Diabetes/Heart Disease Division:Is it Blurring?

Peter W. F. Wilson, MD

Atlanta VA Medical Center

Emory Clinical Cardiovascular Research Institute

• Background• Lipids• Blood Pressure• Glucose control

Outpatient—fasting, postprandialInpatient—stress hyperglycemia

Outline

Major Causes of DeathPersons in U.S with Diabetes

Wingard Diabetes in America 1995

40

15

13

13

10

4

5

Ischemic heart disease

Other heart disease

Diabetes

Malignant neoplasms

Cerebrovascular disease

Pneumonia/influenza

All other

0 10 20 30 40 50Percent of Deaths

65%

Long term Risk of CVDBy Diabetes Status and BMI Category

Framingham Men and Women

0

20

40

60

80

100

Inci

denc

e (p

er c

ent)

<25 25-30 30+ <25 25-30 30+ <25 25-30 30+ <25 25-30 30+ 1020

30

MenWomen

Fox Diabetes Care 2008; 31: 1582

BMI (kg/m2) Follow Up

(years)

6 7 9

34

17 12 1523

483447 52

42 31

49

3733

22

6979

66 6779

5654 58

19 2230

9

55

44

65

7487

NoDiabetes Yes No Yes

39

Accelerated atherosclerosis

Clinical diabetes

Hyperinsulinemia Impairedglucose

tolerance

HypertriglyceridemiaDecreased HDL-C

Essentialhypertension

Insulin resistance

Insulin Resistance and Atherosclerosis: Proposed Relationships

StressCatechols

Risk Variables for a Metabolic Syndrome

FastingGlucose

2-HourGlucose

FastingInsulin

2-Hour Insulin

Body MassIndex

BPDiastolic

BPSystolic

HDL-C Trig

Waist/Hip

Meigs 1996

Risk Variables for a Metabolic Syndrome

62% VarianceExplainedMeigs 1996

Adiposity and Vascular Inflammation

Modified from Gabay NEJM 1999; 340: 448

Interleukin-6

C-reactive proteinFibrinogen

Interleukin -1

TNF alpha

TGF beta+

+

-

Adipose cells

CVD or Diabetes

Diabetes and CVD Risk in Framingham CohortAge 35-64 Years--30 Year Follow-up

CHD Stroke Int.Claudication

CardiacFailure

CVDTotal

0

2

4

6

8

10

Ris

k R

atio

MenWomen

Wilson Am J Kidney Dis 1998

P<0.001

P<0.001

P<0.05

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

P<0.001

Risk if no DM

CHD Stroke Int.Claudication

CardiacFailure

CVDTotal

0

1

2

3

4

5

Ris

k R

atio

MenWomen

Wilson Am J Kidney Dis 1998

Diabetes and CVD Risk in Framingham CohortAge 65-94 Years--30 Year Follow-up

p<0.05

p<0.001

p<0.001

p<0.001p<0.001p<0.001p<0.001p<0.001p<0.01

Risk ifno DM

Risk of Fatal or Nonfatal MIHistory of DM Alone or Prior MI Alone

Buluhagapitiya Diabet Med 2009; 26: 142

Metabolic Syndrome Factors

Impaired Glucose Tolerance

Elevated Blood Pressure

Increased abdominal circumference

Low HDL cholesterol

Elevated triglycerides

Metabolic Syndrome FactorsAge-Adjusted Risk for Outcomes

Framingham Offspring—8 Year Follow up

Event Number of MetS Factors

MenRelative

Risk and 95% Confidence Interval

WomenRelative

Risk and 95% Confidence Interval

CVD 0 Referent Referent1 or 2 1.48 (0.69-3.16) 3.39 (1.31-8.81)

>3 3.99(1.89-8.41) 5.95 (2.20-16.11)Hard CHD 0 Referent Referent

1 or 2 0.98 (0.36-2.67) 3.77 (0.45-31.28)>3 2.55 (0.96-6.79) 7.21 (0.81-64.37)

Total CHD 0 Referent Referent1 or 2 1.24 (0.54-2.83) 3.29 (0.95-11.34)

>3 3.01 (1.33-6.83) 3.96 (1.02-15.38)Type 2 DM 0 Referent Referent

1 or 2 4.16 (0.98-17.64) 6.10 (1.85-20.10)>3 23.83 (5.80-98.01) 29.69 (9.10-96.85)

