial(s) should• include patients with T2DM at higher risk of CV events

• Advanced disease, advanced age, renal impairment

• be ≥2 years in duration

US Food and Drug Administration. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed May 10, 2017.

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Traditional Clinical Outcome Trial vs Diabetes Medication CV Safety Trial

• Traditional clinical outcome trial• CV risk of new treatment is significantly less than

comparator, ie, offers CV benefit

• Diabetes medication safety trial• CV risk of new treatment is non-inferior (similar) to

placebo

• If non-inferiority is demonstrated, the possible superiority (ie, CV benefit) of new treatment can be assessed

Nomenclature

• Primary end point:• Composite of: CV death, non-fatal MI, and non-fatal

stroke

• Heart failure hospitalization

• All cause death• Total number of deaths due to that condition during a

specific time. Death from any cause.

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Nomenclature (cont)

• Non-inferiority: No increase in CV risk compared to placebo

• Superiority: If non-inferiority is demonstrated, can look for superiority

• CV risk significantly reduced compared to placebo

Diabetes Medication CV Safety Trials

DPP‐4i GLP‐1RA SGLT‐2i

Alogliptin EXAMINE Albiglutide HARMONY

Canagliflozin

CANVAS

Linagliptin

CARMELINA Dulaglutide REWIND CANVAS‐R

CAROLINAExenatide QW

EXSCEL CREDENCE

SaxagliptinSAVOR‐TIMI53

Exenatide in EUROSa

ITCA 650 DapagliflozinDECLARE‐TIMI 58

Sitagliptin TECOS

Liraglutide LEADER EmpagliflozinEMPA‐REG OUTCOME

Lixisenatide ELIXAErtugliflozin VERTIS CV

Semaglutide SUSTAIN 6

NOTE: All trials are randomized, double‐blind, parallel, placebo‐controlled, multi‐center

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Medications Whose CV Safety Has Been Shown to Be Non-Inferior to Placebo

DPP‐4 Inhibitors GLP‐1 Receptor Agonists

SGLT‐2 Inhibitors

Alogliptin1

Saxagliptin2

Sitagliptin3

Exenatide QW4

Liraglutide5

Lixisenatide6

Semaglutide7

Canagliflozin8

Empagliflozin9

1. White WB, et al. N Engl J Med. 2013;369(14):1327‐1335.   2. Scirica BM, et al. N Engl J Med. 2013;369(14):1317‐1326.   3. Green JB, et al. N Engl J Med. 2015;373(3):232‐242.   4. Holman RR, et al. N Engl J Med. 2017;377(13):1228‐1239.   5. Marso SP, et al. N Engl J Med. 2016;375(4):311‐33.   6. Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247‐2257.   7. Marso SP, et al. N Engl J Med. 2016;375(19):1834‐1844.   9. Neal B, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611925.   10. Zinman B, et al. N Engl J Med. 2015;373(22):2117‐2128.

Case Scenario: Rafael• 62 yo man diagnosed with T2DM 4 months ago

(HbA1c 8.6%)• Lifestyle + Metformin HbA1c 7.5%• BMI 31.4 kg/m2

• BP 134/86 mmHg• LDL-C 114 mg/dL• Triglycerides 320 mg/dL• Medications

• Metformin 1 g BID• HCTZ 25 mg QD• Enalapril 10 mg BID• Simvastatin 20 mg QD• ASA 81 mg QD

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Which class of medication would you add to metformin?

1. DPP-4i

2. GLP-1RA

3. SGLT-2i

4. Sulfonylurea

5. Thiazolidinedione

?

Case Scenario: Julie• 69 yo woman diagnosed with T2DM 3 years ago (HbA1c 9.4%)

when she suffered a myocardial infarction

• Lifestyle + Metformin + SU HbA1c 6.9% (now 7.7%)

• BMI 36.8 kg/m2 → 31.2 kg/m2

• BP 130/78 mmHg

• eGFR 63 mL/min/1.73 m2

• LDL-C 64 mg/dL

• Triglycerides 156 mg/dL

• Medications• Metformin 1 g BID• Glimepiride 6 mg QD• Lisinopril/HCTZ 20 mg/25 mg QD• Atorvastatin 80 mg QD• ASA 81 mg QD

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Case Scenario: Julie

• Adherence with glimepiride has been poor since she experienced a severe hypoglycemia episode 7 months ago

• Has experienced several episodes of asymptomatic hypoglycemia since

• HbA1c has risen over the past year (now 7.7%)

• Plan• Discontinue glimepiride

• Start another medication

Which class of medication would you add to metformin?

1. DPP-4i

2. GLP-1RA

3. SGLT-2i

4. Thiazolidinedione

?

