macrovascular disease in diabetes
TRANSCRIPT
Macrovascular Disease in Diabetes
Jamie Smith
52%48%
CVD deaths Other deaths
CVD related mortality increases in pa3ents with type 2 diabetes
1AHA in h;p://www.americanheart.org/downloadable/heart/1236204012112INTL.pdf 2Morish et al. Diabetologia 2001;44(Suppl 2):S14-‐S21. Lancet 1997;350(Suppl. 1):SI23–8
People with type 2 diabetes: • will die 5-‐10 years before people
without diabetes • are twice as likely to have a heart a;ack
or stroke as people who do not have diabetes
• are 15-‐40 3mes more likely to have a lower limb amputa3on
•
Age adjusted
Women
Men
Mul-ple adjusted*
Women
Men
Rela-ve risk
3.69
2.16
3.12
1.99
Rela3ve risk (95% CI)
1 1.5 2 3 4 8
Excess risk for coronary heart disease in pa3ents with type 2 diabetes
*All studies adjusted for systolic blood pressure and total cholesterol. All but two studies also adjusted for smoking
Huxley et al. BMJ 2006;332:73–8 CI, confidence interval
Does Primary Preven3on Exist in Type 2 Diabetes?
Diabetic patients without previous MI have as high a risk of MI as non-diabetic patients with previous MI
Haffner SM, et al. New England Journal of Medicine 1998;339:229–234.
Without previous MI With previous MI
7-ye
ar in
cide
nce
of M
I (%
)
05
1015202530354045
non-diabetic with diabetes
Kaplan-Meier survival curves for a coronary heart disease event by baseline diabetes and MI status; the ARIC study, 1987 to 1997.
Modified from Reaven G. In: Le Roith D, et al. (eds). Diabetes Mellitus: A Fundamental and Clinical Text. 2000;pp604-‐614
Genetic influences!
Insulin Resistance! Environmental
influences!
Hyperinsulinaemia"
Glucose intolerance!
Increased triglycerides!
Decreased HDL !
Small dense LDL!
Hypertension!
Endothelial dysfunction! Procoagulant state!
Cardiovascular disease!
Insulin Resistance Syndrome
LDL
Risk factors for cardiovascular disease
Libby and Plutzky. Circula0on 2002;106:2760–3
The Major Suspects
HYPERGLYCAEMIA
DYSLIPIDAEMIA
HYPERTENSION
*Adjusted for age, sex, and duration of diabetes Stratton IM et al. BMJ. 2000;321:405-412
A1C Predicts Myocardial Infarc-on in Type 2 Diabetes
UKPDS
1 1.3
1.8 1.9
2.5 2.4
0
1
2
3
<6 6 to <7 7 to <8 8 to <9 9 to <10 ≥10
Relative risk
A1C (%)
4585 Patients Followed for 10 Years*
Selvin et al. New Eng J Med 362:800-‐811, 2010
Glycated Hemoglobin, Diabetes and Cardiovascular Risk in Non Diabe-c Adults
Currie et al. Lancet 375:2010
HbA1c and All Cause Mortality
Met + SU Insulin based regime
CV benefits of tight glycaemic control 10 years after intensive treatment discontinuation:
UKPDS
SU/insulin vs. conventional Metformin vs. conventional
Holman et al. N Engl J Med 2008;359:113
Conventional: 21 24 27 31 34 36
0.4
0.6
0.8
1.0
1.2
1.4
Haz
ard
ratio
MI HR=0.84 p=0.052
HR=0.85 p=0.014
Percentage of events
SU/insulin: 18 21 24 27 30 32
1997 1999 2001 2003 2005 2007
Haz
ard
ratio
0.4
0.6
0.8
1.0
1.2
1.4 MI HR=0.61 p=0.010
HR=0.67 p=0.005
Conventional: 24 27 30 34 38 41
Percentage of events
Metformin: 14 16 20 23 24 29
1997 1999 2001 2003 2005 2007
All Cause Mortality in ACCORD Study
1.41%/yr
1.14%/yr
HR = 1.22 (1.01-‐1.46) P = 0.04
Primary & Secondary Outcomes: ACCORD
Intensive N (%)
Standard N (%) HR (95% CI) P
Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16
Secondary
Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04
Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004
Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74
CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02
CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17
Concern of cardiovascular risk with traditional oral anti-diabetic drugs
“Rosiglitazone was associated with a significant
increase in the risk of myocardial infarction and
with an increase in the risk of death from cardiovascular causes that had borderline
significance.”
