cardiovascular risk reduction and other co-morbidities in...
TRANSCRIPT
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
r 1
00
pe
rso
n-y
ear
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
om
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