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Welcome and Agenda Overview

Harold Bays, MD, FTOS, FACC, FACE, FNLAMedical Director and President,Louisville Metabolic and Atherosclerosis Research CenterLouisville, Kentucky

Disclosure: Harold Bays, MD, FTOS, FACC,FACE, FNLA

Research grants: Amarin Corporation, Amgen, Ardea Biosciences, Arisaph Pharmaceuticals, AstraZeneca, Bristol-Meyers Squibb, Catabasis Pharmaceuticals, CymaBay Therapeutics, Eisai, Elcelyx Therapeutics, Eli Lilly and Company, Esperion Therapeutics, Ferrer/Chiltern International, Gilead Sciences, GlaxoSmithKline, Hanmi Pharmaceutical, Hisun USA, Home Access Health Corporation, Janssen Pharmaceuticals, Inc., Johnson & Johnson, Kowa American Corporation, Merck & Co., Necktar, Novartis, Novo Nordisk, Omthera Pharmaceuticals, Orexigen Therapeutics, Pfizer, ProNova Solutions, Regeneron Pharmaceuticals, Roche, Sanofi, Takeda Pharmaceuticals U.S.A., and TimPharma LLC

Consultant/advisor: Alnylam Pharmaceuticals, Akcea Therapeutics, Amgen, AstraZeneca, Eli Lilly and Company, Ionis Pharmaceuticals (ISIS), Janssen Pharmaceuticals, Inc., Johnson & Johnson, Merck & Co., Moderna Therapeutics, Novartis, Procter & Gamble, ProNova Solutions, Regeneron Pharmaceuticals, Sanofi, and Takeda Pharmaceuticals U.S.A.

Speaker: Amarin Corporation, Amgen, AstraZeneca, Eisai, Regeneron Pharmaceuticals, Sanofi, and Takeda Pharmaceuticals U.S.A.

Cardiovascular Disease Is a Significant Cause of Mortality in Patients With Type 2 Diabetes

Geiss LS. In: Harris MI, ed. Diabetes in America; 1995:233-257.

0.0

10.0

20.0

30.0

40.0

50.0

% P

rop

ort

ion

of D

ea

ths

Ischemic Heart

Disease

Other Heart

Disease

Stroke Diabetes Infection OtherCancer

The Effect of Glucose on Vasculature and Lipids

Glucose may have direct and indirect effects on vasculature that are typical of those observed in atherosclerosis

• High glucose concentrations induce oxidative stress in endothelial cells, resulting in LDL oxidation and eNOS dysfunction1

• Metabolic memory of hyperglycemia damage to endothelium may contribute to the long-term complications associated with diabetes2-4

Insulin resistance and hyperglycemia may contribute to the atherogenic dyslipidemia associated with type 2 diabetes

• Insulin resistance to NEFA suppression increases VLDL concentrations5

• Elevated triglyceride concentrations contribute to the formation of small, dense LDL particles6

• Hyperglycemia may contribute to hypertriglyceridemia by increasing apoCIII; LDL containing apoCIII is an independent risk factor for coronary events in patients with diabetes7,8

1. Tanaka J, et al. Diabetes. 2009;58(10):2344-2354. 2. Zheng Z, et al. Diabetes. 2012;61(1):217-228. 3. El-Osta A, et al. J Exp Med. 2008;205(10):2409-2417. 4. Villeneuve LM, et al. Proc Natl Acad Sci U S A. 2008;105(26):9047-9052. 5. Vergés B. Atherosclerosis. 2010;211(2):353-36. 6. Laws A. In: Reaven G, et al., eds. Contemporary Endocrinology: Insulin Resistance; 1999:267-280. 7. Caron S, et al. Arterioscler Thromb Vasc Biol. 2011;31(3):513-519. 8. Lee SJ, et al. Arterioscler Thromb Vasc Biol. 2003;23(5):853-858.

eNOS=endothelial constitutive nitric oxide synthase. LDL=low-density lipoprotein. NEFA=nonesterified fatty acid. VLDL=very low-density lipoprotein.

Primary Prevention Trials of Lipid-Altering Therapy Including Patients With Diabetes

TrialDiabetic*

(n)Total in Study

(N)Lipid-Altering Drug

(mg/day)% CHD* Risk vs Placebo

in Patients With Diabetes

CARDS† 2838 2838 Atorvastatin 10 -37 (P=0.001)

AFCAPS 155 6605 Lovastatin 20-40‡ -44 (NS)

HPS§ 2912 7150 Simvastatin 40 -33 (P=0.0003)

ASCOT 2532 10,305 Atorvastatin 10 -16 (NS)

PROSPER 623 5804 Pravastatin 40 +27 (NS)

HHS 135 4081 Gemfibrozil 1200 -68 (NS)

Bays H, et al. Future Cardiol. 2005;1(1):39-59. Colhoun HM, et al. Lancet. 2004;364(9435):685-696. Downs JR, et al. JAMA. 1998;279(20):1615-1622. Collins R, et al. Lancet. 2003;361(9374):2005-2016.Sever PS, et al. Lancet. 2003;361(9364):1149-1158. Shepherd J, et al. Lancet. 2002;360(9346):1623-1630. Koskinen P, et al. Diabetes Care. 1992;15(7):820-825.

*By history. †Prospective trial in diabetic subjects; others are subgroup analyses. ‡Mean 30 mg/day. §Type 1 or 2 diabetes. CHD=coronary heart disease. NS=not significant.

Secondary Prevention Trials of Lipid-Altering Therapy Including Patients With Diabetes

TrialDiabetic

(n)Total in Study

(N)Lipid-Altering Drug

(mg/day)% CHD* Risk vs Placebo

in Patients With Diabetes

4SReanalysis

202†

483‡ 4444 Simvastatin 20-40-55 (P=0.002)-42 (P=0.001)

CARE 586† 4159 Pravastatin 40 -25 (P=0.05)

LIPID 1077‡ 9014 Pravastatin 40 -19 (NS)

LIPS§ 202† 1677 Fluvastatin 80 -47 (P=0.04)

HPS§ 3051† 13,386 Simvastatin 40 -18 (P=0.002)

4D|| 1255† 1255 Atorvastatin 20 -8 (NS)

VA-HIT 769‡ 2351 Gemfibrozil 1200 -32 (P=0.004)

DAIS||,¶ 418† 418 Fenofibrate 200 -23 (NS)

Bays H, et al. Future Cardiol. 2005;1(1):39-59. Pyŏrälä K, et al. Diabetes Care. 1997;20(4):614-620. Haffner SM, et al. Arch Intern Med. 1999;159(22):2661-2667. Goldberg RB, et al. Circulation. 1998;98(23):2513-2519. Keech A, et al. Diabetes Care. 2003;26(10):2713-2721. Serruys PW, et al. JAMA. 2002;287(24):3215-3222. Collins R, et al. Lancet. 2003;361(9374):2005-2016. Wanner C. Presented at: 37th ASN Annual Meeting; Oct 29-Nov 1, 2004; St. Louis, MO. Rubins HB, et al. Arch Intern Med. 2002;162(22):2597-2604. DAIS Investigators. Lancet. 2001;357(9260):905-910.