Wilson Circulation 2005; 112: 3066

Statins and CVD in Diabetic PatientsCTT Meta Analysis

Cholesterol Treatment Trialists--Lancet 2008; 371: 117

Diabetes and Lipid ExtremesFramingham Offspring

Men

HDL-C<35 Total-C 240+ LDL-C 160+ Trig 250+ HDL-C<35Total-C 240+

0

10

20

30

40

50

60

Per c

ent

Non-DiabeticDiabetic

p<0.001

p<0.001

p<0.001

Siegel Metabolism 1996; 96: 1267

HDL-C<35 Total-C 240+ LDL-C 160+ Trig 250+ HDL-C<35Trig 250+

0

10

20

30

40

50Pe

r cen

t

Non-DiabeticDiabetic

Siegel Metabolism 1996; 96: 1267

p<0.001p<0.001

p<0.001

p<0.001

Diabetes and Lipid ExtremesFramingham Offspring

Women

TrialName Fibrate Number T2DM Endpoint Risk Ratio P

Value

Helsinki Gemfibrozil1200 mg

4081 M Some MI, CAD

Death0.66

(0.47-0.92 <0.02

VA-HIT Gemfibrozil1200 mg

2531 M Some Nonfatal MI,

CAD Death0.78

(0.65-0.95) 0.006

BIP Bezafibrate400 mg

3090 M/F Some MI or SCD 0.91

(0.76-1.08) 0.26

FIELD Fenofibrate200 mg

9795 M/F All Nonfatal MI,

CAD Death0.89

(0.75-1.05) 0.16

ACCORD

Statin +/-Fenofibric

Acid 160 mg

5518 M/F All

Nonfatal MI, Nonfatal

Stroke, CVD Death

0.92(0.79-1.08) 0.32

CVD Outcomes in Fibrate Trials

Goldfine N Engl J Med 2011; 365: 481

TrialName

Subgroup Criteria

Prevalence Risk RatioTriglycerides

(mg/dL)HDL

(mg/dL)

Helsinki >204 <42 14% Subgroup 0.35 (0.16-0.77)Others 0.79 (0.54-1.14)

BIP >204 <35 11% Subgroup 0.58 (0.37-0.94)Others 0.97 (0.80-1.16)

FIELD >204 <40 M<50 F 21% Subgroup 0.73 (0.58-0.91)

Others 0.94 (0.83-1.06)

ACCORD >204 <34 17% Subgroup 0.69 (0.49-0.97)Others 0.99 (0.83-1.19)

CVD Outcomes in Fibrate TrialsTriglyceride-HDL Subgroups

Goldfine N Engl J Med 2011; 365: 481

• LDL cholesterol loweringStatin at max tolerated doseSecond choice: Bile acid binding resin or fenofibrate

• HDL cholesterol raisingBehavior --weight loss, physical activity, smoking cessationGlycemic control

• Triglyceride loweringGlycemic control first priorityFibric acid derivative (gemfibrozil, fenofibrate) Statins at high dose also have some TG loweringTriglyceride goal is < 500 mg/dL at present time

Priorities for Lipid Levels inAdult Diabetic Patients

Diabetes Care 2015

ACC / AHA 2013 RecommendationsCVD Primary Prevention-- US Adults

GroupATP III

2001 & 2004 Update

ACC/AHA 2013

Diabetes Mellitus

MI Risk Equivalent

LDL-C <100 mg/dL

LDL-C <70/mg/dLin some patients

All > 40 y/o with DM considered high CVD risk

Rx high potency statin

No fixed LDL-C targets

Stone Circulation 2013

Statin Therapy in DiabetesAmerican Diabetes Association 2016

ADA Diabetes Care 2015; 38:S49

Age(years)

Risk Factors

Statin Dose*

Lipid Monitoring

<40NoneCVD risk factor(s)**Overt CVD***

NoneModerate or highHigh

Yearlyor as needed

40-75NoneCVD risk factorsOvert CVD

ModerateHighHigh

To monitor adherence

>75 NoneCVD risk factorsOvert CVD

ModerateModerate or highHigh

To monitor adherence

*In addition to lifestyle** LDL-C>100 mg/dL, hypertension, smoking, overweight or obesity***History of CVD event or ACS

HOT TrialCVD Events in DM and Non-DM Patients

According to Diastolic BP Target at 4 Years

Hansson Lancet. 1998;351: 1755

<90Even

ts/1

000

Pt-Y

ears

Diabetic n=1,501; p=0.016

<85 <80 <90 <85 <80Non-Diabetic

n=18,790; p=NS

48% Risk Reduction

mm Hg

Hypertension Optimal Treatment (HOT) Trial: Diabetes Subgroup

Hansson Lancet. 1998;351: 1755

Major CV Events MI

Even

ts/1

000

Pt-Y

ears

CV Mortality

90 mmHg (N=501)

85 mmHg (N=501)

80 mmHg (N=499)

Diastolic Target

p<0.045p<0.016

p<0.005

ACCORD Trial Blood Pressure and Risk of Outcomes

FeatureIntensive

Rx(n=2362)

Standard Care

(n=2371)

RelativeRisk

TargetBP Systolic (mm Hg) < 120 <140

MeanStart BPs (mm Hg)1 Year BPs (mm Hg)

139121

139134

MACE / yearStroke / year

1.87%0.32%

2.09%0.53%

0.88 (P=0.20)0.59 (P=0.01)

ACCORD N Engl J Med 2010; 362: 1575

Topic Specifics

Lifestyle

All patients with hypertensionWeight controlDASH dietModerate alcoholIncreased physical activity

Target <140/90 mm Hg Most diabetic patients

Target<130/80 mm Hg

Pregnant womenPossible for CKD patientsPossible if elevated urine albuminEspecially for those with long life expectancy

Medications

ACE inhibitor or ARB(monitor eGFR and serum K+)

