Cardiovascular Risk Reduction and Other Co-Morbidities in Type 2 Diabetes

Following this presentation, you will be able to:

• Describe the relationship between major CV risk factors and CVD outcomes

• Select therapeutic modalities available to practitioners to improve CV risk factors

• Discuss other co-morbid/microvascular conditions seen in patients with type 2 diabetes

• Recognize the implications of recent large trials on guiding clinical decisions and targets for blood pressure and lipid abnormalities

• Explain the role of pharmacologic intervention in the treatment of type 2 diabetes

CV = cardiovascular; CVD = cardiovascular disease.

Type 2 Diabetes and CVD

Lewis GF. Can J Cardiol. 11(suppl C):24C-28C, 1995; Norhammar A, et.al. Lancet 359;2140-2144, 2002; NCEP ATP III. Circulation. 2002;106(25):3143; Meigs, et al. Am J Med. 1997;102:38-47.

CAD = coronary artery disease; CHD = coronary heart disease; CVD = cardiovascular disease; MI = myocardial infarction.

• Type 2 diabetes is considered a CHD equivalent

• Atherosclerotic complications are responsible for:

– 80% of mortality among patients with diabetes

– More than 75% of all hospitalizations for diabetic complications

• 50% of patients with type 2 diabetes have preexisting CAD

• One-third of patients presenting with MI have undiagnosed diabetes mellitus

Absolute Risk of MI Is Higher in Patients with DM

Booth GL, et al. Lancet 368:29-36, 2006.

DM = diabetes mellitus; MI = myocardial infarction.

20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85

Age group

0.5

1.0

1.5

2.0

2.5

3.0

0

No

. eve

nts

pe

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00

pe

rso

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s

All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each

Diabetes n = 379,003 No Diabetes n = 9,018,082 Database 1994-2000

No diabetesMen

Women

DiabetesMen

Women

T2DM for >15 Years Duration Confers Similar Risk of Fatal CHD as Prior CHD and No Diabetes

20-year Follow-Up of 121,046 Women Aged 30 to 55 Years in Nurses’ Health Study

Hu F, et al. Arch Intern Med. 161:1717-1723, 2001.

CHD = coronary heart disease; DM = diabetes mellitus; T2DM = type 2 diabetes mellitus.

Age-standardized Rates ofDiabetes Complications: 1990-2010

Gregg EW, et al. N Engl J Med 370:1514-1523, 2014.

ESRD = end-stage renal disease.

Rates of diabetes-related complications declined between 1990 and 2010

(relative risk reductions):Myocardial infarction -68.8%, death from hyperglycemic crisis -64.4%,

end-stage renal disease -28.3%, stroke and amputation ~50%

Event Rates/10,000 Adults/Year

Gregg EW, et al. N Engl J Med 370:1514-1523, 2014.

ESRD = end-stage renal disease.

How Is CAD Different in Diabetes?

• > CAD extent• Multi-vessel disease

• Distal disease – more difficult to revascularize

• Silent ischemia/MI

• Younger

• Women

• Worse outcomes despite revascularization• Increased re-stenosis after PCI even with stents

• ACB: worse perioperative and long-term outcomes

ACB = aortocoronary bypass; CAD = coronary artery disease; MI = myocardial infarction; PCI = percutaneous coronary intervention.

Adipose Tissue in Obesity

Després J-P. Eur Heart J Suppl. 8(suppl B):B4-12, 2006.Gustafson. Arterioscler Thromb Vasc Biol, 27(11): 2276-2283, 2007.

Lean Obese

Abdominal Obesity and Increased Risk of Cardiovascular Events: HOPE Study

Dagenais GR, et al. Am Heart J. 149(1):54-60, Jan 2005.

BMI = body mass index; C = cholesterol; CVD = cardiovascular disease; DM = diabetes mellitus; HDL = high density lipoprotein; MI = myocardial infarction.