*Includes stroke in 4D and VA-HIT. †By history. ‡By history or glucose ≥126 mg/dL. §Type 1 or 2 diabetes. ||Prospective trial in diabetic subjects; others are subgroup analyses. ¶Angiographic study.

Effect of Intensive Control of Glucose on CV Outcomes and Death in Patients With Diabetes Mellitus: A Meta-Analysis of Randomized, Controlled Trials

Nonfatal MI CHD Stroke All-Cause Mortality

Intensive Treatment

StandardTreatment

Intensive Treatment

StandardTreatment

Intensive Treatment

StandardTreatment

Intensive Treatment

StandardTreatment

UKPDS 7.2 9.1 12.8 16.7 4.5 5.0 16.2 19.5

PROactive*,† 15.9 19.0 21.9 26.7 11.5 14.1 23.6 24.6

ADVANCE 5.5 5.6 11.1 12.1 8.5 8.8 17.9 19.1

VADT 12.8 15.5 15.4 17.9 4.6 7.2 20.4 18.9

ACCORD 10.4 13.1 11.4 13.8 4.2 4.0 14.3 11.3

Overall‡ 10.0 12.3 14.3 17.2 6.8 7.7 18.3 18.6

Ray KK, et al. Lancet. 2009;373(9677):1765-1772.

*Non-fatal strokes only. †CHD includes cardiac mortality. ‡Calculated by pooling study specific rates with a random-effects model meta-analysis. Event rates per 1000 person-years; calculated with the total person-years in each study group, which was estimated from the average follow-up in each study.CV=cardiovascular. MI=myocardial infarction.

Overall, intensive compared with standard glycemic control significantly reduces coronary events without an increased risk of death. However, the optimum mechanism, speed, and extent of A1c reduction might be different in differing populations.

Metformin+Sulfonylurea+

Triple Therapy Metformin+Thiazolidinedione+

Metformin+DPP-4 i+

Metformin+SGLT2 i+

Metformin+GLP-1 RA+

Metformin+Insulin (basal)+

Healthy Eating, Weight Control, Increased Physical Activity, and Diabetes Education

MonotherapyEfficacy*Hypoglycemia riskWeightSide effectsCosts

MetforminHighLow riskNeutral/lossGI/lactic acidosisLow

If A1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference—choice dependent on a variety of patient- and disease-specific factors).

highmoderate riskgainhypoglycemialow

Metformin+Sulfonylurea

Dual Therapy†

Efficacy*Hypoglycemia riskWeightSide effectsCosts

highlow riskgainedema, HF, fxslow

Metformin+Thiazolidinedione

intermediatelow riskneutralrarehigh

Metformin+DPP-4 i

intermediatelow risklossGU, dehydrationhigh

Metformin+SGLT2 i

highlow risklossGIhigh

Metformin+GLP-1 RA

highesthigh riskgainhypoglycemiavariable

Metformin+Insulin (basal)

If A1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference—choice dependent on a variety of patient- and disease-specific factors).

TZDDPP-4 iSGLT2 i

GLP-1 RAInsulin‡

orororor

SUDPP-4 iSGLT2 i

GLP-1 RAInsulin‡

orororor

SUTZD

SGLT2 iInsulin‡

ororor

SUTZD

DPP-4 iInsulin‡

ororor

SUTZD

Insulin‡

oror

TZDDPP-4 iSGLT2 i

GLP-1 RA

ororor

If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1 RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1 RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2 i.

Combination Injectable Therapy

Metformin+

Basal insulin Mealtime insulin GLP-1 RA+ or

*Consider initial therapy at this stage when A1c is ≥9% (≥75 mmol/mol). †Consider initial therapy at this stage when blood glucose is ≥300-350 mg/dL (≥16.7-19.4 mmol/L) and/or A1c ≥10-12% (≥86-108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. ‡Usually a basal insulin (eg, NPH, glargine, detemir, degludec).DPP-4=dipeptidyl peptidase-4. fxs=fractures. GI=genitourinary infections. GU=genitourinary. HF=heart failure. i=inhibitor. SGLT2=sodium-glucose cotransporter 2. SU=sulfonylurea. TZD=thiazolidinedione. Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149. Inzucchi SE, et al. Diabetologia. 2015;58(3):429-442.

Uncontrolled hyperglycemia(catabolic features, BG ≥300-350 mg/dL, A1c ≥10-12%)

Metformin intolerance or contraindication

A1c ≥9%

Antihyperglycemic Therapy in T2DM


Metformin+DPP-4 i+

Metformin+SGLT2 i+

Metformin+GLP-1 RA+





Dual Therapy†





Metformin+DPP-4 i


Metformin+SGLT2 i


Metformin+GLP-1 RA


DPP-4 iSGLT2 i

GLP-1 RA

oror

TZDSGLT2 ior

TZDDPP-4 ior

TZD

*Consider initial therapy at this stage when A1c is ≥9% (≥75 mmol/mol). †Consider initial therapy at this stage when blood glucose is ≥300-350 mg/dL (≥16.7-19.4 mmol/L) and/or A1c ≥10-12% (≥86-108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen.Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149. Inzucchi SE, et al. Diabetologia. 2015;58(3):429-442.

Antihyperglycemic Therapy in T2DM: Avoidance of Hypoglycemia

Triple Therapy Metformin+DPP-4 i+

Metformin+SGLT2 i+





Dual Therapy†



Metformin+DPP-4 i


Metformin+SGLT2 i


Metformin+GLP-1 RA


SGLT2 i DPP-4 i

*Consider initial therapy at this stage when A1c is ≥9% (≥75 mmol/mol). †Consider initial therapy at this stage when blood glucose is ≥300-350 mg/dL (≥16.7-19.4 mmol/L) and/or A1c ≥10-12% (≥86-108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen.Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149. Inzucchi SE, et al. Diabetologia. 2015;58(3):429-442.