If eGFR < 30 ml/min then add loop diureticMultiple drugs usually required

ADA 2016 BP Recommendations

Diabetes Care 2015: Supp 1; p49

Antiplatelet Therapy in DiabetesAmerican Diabetes Association 2016

ADA Standards of Care: Diabetes Care 2015; 38:S49

GroupCVD RiskEstimate(10 year)

Recommendation(ASA 75-162 mg/d)

Primary Prevention

<5%5-10%>10%

No ASAPossible ASAYes ASA

SecondaryPrevention --- Yes ASA

ASAIntolerance Clopidogrel

Up to1 Year Post Acute Coronary Syndrome

ASA + Clopidogrel

HbA1c and Vascular RiskUKPDS Trial

5 6 7 8 9 10 11Inci

denc

e pe

r100

0 P-

Year

s (%

)

Stratton BMJ. 2000;321:405

Updated Mean HbA1c Concentration (%)Adjusted for age, sex, and ethnic group

Myocardial Infarction

Microvascular Endpoints

ACCORD Trial Glycemia and Risk of Outcomes

FeatureIntensive

Rx(n=5128)

Usual Care

(n=5123)

RelativeRisk

TargetHbA1c Level < 6.0 < 7.0 to 7.9

MedianStart HbA1c1 Year HbA1c

8.16.4

8.17.5

Death risk / yearMACE / yearCVD Death / year

1.4%6.9%2.6%

1.1%7.2%1.8%

1.22 (P=0.04)0.90 (P=0.16)1.35 (P=0.02)

ACCORD N Engl J Med 2008; 358: 2545

Risk of MI or CVD DeathRosiglitazone vs Controls Meta-Analysis

Study Rosiglitazone Controls Odds Ratio P Value

Outcome--Myocardial InfarctionSmall trials combined 44/10,280 (0.43) 22/6105 (0.36) 1.45 (0.88-2.39) 0.15

DREAM 15/2,635 (0.57) 9/2,634 (0.34) 1.65 (0.74-3.68) 0.22

ADOPT 27/1,456 (1.85) 41/2,895 (1.44) 1.33 (0.80-2.21) 0.27

Overall 1.43 (1.03-1.98) 0.03

Outcome--CVD DeathSmall trials combined 25/6,557 (0.38) 7/3,700 (0.19) 2.40 (1.17-4.91) 0.02

DREAM 12/2,365 (0.51) 10/2,634 (0.38) 1.20 (0.52-2.78) 0.67

ADOPT 2/1,456 (0.14) 5/2,854 (0.28) 0.80 (0.17-3.86) 0.78

Overall 1.64 (0.98-2.74) 0.06

Nissen N Engl J Med 2007; 356

CHF Risk with Thiazolidinediones

Lago Lancet 2007 370: 1129

Overall

Pioglitazone

Rosiglitazone

IncreasedDecreased

Risks & Benefits Glucose Rx inType 2 Diabetes Mellitus (1)

Drug Class(example) Benefits Risks

Biguanides(Metformin) Incrrease CVD?

GI EffectsLactic AcidosiseGFR Restricted

Sulfonylureas(Glipizide)

Decr MicrovascularDisease

Incr WeightHypoglycemia

Thiazolidinediones(Pioglitazone)

Incr HDL-CDecr TrigDecr ASCVD

Incr WeightEdemaIncr CHF Risk

Risks & Benefits Glucose Rx inType 2 Diabetes Mellitus (2)

Drug Class(example) Benefits Risks

DPP-4 Inhibitors(Saxagliptin)

Well tolerated

Angioedema, Pancreatitis?Incr CHF Hospitalization?

GLP-1 Receptor Agonist(Exenatide) Decr weight GI Effects

Injection Subq

SGLT2 Inhibitors(Canagliflozin)

Can even use with insulin

GU InfectionIncrease LDL-CPolyuriaKetoacidosisLimb ischemia

Heart Failure Hospital Admissions in DPP-4 CVD Safety TrialsTrial

(Glycemia Rx vs placebo)

Heart Failure HospitalizationHazard Ratio

(95% Confidence Interval)

SAVOR-TIMI 53(saxagliptin)

1.27(1.07 to 1.51)

EXAMINE(alogliptin)

1.19(0.90 to 1.58)

TECOS(sitagliptin)

1.00(0.83 to 1.20)

White N Engl J Med 2013; 369; 1327Zannat Lancet 2015; 385: 2067Green N Engl J Med 2015; June 10

Major Adverse CVD Events RiskEMPAREG Trial

Zinman N Engl J Med 2015; 373: 2117

CVD Death Risk EMPAREG Trial

Zinman N Engl J Med 2015; 373: 2117

Major Adverse CVD Events RiskLEADER Trial

Marso N Engl J Med 2016; 373: 311

CVD Death Risk LEADER Trial

Marso N Engl J Med 2016; 373: 311

Development of T2DM and CVD

Type 2 Diabetes Mellitus

CardiovascularDisease

Adiposity(Abdominal)

High Triglycerides

Elevated Glucose

Low HDL-C

Elevated BP

Smoking

Risk Factors

Family Hx T2DM

Family Hx CVD

High LDL-C

Age and Gender