AdjustedRelativeRisk

1 1 1

1.17 1.16 1.14

1.29 1.27

1.35

0.8

1

1.2

1.4

CVD death MI All-cause deaths

Tertile 1

Tertile 2

Tertile 3

Men Women<37.4

37.4–40.5

>40.5

<34.3

34.3–38.5

>38.5

Waistcircumference (in):

*Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C

Glucose Control and CHD Events

Ray KK, et al. Lancet. 373:1765-1772, 2009.

ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; CHD = coronary heart disease; PROactive = Prospective Pioglitazone Clinical Trial in Macrovascular Events; UKPDS = United Kingdom Prospective Diabetes Study Group; VADT = Veterans Affairs Diabetes Trial.

A1C During DCCT and EDIC Observation

A1C = glycated hemoglobin; DCCT = Diabetes Control and Complications Trial; EDIC = Epidemiology of Diabetes Interventions and Complications.

Nathan DM, et al. N Engl J Med 353:2643–53, 2005.

5

6

7

8

9

10

11

Gly

cosy

late

d h

em

ogl

ob

in (

Pe

rce

nt)

0 1 2 3 4 5 86 7 9 10 1 2 3 4 5 86 7 9

Intensive -mean A1C 8.0 %

Study year

Conventional -mean A1C 8.2 %

DCCT Intervention EDIC Observation

Training

Intensive - mean A1C 7.2 %

Conventional - mean A1C 9.1 %

Cumulative Incidence of the First of Any Predefined Cardiovascular Disease Outcomes

Nathan DM, et al. N Engl J Med 353:2643–53, 2005.

Years since entry

Cu

mu

lati

ve in

cid

en

ce o

f an

y p

red

efin

ed

car

dio

vasc

ula

r o

utc

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e

Intensive 705 683 629 113

Conventional 714 688 618 92

No. at Risk

Conventional treatment

Intensive treatment

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Risk reduction 42% 95% CI: 9, 63

Log-rank P = 0.016

Strategies for Reducing Macrovascular Complications

Prevention proven by intervention

Hyperglycemia

Hypertension

Dyslipidemia

Antiplatelet therapy

Smoking Cessation

Exercise

Association of SBP and CV Mortality in Men with T2DM

Stamler J, et al. Diabetes Care. 16:434-444, 1993.

CV = cardiovascular; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus.

250

200

150

100

50

0<120 120-139 140-159 160-179 180-199

SBP (mmHg)

CV

mo

rtal

ity

rate

Pe

r 1

0,0

00

pe

rso

n-y

ears

No diabetesDiabetes

≥200

Effect of Intensive BP Lowering on Risk of Micro-and Macrovascular Complications: UKPDS

UKPDS Group. UKPDS 38. BMJ. 317:703-713, 1998.

Benefits of 144/82 mmHG vs 154/87 mmHG

Any diabetes-related

endpoint

Diabetes-relateddeath

Heartfailure

Myocardialinfarction

Renalfailure

Vision deterioration

-21-24

-32-34

-42-44

-47

-56-60

-50

-40

-30

-20

-10

0

Ris

k R

ed

uct

ion

(%

)

Retinopathy Stroke

BP = blood pressure; UKPDS = United Kingdom Prospective Diabetes Study Group.

Guideline Recommendations for Uncomplicated and Complicated Hypertension

Chobanian, et al. Hypertension. 42:1206–52, 2003. Garber AJ, et al. Endocr Pract. 19(suppl 2):1-48, 2013.Handelsman Y, et al. Endocr Pract. 17(suppl 2):1-53, 2011. Torre JJ, et al. Endocr Pract. 12:193-222, 2006.

BP = blood pressure; MI = myocardial infarction.

*Lower if proteinuria is >1 g/day.