Antihyperglycemic Therapy in T2DM: Avoidance of Weight Gain

Metformin+Sulfonylurea+


Metformin+Insulin (basal)+





highmoderate riskgainhypoglycemialow

Metformin+Sulfonylurea

Dual Therapy†




highesthigh riskgainhypoglycemiavariable

Metformin+Insulin (basal)


TZD

Insulin‡ or

SU

Insulin‡or

TZD

If A1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables; (2) on GLP-1-RA, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2 i.

Combination Injectable Therapy

Metformin+

Basal insulin Mealtime insulin+

*Consider initial therapy at this stage when A1c is ≥9% (≥75 mmol/mol). †Consider initial therapy at this stage when blood glucose is ≥300-350 mg/dL (≥16.7-19.4 mmol/L) and/or A1c ≥10-12% (≥86-108 mmol/mol), especially if patient is symptomatic or if catabolic features (weight loss, ketosis) are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. ‡Usually a basal insulin (eg, NPH, glargine, detemir, degludec).Inzucchi SE, et al. Diabetes Care. 2015;38(1):140-149. Inzucchi SE, et al. Diabetologia. 2015;58(3):429-442.

Antihyperglycemic Therapy in T2DM: Minimization of Costs

But What About the Heart?Anatomy of a Heart Attack

Healthy artery

Atherosclerotic plaque with blood clot

What are Different Types of Heart Disease? Available at: http://www.wisegeek.org/what-are-different-types-of-heart-disease.htm. Accessed October 24, 2016.

The Evidence-Based Recommendations for Management of Cardiovascular Risk Factors in Patients With Diabetes

Yehuda Handelsman, MD, FACP, FACE, FNLAMedical Director and Principal Investigator,Metabolic Institute of AmericaTarzana, California

Disclosure: Yehuda Handelsman, MD, FACP, FACE, FNLA

Research grants: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Esperion, GlaxoSmithKline, Grifols, Hanmi Pharmaceutical, Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Novo Nordisk, and Sanofi

Consultant: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb,Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Inc., Merck & Co., Novo Nordisk, Regeneron Pharmaceuticals, Inc., and Sanofi

Speaker’s Bureau: Amarin Corporation, Amgen, AstraZeneca, Boehringer Ingelheim-Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals, Inc., and Sanofi

IP-President: American College of Endocrinology

Associate Editor: Journal of Diabetes

Case: Diane

• 59-year-old woman comes for second opinion

• T2 DM for 5 years

• Denies history of CVD

• Family history of DM and CKD

• 95-140 mg, mostly prebreakfast

• Blood pressure=138/87 mm Hg

• BMI=32.5 kg/m2

• Heart rate=84 bpm

• Neck: acanthosis nigricans

• Fatigue

• Sleep disturbance

• Joint pain

SMBG

PHYSICAL FINDINGS ROS

HISTORY

Image is not the actual patient.CVD=cardiovascular disease. DM=diabetes mellitus. CKD=chronic kidney disease. BMI=body mass index. BPM=beats per minute. ROS=review of symptoms. SMBG=self-monitored blood glucose.

Case: Diane (cont.)

• Office manager

• Married with 2 adult children

• Diet: variable

• Exercise: none

• A1c: 7.4%• Lipids

• TC=189 mg/dL• LDL=112 mg/dL• HDL=42 mg/dL• Triglycerides=175 mg/dL

• Creatinine=1.3 mg/dL• TSH=1.8 mU/L, free T4=1.2 ng/dL• BUN=22 mg/dL• Urinary albumin=100 mcg/min• ALT=47 U/L• ECG consistent with LVH

• Metformin 1000 mg BID

• Atorvastatin 40 mg/day

LABS

MEDICATIONS

SOCIAL

Image is not the actual patient.LDL=low-density lipoprotein. HDL=high-density lipoprotein. TC=total cholesterol. TSH=thyroid stimulating hormone. BUN=blood urea nitrogen. ALT=alanine aminotransferase. ECG=electrocardiogram. LVH=left ventricular hypertrophy.

Type 2 Diabetes Is aCardiovascular Disease

Treat All Risk Factors

Risk of CVD Is Elevated Prior to Diagnosis of Type 2 DM

Adapted from: Hu FB, et al. Diabetes Care. 2002;25(7):1129-1134.

1.00

2.40

3.19

3.64

0.00

1.00

2.00

3.00

4.00

5.00

NondiabeticThroughout Study

15 Years or MoreBefore Diagnosis

10-14.9 YearsBefore Diagnosis

<10 YearsBefore Diagnosis

RR

of

MI o

r S

tro

ke

RR=relative risk. MI=myocardial infarction.

Algorithm for Managing Microvascular Complications of Type 2 Diabetes

Adapted with permission from Bergenstal R. In: DeGroot L, et al., eds. Endocrinology; 2001. Hu FB, et al. Diabetes Care. 2002;25(7):1129-1134.

Microvascular Complications

Retinopathy Nephropathy NeuropathyAnnual exam

Dilated examRetinal vesselsCataractsIntraocular pressure

Annual microalbuminScreen urine albumin• Repeat to confirm

Measure serum creatinine at least annually and calculate estimated GFR

Comprehensive foot examInspectionVascular (pulses, ABI)Vibratory perceptionMonofilament sensation

Treatment Priorities

Glucose controlHypertensionACE inhibitor

Glucose controlHypertension

ACE inhibitor or ARB

Glucose controlFoot care/footwear

GFR=glomerular filtration rate. ABI= ankle brachial index. ACE=angiotensin converting enzyme. ARB=angiotensin II receptor blocker.

Screening/Prevention and Treatment

Comprehensive Goals for Diabetes Control: Individualized

≤6.5% (≤ 7%)for most; provided safely

<6.5% (5%)as close to health (normal) for new, relatively

young, healthy; provided safely

≥7% (7.5/8/8.5%—glucose?) less stringent for “less healthy”;

multiple comorbidities, labile, short life expectancy

A1c Goals

130/80 (140/90)general

120/80with CKD or stroke risk

>140/90 hypotension/dizzy risk

Blood Pressure Lipids

LDL-C <100general risk

LDL-C <70high risk

(statin to all)

AACE (ADA)

ADA. Diabetes Care. 2016;39 (suppl 1):S72-80. Handelsman Y, et al. Endocr Pract. 2015;21 (suppl 1):1-87.

AACE=American Association of Clinical Endocrinologists. ADA=American Diabetes Association.

Diane

Obesity:BMI=32.5

Treatment:None

Consider:Lifestyle and Intervention (?)

Weight Change and Mortality in Diabetes

Williamson DF, et al. Diabetes Care. 2000;23(10):1499-1504.