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Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: SGLT-2 Inhibitors

Canagliflozin

Endpoint

Rate/100 patient‐years

Hazard Ratio(95% CI)

Canagliflozin Placebo

CV death, nonfatal MI, nonfatal strokea 2.69 3.15 0.86 (0.75‐0.97)

HF hospitalization 0.55 0.87 0.67 (0.52‐0.87)

CV death or HF hospitalization 1.63 2.08 0.78 (0.67‐0.91)

Progression of albuminuria 8.94 12.87 0.73 (0.67‐0.79)

40% reduction eGFR, renal dialysis or transplantation, renal death

0.55 0.90 0.60 (0.47‐0.77)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; MI, myocardial infarctionaPrimary endpoint

Neal B, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1611925.

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: SGLT-2 Inhibitors (cont)

Empagliflozin

Endpoint

Rate/100 patient‐years

Hazard Ratio(95% CI)

Empagliflozin Placebo

CV death, nonfatal MI, nonfatal strokea 3.74 4.39 0.86 (0.74‐0.99)

All‐cause deathb 1.94 2.86 0.68 (0.57‐0.82)

CV death 1.24 2.02 0.62 (0.49‐0.77)

HF hospitalization 0.94 1.45 0.65 (0.50‐0.85)

HF hospitalization or CV death (excluding fatal stroke)

1.97 3.01 0.66 (0.55‐0.79)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; MI, myocardial infarctionaPrimary endpoint   bNNT=39 over 3 years

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

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Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor AgonistsLiraglutide

Endpoint

Rate/100 patient‐years

Hazard Ratio(95% CI)

Liraglutide Placebo

CV death, nonfatal MI, nonfatal strokea,b 3.4 3.9 0.87 (0.78‐0.97)

CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for UA or HF

5.3 6.0 0.88 (0.81‐0.96)

All‐cause deathc 2.1 2.5 0.85 (0.74‐0.97)

CV death 1.2 1.6 0.78 (0.66‐0.93)

Microvascular event 2.0 2.3 0.84 (0.73‐0.97)

Nephropathy 1.5 1.9 0.78 (0.67‐0.92)

aPrimary endpoint   bNNT=66 over 3 years   cNNT=98 over 3 years

Marso SP, et al. N Engl J Med. 2016;375(4):311‐322.

Antihyperglycemic Medications Demonstrating Cardiovascular Benefit: GLP-1 Receptor Agonists (cont)

Semaglutide

Endpoint

Rate/100 patient‐years

Hazard Ratio(95% CI)

Semaglutide Placebo

CV death, nonfatal MI, nonfatal strokea,b 3.24 4.44 0.74 (0.58‐0.95)

CV death, nonfatal MI, nonfatal stroke, revascularization, hospitalization for UA or HF

6.17 8.36 0.74 (0.62‐0.89)

All‐cause death, nonfatal MI, nonfatal stroke

3.66 4.81 0.77 (0.61‐0.97)

Nonfatal stroke 0.80 1.31 0.61 (0.38‐0.99)

Revascularization 2.50 3.85 0.65 (0.50‐0.86)

New or worsening nephropathy 1.86 3.06 0.64 (0.46‐0.88)

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

aPrimary endpointbNNT=45 over 2 years

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Cardiovascular Outcomes Over 30 Months: Canagliflozin vs Other non-SGLT-2 Inhibitors

8.9

7.5 7.3

12.8 12.4

14.4

0

2

4

6

8

10

12

14

16

Inciden

ce Rate per 1000 person‐years

Heart Failure Hospitalization

9.9

8.8 8.8

11.1

8.5

10.3

0

2

4

6

8

10

12

14

16

Inciden

ce Rate per 1000 person‐years

Composite CV Endpoint*

HR=0.70P<0.05

HR=0.61P<0.05

HR=0.51P<0.05 HR=0.89

P=NSHR=1.03P=NS

HR=0.86P=NS

*Admitted to hospital for acute myocardial infarction, ischemic stroke, or hemorrhagic stroke

Cana/DPP‐4i cohort, n=17,667 pairsCana/GLP‐1RA cohort, n=20,539 pairsCana/SU cohort, n=17,354 pairs

Patorno E, et al. BMJ. 2018;360:k119.

Summary & Implications for Primary Care• Reducing cardiovascular risk is the key

treatment objective for patients with diabetes

• Available evidence shows that medications from 3 classes do not pose an increased risk of major adverse cardiovascular events

• Canagliflozin, empagliflozin, liraglutide, semaglutide reduce the risk of key cardiovascular outcomes

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In patients with type 2 diabetes mellitus, the primary treatment goal is to control/reduce:1. Blood glucose

2. Blood lipid

3. Blood pressure

4. Cardiovascular risk

?

The goal of cardiovascular safety trials is to demonstrate that the CV safety of the new therapy is

1. similar to placebo

2. similar to metformin

3. superior to placebo

4. superior to metformin

?

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Medications in which two classes have been shown to reduce the risk of cardiovascular events compared to placebo as part of standard care?

1. Sulfonylurea and DPP-4i

2. DPP-4i and SGLT-2i

3. SGLT-2i and GLP-1RA

4. GLP-1RA and meglitinide

?

Case Studies in Type 2 Diabetes Mellitus: Focus on

Cardiovascular Outcomes TrialsTHANK YOU!