Type of hypertension BP goal (mmHg)

Uncomplicated <140/90

Complicated

Diabetes mellitus <130/80

Kidney disease <130/80*

Other high risk (stroke, MI) <130/80

Garber AJ et al. Endocr Pract. 2015;21(No. 4)

AACE = American Association of Clinical Endocrinologists

Strategies for Reducing Macrovascular Complications

Prevention proven by intervention

Hyperglycemia

Hypertension

Dyslipidemia

Antiplatelet therapy

Smoking Cessation

Exercise

Priorities for Lipid Levels in Adult Patients with Diabetes

Handelsman Y et al. Endocr Pract. Vol 21; (Suppl 1). 2015

HDL = high density lipoprotein; LDL = low density lipoprotein; TG = triglyceride.

• LDL cholesterol lowering

Statin at maximally tolerated dose

• HDL cholesterol raising

Behavior: weight loss, physical activity, smoking cessation

Glycemic control

• Triglyceride lowering

Glycemic control first priority

Fibric acid derivative (gemfibrozil, fenofibrate)

Statins at high dose also have some TG lowering

Niacin or high-dose omega-3 fatty acids

Triglyceride goal presently <150 mg/dL

Cholesterol Lowering in High Risk Patients: The Heart Protection Study

LDL lowering resulted in 22% reduction in CVD events across all LDL categories

CHD = coronary heart disease; CVD = cardiovascular disease; LDL = low density lipoprotein; MI = myocardial infarction.

HPS Collaborative Group. Lancet. 2002;360:7-22.

Statins and CVD in Patients with Diabetes:CTT Meta-analysis

Cholesterol Treatment Trialists. Lancet 371: 117, 2008.

CTT = Cholesterol Trialists Collaboration; CVD = cardiovascular disease; RR = rate ratio.

Statin Therapy in DiabetesAmerican Diabetes Association 2016

ADA Diabetes Care 38:S63, 2016.

ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; LDL = low density lipoprotein; LDL-C = low density lipoprotein-cholesterol.

Age(years)

Risk Factors

Statin Dose

Lipid Monitoring

<40None

ASCVD risk factor(s)**ASCVD***

No medicationModerate or high

High

Yearlyor as needed

40-75

NoneASCVD risk factors

ASCVDACS and LDL> 50 mg/dL*

ModerateHighHigh

Moderate + Ezetimibe

To monitoradherence

>75

NoneCVD risk factors

Overt CVDACS and LDL>50 mg/dL*

ModerateModerate or high

HighModerate + Ezetimibe

To monitor adherence

* On basis of IMPROVE-IT subgroup** LDL-C>100 mg/dL, hypertension, smoking, overweight or obesity

Intensity of Statin Therapy (Doses in mg/day)

Stone NJ et al. Circulation. 2014;129[suppl 2]:S1-S45

Boldface type indicates specific statins and doses that were evaluated in RCTs included in CQ1, CQ2, and the Cholesterol Treatment Trialists 2010 meta-analysis

included in CQ3. All of these RCTs demonstrated a reduction in major cardiovascular events. Italic type indicates statins and doses that have been approved by the FDA

but were not tested in the RCTs reviewed.

Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biological basis for a less-than-average

response.

†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental Decrease through Aggressive Lipid Lowering) study.

‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of the increased risk

of myopathy, including rhabdomyolysis.

BID indicates twice daily; CQ, critical question; FDA, Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; and RCTs,

randomized controlled trials.

Low-intensity daily statin

Moderate-intensity daily statin

High-intensity daily statin

Reduce LDL-C <30%

Reduce LDL-C 30% to <50%

Reduce LDL-C >50%

Simvastatin 10Pravastatin 10-20Lovastatin 20Fluvastatin 20-40Pitavastatin 1

Atorvastatin 10-20Rosuvastatin 5-10 Simvastatin 20-40‡Pravastatin 40-80 Lovastatin 40 Fluvastatin XL 80 Fluvastatin 40 BIDPitavastatin 2-4

Atorvastatin (40†)-80 Rosuvastatin 20-40

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

New Eng J Med 372:1489-1499, 2015.New Eng J Med 372:1500-1509, 2015.