Ag

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ste

d D

ea

th R

ate

*

40.345.6

33.631.8 31.4

26.1†

0

10

20

30

40

50

No Change Unintended Gain Intentional Loss

All causes CVD+DM

Intentional loss resulted in a relative risk reduction† of 22% ↓ all-cause death and 24% ↓ death from CVD+ DM

BMI 30→34 BMI 34→28

*Mortality rates are directly age-standardized to the age distribution of the cohort and expressed per 1000 person-years. †Adjusted for age, sex, initial BMI.

SYNERGIE: Weight Loss and HDL Cholesterol Over 3-Year Study

-6

-4

-2

0

2

4

Re

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on

in B

od

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(kg

)

1 2 3

Body Weight in Men,Followed For 3 Years

Follow-up (years)

Despres J. Presented at: ADA Symposium; June 5-9, 2009; New Orleans, LA.

**

*

0 0/1 0/1/2

1.0

1.1

1.2

0 1 2 3

HDL Cholesterol in Men,Followed For 3 Years

Follow-up (years)

HD

L C

ho

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ero

l (m

mo

l/L

)

Baseline*Years 0/1/2 significantly different from the corresponding time points, P<0.0001.†All measures significantly different from baseline and each other, P<0.0001.

†††

Weight

Effects of Phentermine/Topiramate ER in Advanced Type 2 DM

Garvey WT, et al. Diabetes Care. 2014;37(12):3309-3316.

-2.7%

-9.4%

-10

-8

-6

-4

-2

0

Me

an

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(%)

-1.2%

-1.61%

-2

-1

0

LS

Me

an

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in

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c (%

)

30

-16

-20

0

20

40

Ch

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s (S

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re*)

Placebo (n=55) Phentermine/Topiramate 15/92 mg (n=75)

P<0.0001

P=0.038

ER=extended release. LS=least squares.*Net score reflecting change in medication number and change in dose level of diabetes medications

Glucose Control8.6 8.6

Effect of Lorcaserin in Type 2 DM: BLOOM-DM Study

O’Neil PM, et al. Obesity (Silver Spring). 2012;20(7):1426-1436.

-1.5%

-4.5%

-5.0%

-6

-5

-4

-3

-2

-1

0

LS

Me

an

Ch

an

ge

in A

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(%)

-0.4%

-0.9%-1.0%

-1.5

-1.0

-0.5

0.0

LS

Me

an

Ch

an

ge

in

A1

c (%

)

88.3% 82.9% 76.6%

0

20

40

60

80

100

Pa

tie

nts

Inc

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sin

g

Use

of

An

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iab

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Ag

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)

Placebo (n=248) Lorcaserin 10 mg BID (n=251) Lorcaserin 10 mg QD (n=95‡)

*P<0.001 vs placebo. †P=0.087 vs placebo. ‡Mean A1C from 93 patients in lorcaserin 10 mg QD group.

*

†

*

**

Baseline Mean A1C (%)

†

8.0 8.1 8.1

Diane

Lipid Control:TC=189 mg/dL

LDL=112 mg/dLHDL=42 mg/dLTG=175 mg/dL

Medication:Atorvastatin 40 mg

Consider:Combination medication: ezetimibe, PCSK9 inhibitor,

omega-3 fish oil, fibrates

PCSK9=proprotein convertase subtilisin kexin 9.

Benefits of Aggressive LDL-C Loweringin Diabetes

1. Shepherd J, et al. Diabetes Care. 2006;29(6):1220-1226. 2. Sever PS, et al. Diabetes Care. 2005;28(5):1151-1157. 3. Colhoun HM, et al. Lancet. 2004;364(9435):685-696. 4. Collins R, et al. Lancet. 2003;361(9374):2005-2016.

Primary Event Rate (%)

Treatment Control

TNT1

DM, CHD 13.8 17.9

ASCOT-LLA2

DM, HTN 9.2 11.9

CARDS3

DM, no CVD 5.8 9.0

HPS4

All DM

DM, no CVD

9.4

9.3

12.6

13.5

0.5 0.7 0.9 1.0

Aggressive Lipid-Lowering

Better

1.7

Aggressive Lipid-LoweringWorse

0.75

0.77

0.63

0.73

0.67

P-ValueDifference in LDL-C(mg/dL)

0.026 22*

0.036 35†

0.001 46†

<0.0001

0.0003

39†

39†

CHD=coronary heart disease. HTN=hypertension. LDL-C=low-density lipoprotein cholesterol.*Atorvastatin 10 vs 80 mg/day. †Statin vs placebo.

Outcomes in Fibrate Trials: Patients With Diabetic or Metabolic Syndrome

1. Manninen V, et al. Circulation. 1992;85(1):37-45. 2. Keech A, et al. Lancet. 2005;366(9500):1849-1861.3. Tenenbaum A, et al. Arch Intern Med. 2005;165(10):1154-1160. 4. Rubins HB, et al. Arch Intern Med. 2002;162(22):2597-2604.

RRR= relative risk reduction. MS=metabolic syndrome.*Patients with TG >204 mg/dL and an LDL/HDL >5 (may or may not have had DM or MS). †Patients with diabetes and no prior CVD. ‡Patients with MS. §Patients with diabetes.

Major CVD Event Rate

Trial N % Control % Drug % RRR P-Value

Primary Prevention

HHS1*

FIELD2†

292

7664

13.0

10.8

3.9

8.9

71

19

<0.005

0.004

Secondary Prevention

BIP3‡

VA-HIT4§

1470

769

18.4

29.4

14.1

21.2

25

32

0.03

0.004

ARBITER 2B

ase

line

CIM

T 0.87 0.89

0.0

0.2

0.4

0.6

0.8

1.0

Statin+Placebo Statin+ER Niacin

Ch

an

ge

in C

IMT

(mm

)

0.044

0.0140.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

Statin+Placebo Statin+ER Niacin

*

†

Taylor AJ, et al. Circulation. 2004;110(23):3512-3517.

CIMT=carotid intimamedia thickness. *P<0.001, within group comparison. †P=0.23, within group comparison.

HDL-C ↑ 18% (P=0.002); TG ↓ 10% (P=0.03); No Change in LDL

Diane

Blood Pressure ControlBP=138/87 mm HG

Urinary albumin:100 mcg/min

Medication:None

Consider:ACE inhibitor or ARB

% R

R

-21-24

-32 -34

-42 -44-47

-56

-70

-60

-50

-40

-30

-20

-10

0

UKPDS: Blood Pressure Control in Type 2 DMEffect of Intensive BP Lowering on Risk of Micro- and Macrovascular Complications

Any DM-Related

Endpoint

DM-RelatedDeath Retinopathy Stroke HFMI

RenalFailure

Vision Deterioration

Benefits of 144/82 mm Hg vs 154/87 mm Hg

N=1148

UKPDS Study Group. BMJ. 1998;317(7160):703-713.