Nissen et al. The New England Journal of Medicine 2007; 356:24 Rrosiglitazone now withdrawn from UK market
FDA guidance to industry on cardiovascular outcome trials
FDA request
Retrospectively compare incidence of Major Adverse Cardiovascular
Events (MACE) between drug X and total comparator
Incidence rate ratio
Upper limit of 95% confidence interval
< 1.0 > 1.3 and < 1.8
MACE liraglutide vs. total comparator
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf
Lipids
Why do Patients With Type 2 Diabetes Develop Cardiovascular Disease?
Hypertension
Obesity
Raised LDL cholesterol
Low HDL cholesterol
Hypertriglyceridaemia
♥
♥
Diabetes can be considered as ‘a state of premature cardiovascular death which is associated with chronic hyperglycaemia’.
Type 2 Diabetes Cardiovascular Disease Risk
Carries cholesterol to peripheral -ssues
Carries excess cholesterol from peripheral -ssues back to the liver
Apo A1
“Good Cholesterol” HDL
“Bad Cholesterol” LDL
Apo B
Atherosclero-c plaque forma-on
Cholesterol
Dyslipidaemia: What’s it all about?
Treatment Effect on the Primary Endpoint : CARDS Study
21 (1.5%)
24 (1.7%)
51 (3.6%)
83 (5.8%)
Atorva*
48% (11-‐ 69) 39 (2.8%) Stroke
31% (-‐16-‐ 59) 34 (2.4%) Coronary revascularisa-on
36% (9-‐ 55) 77 (5.5%) Acute coronary events
37% (17-‐ 52) p=0.001
127 (9.0%) Primary endpoint
Hazard Ra-o Risk Reduc-on (CI) Placebo* Event
* N (% randomised)
.2 .4 .6 .8 1 1.2
Favours Atorvasta-n Favours Placebo
Numbers Needed to Treat to Prevent One First Major Cardiovascular Event
NNT for 4 years 27 NNT for 5 years 21.5 Atorvasta-n 10mg daily
Meta-analysis of Statin Trials in Diabetes
?
TNT (80 mg of atorvastatin)
TNT (10 mg of atorvastatin)
Event Rates Plotted Against LDL-C Levels (2o prevention trials)
after LaRosa et al. NEJM 2005
30
25
20
15
10
5
0
Even
t (%
)
Statin Placebo
4S
4S
LIPID
CARE
HPS
LIPID
CARE HPS
LDL-C (mmol/L)
0.3 0.8 1.3 1.8 2.3 2.9 3.4 3.9 4.4 4.9 5.4
What about HDL?
The Framingham Study
Question 3
Uncertainty over future of HDL Raising Therapies……………………………………....
ACCORD Double 2 x 2 Factorial Design
Intensive Glycemic Control 5128
Standard Glycemic Control 5123
Lipid BP
Placebo Fibrate Intensive Standard
2371 2362 2753 2765
1383 1374
1391 1370
1193
1178 1184
1178
10,251
4733* 5518 * 94% power for 20% reduc-on in event rate, assuming standard group rate of 4% / yr and 5.6 yrs follow-‐up
ACCORD Study Design • Overall ACCORD Glycemia Trial: 10,251 par3cipants
• Lipid Trial: 5,518 par3cipants • 2765 randomized to fenofibrate • 2753 randomized to placebo
• Primary Outcome: First occurrence of a major cardiovascular event
(nonfatal MI, nonfatal stroke, cardiovascular death)
• 87% power to detect a 20% reduc3on in event rate, assuming placebo rate of 2.4%/yr and 5.6 yrs follow-‐up in par3cipants without events.