LDL-C = low density lipoprotein-cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.

• Reduce LDL-C levels

• Have been shown to reduce cardiovascular endpoints

The Role of PCSK9 in the Regulation of LDL Receptor Expression

For illustration purposes only

LDL = low density lipoprotein; LDL-R = low density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9; SREBP = sterol response element binding protein.

Lambert G, et al.. J Lipid Res. 2012; Vol 53: 2515-2524.

PCSK9 Inhibitors

IND1ICATIONS

• Adjunct to diet and maximally tolerated statin therapy in adults

• Heterozygous familial hypercholesterolemia

• Clinical atherosclerotic CV disease who require additional lowering of LDL-C

SIDE EFFECTS Injection site reactions; myalgias; neurocognitive (confusion, impaired memory); nasopharyngitis; upper respiratory tract infection; back pain; influenza.

DOSAGE:

Alirocumab(PraluentR)

Evolucumab(RepathaR)

75 mg/2 weeks or 150 mg /2 weeks

140 mg /2 weeks or 420mg/month

CV = cardiovascular; LDL-C = low density lipoprotein-cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9.

-59

-49.3-51.4

-27.2

-62

-52.3-54

-25.6

-63.3

-53.9-55.4

-24.9

-70

-60

-50

-40

-30

-20

-10

0

LDL-C Non-HDL-C Apo B Lp(a)

DM Entire Cohort no DM

Alirocumab in Individuals with and

without Diabetes: ODYSSEY Study

Colhoun HM, et al. Presented September 19, 2015 EASD Stockholm, Sweden.

HeFH or high CV

risk patients on

maximally

tolerated statin ±other LLT, with

LDL >70 mg/dL

Least-squares

mean difference,

baseline to week

24

Apo B=apolipoprotein B;

CV=cardiovascular;

DM=diabetes mellitus;

HeFH=heterozygous

familial

hypercholesterolemia;

Lp(a)= lipoprotein(a);

LDL=low density

lipoprotein; LLT=lipid-

lowering therapy

Strategies for Reducing Macrovascular Complications

Prevention proven by intervention

Hyperglycemia

Hypertension

Dyslipidemia

Antiplatelet therapy

Smoking Cessation

Exercise

What About ASA for 1⁰ Prevention of CVD?

De Berardis G, et al. BMJ 339:b4531, 2009.

ASA = acetylsalicylic acid (aspirin); CVD = cardiovascular disease.

Included: 6 studies, N = 10,117 participants

ASA for 1⁰ Prevention in Diabetes: Meta Analysis of 6 Studies (N=10,117)

De Berardis G, et al. BMJ 339:b4531, 2009.

ASA = acetylsalicylic acid (aspirin); CV = cardiovascular; ETDRS = Early Treatment Diabetic Retinopathy Study; JPAD = Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; MI = myocardial infarction; PHS = Physicians’ Health Study; POPADAD = Prevention of Progression of Arterial Disease and Diabetes; PPP = Primary Prevention Project; RR = rate ratio; WHS = Women’s Health Study.

No overall benefit for: • Major CV events • MI• Stroke• CV mortality• All-cause mortality

0.03 0.125 0.5 12

8Favors ASA Favors control/placebo

JPADPOPADADWHSPPPETDRSTotal

68/1262105/63858/51420/519

350/1856601/4789

86/1277108/63862/51322/512

379/1855657/4795

0.80 (0.59-1.09)0.97 (0.76-1.24)0.90 (0.63-1.29)0.90 (0.50-1.62)0.90 (0.78-1.04)0.90 (0.81-1.00)

Major CV events

No. of events/No. in group

ASA Control/placebo RR (95% CI) RR (95% CI)