HF=heart failure.

Mean Systolic Blood Pressure Levels at Each Study Visit

Accord Study Group, et al. N Engl J Med. 2010;362(17):1575-1585.

3.2 3.4 3.4 3.5 3.5 3.5 3.4 3.41.9 2.1 2.1 2.2 2.2 2.3 2.3 2.3

IntensiveStandard

Mean number of medications prescribed

2174 2071 1973 1792 1150 445 156 1562208 2136 2077 1860 1241 504 203 201

IntensiveStandardNumber of patients

0 1 2 3 4 5 6 7 8

140

130

120

110

0Sys

tolic

Pre

ssu

re (m

m H

G)

Years Since Randomization

Standard

Intensive

Primary and Secondary Outcomes

Accord Study Group, et al. N Engl J Med. 2010;362(17):1575-1585.

Outcome

Intensive Therapy (N=2363)

Standard Therapy(N=2371)

Hazard Ratio (95% CI) P-Value

Number of Events %/Year

Number of Events %/Year

Primary outcome* 208 1.87 237 2.09 0.88 (0.73-1.06) 0.20

Prespecified secondary outcomesNonfatal MI 126 1.13 146 1.28 0.87 (0.68-1.10) 0.25

StrokeAnyNonfatal

3634

0.320.30

6255

0.530.47

0.59 (0.39-0.89)0.63 (0.41-0.96)

0.010.03

DeathFrom any causeFrom cardiovascular cause

15060

1.280.52

14458

1.190.49

1.07 (0.85-1.35)1.06 (0.74-1.52)

0.550.74

Primary outcome plus revascularization or nonfatal heart failure

521 5.10 551 5.31 0.95 (0.84-1.07) 0.40

Major coronary disease event† 253 2.31 270 2.41 0.94 (0.79-1.12) 0.50

Fatal or nonfatal heart failure 83 0.73 90 0.78 0.94 (0.70-1.26) 0.67

*The primary outcome was a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes. †Major coronary disease events, as defined in the protocol, included fatal coronary events, nonfatal MI, and unstable angina.

Diane

Glycemic Control:A1c=7.4%

Medication: Metformin 1000 mg BID

Consider:Combination medications

Benefits of Glycemic Control

Stratton IM, et al. BMJ. 2000;321(7258):405-412.

PVD=peripheral vascular disease. Results are from an epidemiologic analysis.

Every 1% Decrease in A1c Leads to Significant Reductions in Complications

Risk of MI

Risk of DM-Related Death

Risk of MicrovascularComplications

Risk of Amputation or Death from PVD

14%

21%

37%43%

Decrease was statistically significant for all comparisons shown.

Epidemiologic Relationships Between A1c and All-Cause Mortality in the ACCORD Trial

Does A1c achieved predict a risk for all-cause mortality?

Riddle MC, et al. Diabetes Care. 2010;33(5):983-990.

2

1

0

-1

Lin

ea

r P

red

icti

on

6 7 8 9

Standard

Intensive

Average A1c

Adjusted (Model 3) Relationships

Odds Ratio(95% CI)

CHD Events

Ray KK, et al. Lancet. 2009;373(9677):1765-1772.

Effect of Intensive Control of Glucose on Cardiovascular Outcomes and Deathin Patients With DM: A Meta-Analysis of Randomized Controlled Trials

CI=confidence interval.

Intensive Treatment/Standard Treatment

Participants EventsWeight of

Study Size (%)

UKPDS 3071/1549 426/259 8.6

PROactive 2605/2633 164/202 20.2

ADVANCE 5571/5569 310/337 36.5

VADT 892/899 77/90 9.0

ACCORD 5128/5123 205/248 25.7

Overall 17,267/15,773 1182/1136 100

Odds Ratio(95% CI)

0.75 (0.54-1.04)

0.81 (0.65-1.00)

0.92 (0.78-1.07)

0.85 (0.62-1.17)

0.82 (0.68-0.99)

0.85 (0.77-0.93)

0.4 0.6 0.8 1.0 2.01.2 1.4 1.6 1.8

10-Year Follow-Up of Intensive Glucose Control in Type 2 DM

Holman RR, et al. N Engl J Med. 2008;359(15):1577-1589.

SU=sulfonylurea.

Ab

solu

te R

isk

48.1

14.5

26.8

16.8

11.0

52.2

17.0

30.3

19.6

14.2

45.7

14.0

25.9

14.812.4

53.9

18.7

33.1

21.1

13.4

0

10

20

30

40

50

60

SU-insulin intensive SU-insulin conventionalMetformin intensive Metformin conventional

DM-Related Death Death FromAny Cause

MIAny DM-Related Endpoint

MicrovascularDisease

0.91 (0.83-0.99) 0.83 (0.73-0.96) 0.87 (0.79-0.96) 0.85 (0.74-0.97) 0.76 (0.64-0.89)0.79 (0.66-0.95) 0.70 (0.53-0.92) 0.73 (0.59-0.89) 0.67 (0.51-0.89) 0.84 (0.60-1.17)

SU-insulinMetforminIn

ten

sive

-th

era

py

RR

R (9

5%

CI)

P=0.04 P=0.01

P=0.01 P=0.01

P=0.007 P=0.002

P=0.01 P=0.005P=0.001 NS

ADA Recommendations for Aspirin Therapy in DiabetesASA 75-162 mg/day recommended as

Primary prevention in patients with type or type 2 diabetes at increased CVD risk (10-year risk >10%)• Eg, most men >50 years of age or women >60 years of age who have ≥1 additional major risk factor

(family history of CVD, HTN, smoking, dyslipidemia, or albuminuria)

ASA should not be recommended for CVD prevention for adults with DM at low CVD risk (10-year CVD risk >5% [ie, men <50 and women <60 with no additional CVD risk]), since the potential adverse events from bleeding likely offset the potential benefits

Use ASA therapy (75-162 mg/day) as secondary prevention strategy in those with DM with history of CVD

Use clopidogrel (75 mg QD) for those with CVD and documented ASA allergy

Combination therapy with ASA (75-162 mg/day) and clopidogrel (75 mg/day) is reasonable for ≤1 year after ACS

ADA. Diabetes Care. 2011;34 (suppl 1):S11-61.

ASA=aspirin (acetylsalicylic acid). ACS=acute coronary syndrome.

RENAAL: Cardiovascular Endpoints by 6-Month Changes in Albuminuria

HF

% W

ith

CV

En

dp

oin

ts

0 12 24 48

Month

36

40

30

20

10

0

% W

ith

CV

En

dp

oin

ts

0 12 24 48

Month

36

40

30

20

10

0

CV Endpoint

de Zeeuw D, et al. Circulation. 2004;110(8):921-927.

CV=cardiovascular.

N=1513

<0%

>30%

<0%

>30%

Reducing A1c Reduces Retinopathy Progression in Type 2 DM

1. UKPDS Study Group. Lancet. 1998;352(9131):837-853. 2. Ismail-Beigi F, et al. Lancet. 2010;376(9739):419-430. 3. Chew EY, et al. N Engl J Med. 2010;363(3):233-244.

*Intensive vs standard glucose control.

% A1c reduction0.9

UKPDS1

% retinopathy RR*

1.3

ACCORD2,3

29 3317

Retinopathy onset

(P=0.003)

Retinopathy progression

(P=0.017)

Retinopathy progression

(P=0.003)

Potential Target Potential RR

BP reduction 25-40% (ACE inhibitor/ARB/thiazide)

LDL-C reduction 24-37% (statin)

HDL-C and TG 10-20% (fibrate, niacin)

Antiplatelet 20-30% (ASA in secondary prevention)

Glucose lowering Neutral: up to 10-15%

Stop smoking 25-35%

Global Approach: CVD Risk in Diabetes

Does it work?

Steno-2: Effects of Multifactorial Intervention on CV Outcomes

1. Gaede P, et al. N Engl J Med. 2003;348(5):383-393. 2. Gaede P, et al. N Engl J Med. 2008;358(6):580-591.

*CV death, MI, stroke, revascularization, amputation.

0 12 24 36 48 60 72 84 96

60

50

40

30

20

10

0

% P

rim

ary

Co

mp

osi

te O

utc

om

e*

53% RRP=0.01

Conventional1

Intensive2

N=160 with type 2 DM and microalbuminuria

Steno-2: 13-Year Mortality

Gaede P, et al. N Engl J Med. 2008;358(6):580-591.

0 1 2 3 4 5 6 7 8 9 10 11 12 13

80

70

60

50

40

30

20

10

0Cu

mu

lati

ve In

cid

en

ce

of

De

ath

(%)

Conventional therapy

Intensive therapy

50%

2.5%

6.3%30%

P=0.02

Years of Follow-Up

CVD Events

Persons at Target Levels* for A1c, BP, and LDL-C Have Substantially (60%) Lower Risks for CVD and CHD

32.5

25.6 25.9

37.339.0

41.6

0

5

10

15

20

25

30

35

40

45

BP LDL-C A1c

Eve

nt

Ra

tes

(pe

r 1

00

0 P

ers

on

-Ye

ars

)

CHD Events

19.5

13.515.3

20.922.9 23.6

BP LDL-C A1c

CVD Events

51.1

34.3

26.7

20.6

0

10

20

30

40

50

60

Eve

nt

Ra

tes

(pe

r 1

00

0 P

ers

on

-Ye

ars

)

CHD Events

29.6

19.3

14.7 13.7

Controlled Uncontrolled No risk factor controlled Any 1 risk factor controlledAny 2 risk factors controlled All 3 risk factors controlled

Wong ND, et al. Diabetes Care. 2016;39(5):668-676.

By Status of Being at Target Level for Individual Risk Factors By Number of Risk Factors at Target Levels

Unadjusted CVD and CHD Event Rates Per 1000 Person-years for Subjects With DM

*BP <130/80 mm Hg; LDL-C <2.6 mmol/L (100 mg/dL); A1c <7%.

Summary: Diabetes Complications

The obesity epidemic contributes to DM and CVD epidemics

Target multiple conditions to reduce risk

Utilize lifestyle modification for prevention and treatment

Institute intensive treatment for glycemic control

Benefit of LDL-lowering treatment in patients with DM

Benefit of ACE inhibitor/ARB in HTN in DM

Consider comprehensive care of all risk factors, with combination medications,to reduce CVD and complications

T2DM Antihyperglycemic Treatment: State of the Data on CV Benefits and Disadvantages of Glucose-Lowering Agents

Lawrence Blonde, MD, FACP, MACEDirector, Ochsner Diabetes Clinical Research UnitFrank Riddick Diabetes InstituteDepartment of EndocrinologyOchsner Medical CenterNew Orleans, Louisiana

Disclosure: Lawrence Blonde, MD, FACP, MACE

Consultant: AstraZeneca, GlaxoSmithKline, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, and Sanofi

Speakers bureau: AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk, and Sanofi

Grant/research support: AstraZeneca, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, and Sanofi

Outline

Diabetes confers increased CVD risk

Glycemic control in T2DM may modestly decrease CVD and all-cause mortality

Metformin may have a modest CV benefit

Sulfonylurea/insulin showed benefit in UKPDS long-term follow-up

Pioglitazone showed CV benefit in the PROactive and IRIS studies

The DPP-4 inhibitors have a neutral CV effect in short-term trials

SGLT2 inhibitor, empagliflozin, decreased CV death, death from any cause, and HF hospitalizationin the EMPA-REG trial

The GLP-1 receptor agonist, liraglutide, decreased MACE, CV death, and death from any cause; semaglutide also demonstrated CV benefit, reducing MACE that was driven by a decrease in non-fatal MI and stroke

Other CVOTs are currently underway

New data may favor certain agents, at least in patients with overt CVD or at high CV risk

Imperative to treat the ABCs of diabetes (A1c, blood pressure, and cholesterol [dyslipidemia])

CV=cardiovascular. CVD=CV disease. CVOT=CV outcome trial. DPP-4=dipeptidyl peptidase-4. GLP-1=glucagon-like peptide-1. HF=heart failure. MACE=major adverse cardiac event. MI=myocardial infarction. SGLT2=sodium-glucose cotransporter-2. T2DM=type 2 diabetes mellitus.

Outline












The Rate of Patients With Diabetes Dying From CVD Has Decreased Significantly

Gregg EW, et al. Diabetes Care. 2012;35(6):1252-1257.

CV

D M

ort

alit

y R

ate

p

er

10

00

Pe

rso

n-Y

ea

rs

0

1

2

3

4

5

6

7

8

9

10

1998 2000 2002 2004

DiabetesNo diabetes

Outline












Impact of Intensive Therapy for Diabetesin Major Clinical TrialsStudy A1c Microvascular CVD Mortality

Baseline

Study End

Standard Intensive

DCCT/EDIC 9 9 7 ↓ ↓ ↔ ↓ ↔ ↔

UKPDS 9 7.9 7 ↓ ↓ ↔ ↓ ↔ ↓

ACCORD 8.3 7.5 6.4 ↓ ↔ ↑

ADVANCE 7.5 7.0 6.4 ↓ ↔ ↔

VADT 9.4 8.5 6.9 ↓ ↔ ↓ ↔

Bergenstal RM, et al. Am J Med. 2010;123(4):374.e9-18.