JPADPOPADADWHSPPPETDRSPHSTotal

28/126290/63836/5145/519

241/185611/275

395/5064

14/127782/63824/51310/512

283/185526/258

439/5053

0.87 (0.40-1.87)1.10 (0.83-1.45)1.48 (0.88-2.49)0.49 (0.17-1.43)0.82 (0.69-0.98)0.40 (0.20-0.79)0.86 (0.61-1.21)

Myocardial infarction

JPADPOPADADWHSPPPETDRSTotal

12/126237/63815/5149/519

92/1856181/4789

32/127750/63831/51310/512

78/1855201/4795

0.89 (0.54-1.46)0.74 (0.49-1.12)0.46 (0.25-0.85)0.89 (0.36-2.17)1.17 (0.87-1.58)0.83 (0.60-1.14)

Stroke

JPADPOPADADPPPETDRSTotal

1/126243/63810/519

244/1856298/4275

10/127735/6388/512

275/1855328/4282

0.10 (0.01-0.79)1.23 (0.80-1.89)1.23 (0.49-3.10)0.87 (0.73-1.04)0.94 (0.72-1.23)

Death from CV causes

JPADPOPADADPPPETDRSTotal

34/126294/63825/519

340/1856493/4275

38/1277101/63820/512

366/1855525/4282

0.90 (0.57-1.14)0.93 (0.72-1.21)1.23 (0.69-2.19)0.91 (0.78-1.06)0.93 (0.82-1.05)

All-cause mortality

Antiplatelet Agents in Diabetes: 2013

American Diabetes Association. Diabetes Care. 36(Suppl 1):S11-66, Jan 2013.

CV = cardiovascular; CVD = cardiovascular disease; HTN = hypertension.

• Primary prevention (75-162 mg/day)• Type 1 or type 2 diabetes at increased CV risk (10-year risk

>10%)• Men >50 years of age or women >60 years with 1+ additional

major risk factor• Family history of CVD, HTN, smoking, dyslipidemia, or

albuminuria• Not sufficient evidence to recommend aspirin for primary

prevention in lower-risk individuals

• Secondary prevention (75-162 mg/day)• Use aspirin therapy as a secondary prevention strategy in

those with diabetes with a history of CVD

STENO-2

STENO-2: Intensive Group Achieved Targets

Gaede, et al. NEJM. 348;383-393, 2003.

BP = blood pressure.

STENO-2: Intensive Group Had Improved CV Outcomes

CV = cardiovascular; NNT = number needed to treat; RRR = relative risk reduction.

Gaede, et al. NEJM. 348;383-393, 2003.

12 24 36 48 60 72 84 960

10

20

30

40

50

60P = 0.007

Conventional therapy

Intensive therapy

Months of Follow-up

53 % RRRAny CV event

NNT = 5

STENO 2: Microvascular Disease

Gaede, et al. NEJM. 348;383-393, 2003.

STENO 2: 21-Year Follow-up, Death, or CVD Events

Gaede, et al. Diabetologia. 2016;59:2298-2307.

Median

survival was

7.9 years

longer

in intensive

vs

conventional

group

CVD = cardiovascular disease

The Prevalence of U.S. Adults with Diabetes Achieving A1C, Blood Pressure, and LDL-C Goals: 1998—2010: NHANES

Casagrande SS, Cowie CC, Fradkin JE, Rust KF, Saydah SH. Diabetes Care 36:2271-2279, 2013.

A1C = glycated hemoglobin; BP = blood pressure; LDL = low density lipoprotein; LDL-C = low density lipoprotein-cholesterol; NHANES = National Health and Nutrition Examination Survey.

43.1

33.2

9.9

4.5

44.1

38.135.3

7

57

44.248

12

52.5 51.1

56.2

18.8

0

10

20

30

40

50

60

A1C<7.0% BP<130/80 LDL<100mg/dL All 3 at Goal

1988-1994 1999-2002 2003-2006 2007-2010Percent (%)

Still a long way to go