Initial trial Long-term follow-up

Outline












UKPDS 34 Substudy: Metformin ImprovesCVD Outcomes vs Standard Therapy

0

5

10

15

20

MI

Inc

ide

nc

e p

er

10

00

Pa

tie

nt-

Ye

ars

Conventional/Diet

Insulin or Sulfonylureas

Metformin

P=0.01

NS

39%

0

2

4

6

8

10

Coronary Deaths

Inc

ide

nc

e p

er

10

00

Pa

tie

nt-

Ye

ars

Conventional/Diet

Metformin

P=0.02

50%

UKPDS Study Group. Lancet. 1998;352(9131):854-865.

N=951

Outline












Aggregate Endpoint 19971 20072

Any T2DM-related endpointRRR: 12% 9%

P: .029 .04

Microvascular diseaseRRR: 25% 24%

P: .0099 .001

MIRRR: 16% 15%

P: .052 .014

All-cause mortalityRRR: 6% 13%

P: .44 .007

1. UKPDS Study Group. Lancet. 1998;352(9131):837-853. 2. Holman RR, et al. N Engl J Med. 2008;359(15):1577-1589.

UKPDSEffect of Earlier Glucose Control

LegacyEffect

RRR=relative risk reduction.

Outline












PROactive Prioritized Secondary EndpointComposite of All-Cause Mortality, Nonfatal MI, and StrokeN=5238

n=2605, pioglitazone

n=2633, placebo

301 first events occurred in the pioglitazone group and 358 first events occurred in the placebo group during an average follow-up of 34.5 years

HR=0.84 (95% CI 0.72, 0.98); P=0.027

Dormandy JA, et al. Lancet. 2005;366(9493):1279-1289.

CI=confidence interval. HR=hazard ratio.

Overview of CV Outcome Studies With Antidiabetic AgentsDrug Class Trial Drug Primary Endpoint N (Expected Duration) Will Report

DPP-4 inhibitor

SAVOR-TIMI 531 Saxagliptin MACE 16,492 (2.1 years) Data in

EXAMINE2 Alogliptin MACE 5380 (3.3 years) Data in

TECOS3 Sitagliptin MACE + UA 14,000 (6 years) Data in

CAROLINA4 Linagliptin MACE + UA 6000 (7.6 years) Sep 2018

CARMELINA5 Linagliptin ↑ CV risk* 8300 Jan 2018

GLP-1 receptor agonist

EXSCEL6 Exenatide QW MACE 14,000 (5.5 years) Apr 2018

LEADER7 Liraglutide MACE 9340 (5 years) Top line reported

ELIXA8 Lixisenatide MACE 6000 (3.9 years) Data in

REWIND9 Dulaglutide MACE 9622 (6.5 years) April 2019

SUSTAIN 610 Semaglutide MACE 3297 (2.8 years) Data In

SGLT2 inhibitor

DECLARE-TIMI-5811 Dapagliflozin MACE Recruiting (7 years) Apr 2019

CANVAS12 Canagliflozin MACE 4500 (9 years) Apr 2017

EMPA-REG OUTCOME13 Empagliflozin MACE 7000 (8 years) Data in

Insulin DEVOTE14 Degludec MACE 7500 (5 years) Nov 2018

1. Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. 2. White WB, et al. N Engl J Med. 2013;369(14):1327-1335. 3. Green JB, et al. N Engl J Med. 2015;373(3):232-242. 4. Marx N, et al. Diab Vasc Dis Res. 2015;12(3):164-174. 5. Merck Sharp & Dohme Corp. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01986881?term=NCT01986881&rank=1. NLM identifier: NCT01986881. Accessed October 20, 2016. 6. Holman RR, et al. Am Heart J. 2016;174:103-110. 7. Marso SP, et al. N Engl J Med. 2016;375(4):311-322. 8. Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257. 9. Eli Lilly and Company. Available at: https://clinicaltrials.gov/ct2/show/NCT01394952?term=NCT01394952&rank=1:. NLM identifier: NCT01394952. Accessed October 20, 2016. 10. Marso SP, et al. N Engl J Med. 2016. In press. 11. AstraZeneca. Available at: https://clinicaltrials.gov/ct2/show/NCT01730534?term=NCT01730534&rank=1:. NLM identifier: NCT01730534. Accessed October 20, 2016.. 12. Neal B, et al. Am Heart J. 2013;166(2):217-223. 13. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128. 15. Marso SP, et al. Am Heart J. 2016;179:175-183.

*Albuminuria+prior CV disease and/or chronic kidney disease (CKD).UA=unstable angina.

Outline












SAVOR, EXAMINE, and TECOSKey Results

SAVOR1 EXAMINE2 TECOS3

Saxagliptin vs Placebo Alogliptin vs Placebo Sitagliptin vs Placebo

Median follow-up: 2.1 years

Endpoint A1c

• Saxagliptin 7.7% (P <0 .001 vs placebo)

• Placebo 7.9

CV outcomes

• Primary HR 1.00 (0.89, 1.12); P =0.99

• Secondary HR 1.02 (0.94, 1.11); P =0.66

Median follow-up: 18 months

LS mean difference in A1c -0.36% (95% CI: -0.43, -0.28; P <0 .001) for alogliptinvs placebo

CV outcomes

• Primary HR 0.96 (≤1.16); P =0.32

• Secondary HR 0.95 (≤1.14); P =0.26

Median follow-up: 3.0 years

LS mean difference in A1c -0.29% (95% CI -0.32, -0.27) for sitagliptin vs placebo

Noninferior to placebo for CV outcomes

• Primary HR 0.98 (0.88, 1.09); P <0.001

• Secondary HR 0.99 (0.89, 1.11); P <0.001

1. Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. 2. White WB, et al. N Engl J Med. 2013;369(14):1327-1335. 3. Green JB, et al. N Engl J Med. 2015;373(3):232-242..

FDA Drug Safety Communication: DPP-4 Inhibitors (April 5, 2016)

FDA adds warnings about HF risk to labels of T2DM medicines containing saxagliptinand alogliptin

In the saxagliptin trial, 3.5% of patients who received the drug were hospitalized for HF vs 2.8% of patients who received a placebo; risk factors included a history of HF or kidney impairment

In the alogliptin trial, 3.9% of alogliptin-treated patients were hospitalized for HF vs 3.3% in the placebo group

FDA. Diabetes medications containing saxagliptin and alogliptin: drug safety communication - risk of heart failure. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494252.htm. Accessed October 14, 2016.

Outline












EMPA-REG Cardiovascular Outcomes and Death From Any CauseN=7020, patients followed for median of 3.1 years

n=4687, empagliflozin; n=2333, placebo

Primary outcome, defined as death from CV causes, nonfatal MI, or nonfatal stroke, occurred in 12.1% of empagliflozin group vs 10.5% in placebo group

HR=0.86 (95.02% CI 0.74, 0.99); P=0.04 for superiority, P<0.001 for noninferiority

Secondary endpointsDeath from CV causes

• HR=0.62 (95% CI 0.49, 0.77); P<0.001

Death from any cause• HR=0.68 (95% CI 0.57, 0.82); P<0.001

Hospitalization for HF• HR=0.65 (95% CI 0.50, 0.85); P=0.002

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

Outline












Leader Trial

N=9340, patients followed for 3.5 yearsn=4668, liraglutide; n=4672, placebo

Primary endpoint, defined as first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke, occurred in 13% of the liraglutide group and 14.9% of the placebo group

HR=0.87 (95% CI 0.78, 0.97); P<0.001 for noninferiority, P=0.01 for superiority

Secondary endpointsDeath from CV causes• HR=0.78 (95% CI 0.66, 0.93); P=0.007

Death from any cause• HR=0.85 (95% CI 0.74, 0.97); P=0.02

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

SUSTAIN 6 Primary Endpoint:First of CV Death, Nonfatal MI, or StrokeN=3297

n=1648, semaglutide

n=1649, placebo

108 (6.6%) events occurred in the semaglutide group vs 146 (8.8%) in the placebo group during an average follow-up of 2.1 years

HR=0.74 (95% CI 0.58, 0.95); P<0.001 for noninferiority, P=0.02 for superiority

Patients taking semaglutide experienced a meaningful reduction in A1c from 8.7%to 7.6% in the 0.5 mg group and 7.3% in the 1.0 mg group

Marso SP, et al. N Engl J Med. 2016. In press.

Outline












Large CV Outcomes Trials in Diabetes (Noninsulin)

Study SAVOR1 EXAMINE2 TECOS3 CAROLINA4 CARMELINA5

DPP4-1 Saxagliptin Alogliptin Sitagliptin Linagliptin Linagliptin

Comparator Placebo Placebo Placebo Sulfonylurea Placebo

N 16,500 5400 14,700 6000 8300

Results 2013 2013 2015 2017 2017

Study LEADER6 ELIXA7 SUSTAIN 68 EXSCEL9 REWIND10

GLP1-RA Liraglutide Lixisenatide Semaglutide Exenatide QW Dulaglutide

Comparator Placebo Placebo Placebo Placebo Placebo

N 16,500 6100 6000 5400 8300

Results 2016 2015 2016 2018 2019

Study EMPA-REG11 CANVAS12 DECLARE13 VERTIS CV14

SGLT-2-I Empaglifozin Canagliflozin Dapagliflozin Ertugliflozin

Comparator Placebo Placebo Placebo Placebo

N 7300 4300 22,200 3900

Results 2015 2017 2019 2020

1. Scirica BM, et al. N Engl J Med. 2013;369(14):1317-1326. 2. White WB, et al. N Engl J Med. 2013;369(14):1327-1335. 3. Green JB, et al. N Engl J Med. 2015;373(3):232-242. 4. Marx N, et al. Diab Vasc Dis Res. 2015;12(3):164-174. 5. Rosenstock J, et al. Cardiovasc Diabetol. 2015;14:57. 6. Marso SP, et al. N Engl J Med. 2016;375(4):311-322. 7. Pfeffer MA, et al. N Engl J Med. 2015;373(23):2247-2257. 8. Marso SP, et al. N Engl J Med. 2016. In press. 9. Holman RR, et al. Am Heart J. 2016;174:103-110. 10. Eli Lilly and Company. Available at: https://clinicaltrials.gov/ct2/show/NCT01394952?term=NCT01394952&rank=1:. NLM identifier: NCT01394952. Accessed October 20, 2016. 11. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128. 12. Neal B, et al. Am Heart J. 2013;166(2):217-223. 13. AstraZeneca. Available at: https://clinicaltrials.gov/ct2/show/NCT01730534?term=NCT01730534&rank=1:. NLM identifier: NCT01730534. Accessed October 20, 2016. 14. Merck Sharp & Dohme Corp. Available at: https://clinicaltrials.gov/ct2/show/NCT01986881?term=NCT01986881&rank=1:. NCT01986881. Accessed October 20, 2016.

Completed Trials Neutral Studies Beneficial Studies

Summary












Case Studies of Complicated Diabetic Patients With Multiple CV Risk Factors/CVD With Discussion

Harold Bays, MD, FTOS, FACC, FACE, FNLA

Yehuda Handelsman, MD, FACP, FACE, FNLA

Lawrence Blonde, MD, FACP, MACE

Case 1: UKP

• UKP is a 63-year-old Caucasian man with new-onset type 2 diabetes mellitus and no history of heart disease

• The patient requests nutritional or generic therapy

• Metoprolol 50 mg BID

• Blood pressure=140/77 mm Hg• Body mass index=30 kg/m2

• A1c: 8.2%• Total cholesterol=200 mg/dL• Triglycerides=130 mg/dL• Creatinine=1.0 mg/dL

MEDICATIONS

LABS

HISTORY

Image is not the actual patient.

PHYSICAL FINDINGS

Case 2: EMP

• EMP is a 64-year-old man of Asian descent who has had type 2 diabetes mellitus for over 10 years, and experienced a myocardial infarction 1 year ago

• Metformin• Insulin• Aspirin• Statin• Angiotensin receptor blocker


• A1c: 8.1%• LDL cholesterol=85 mg/dL• HDL cholesterol=46 mg/dL• Triglycerides=194 mg/dL• eGFR according to MDRD

(mL/min/1.73 m2)=74

HISTORY MEDICATIONS

LABS


PHYSICAL FINDINGS

Case 3: SUS

• SUS is a 50-year-old woman who has had type 2 diabetes mellitus for 14 years along with coronary heart disease

• Metformin• Glimepiride• Beta blocker• ACE inhibitor• Statin• Aspirin


• A1c: 8.7• LDL cholesterol=82 mg/dL• HDL cholesterol=44 mg/dL• eGFR according to MDRD

(mL/min/1.73 m2)=75

HISTORY MEDICATIONS

LABS


PHYSICAL FINDINGS

Coming in December:ONLINE E-FORUMon myCME!

myCME.com/CV_Diabetes

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