Plasma Lipid Levels During Trial
Adverse Experiences During Follow-‐up
Revised 06/16/10
Fenofibrate PlaceboAdverse events (no. (%)) (N=2765) (N=2753) P value
regardless of CPK 1110 (40.1%) 1115 (40.5%) 0.79plus CPK > 5 X ULN 7 (0.3%) 8 (0.3%) 0.79
plus CPK > 10 X ULN 1 (0.04%) 2 (0.07%) 0.62
Any nonhypoglycemic SAE 54 (2.0%) 43 (1.6%) 0.27
Any Myopathy/Myositis/ Rhabdomyolysis SAE
4 (0.1%) 3 (0.1%) 1.00
Any Hepatitis SAE 3 (0.1%) 0 (0.0%) 0.25
Any SAE attributed to lipid meds 27 (1.0%) 18 (0.7%) 0.18
Out of the ordinary severe muscle aches/pains:
Primary Outcome
Rate Rate (%/yr) (%/yr) HR (95% CI) P Value
Primary Outcome: Major Fatal or Nonfatal Cardiovascular Event 291 2.24 310 2.41 0.92
(0.79 -‐ 1.08) 0.32
Fenofibrate Placebo (N=2765) (N=2753)
N of Events
N of Events
Primary Outcome By Treatment Group and Baseline Subgroups
Comparison of ACCORD subgroup results with those from prior fibrate studies
Trial (Drug)
Primary Endpoint: Entire Cohort (P-value)
Lipid Subgroup Criterion
Primary Endpoint: Subgroup
HHS (Gemfibrozil)
-34% (0.02)
TG > 200 mg/dl LDL-C/HDL-C > 5.0
-71% (0.005)
BIP (Bezafibrate)
-7.3% (0.24)
TG > 200 mg/dl -39.5% (0.02)
FIELD (Fenofibrate)
-11% (0.16)
TG > 204 mg/dl HDL-C < 42 mg/dl
-27% (0.005)
ACCORD (Fenofibrate)
-8% (0.32)
TG > 204 mg/dl HDL-C < 34 mg/dl
-31%
Lipid Guidance in Diabetes : NICE 2008
High serum Triglyceride (fasting > 4.5mmol/L) • Assess and treat secondary causes
• NB. Trigs > 10 mmol/L risk of pancreatitis
• If persists – offer fibrate
• Consider omega-3 fish oils if needed
• If high CV risk and TG 2.3-4.5 mmol/L despite statin, consider adding fibrate
Lipid Guidance in Diabetes : JBS 2 Statins recommended for: 1. All those aged 40 or more with type 1 or type 2 diabetes
2. Those aged 18-39yrs with type 1 or 2 who have the following: retinopathy (not BDR) nephropathy (inc. microalb +) poor glycaemic control (HbA1c>9%)
hypertension cholesterol > 6mmol/L features of “metabolic syndrome” family history of premature CVD in 10 relative
Joint British Societies’ Guidelines 2: Heart, vol 91; December 2005
Lipid Guidance in Diabetes : JBS 2
Joint British Societies’ Guidelines 2: Heart, vol 91; December 2005
Lipid targets:
Total cholesterol 4mmol/L
LDL cholesterol 2mmol/L
“Other lipid-lowering drugs should be considered in addition to a statin if cholesterol (total / LDL) not achieved or if other lipid parameters such as HDL cholesterol or triglycerides need to be addressed.”
Blood Pressure
Published online March 14, 2010
Systolic Pressures (mean + 95% CI)
Average aner 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3
Medica3ons Prescribed (12 Month Visit)
Adverse Events Intensive N (%)
Standard N (%) P
Serious AE 77 (3.3) 30 (1.3) <0.0001
Hypotension 17 (0.7) 1 (0.04) <0.0001
Syncope 12 (0.5) 5 (0.2) 0.10
Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02
Hyperkalemia 9 (0.4) 1 (0.04) 0.01
Renal Failure 5 (0.2) 1 (0.04) 0.12
eGFR ever <30 mL/min/1.73m2 99 (4.2) 52 (2.2) <0.001
Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93
Dizziness on Standing† 217 (44) 188 (40) 0.36
† Symptom experienced over past 30 days from HRQL sample of N=969 par3cipants assessed at 12, 36, and 48 months post-‐randomiza3on
Primary & Secondary Outcomes Intensive
Events (%/yr) Standard
Events (%/yr) HR (95% CI) P Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20
Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55
Cardiovascular Deaths
60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74
Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25
Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03
Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a composite of the primary outcome, revasculariza0on and unstable angina (HR=0.95, p=0.40)
Blood Pressure Targets 140/80 mmHg for those without complications 130/80 mmHg if kidney, eye or cerebrovascular damage
Effects of Cardiac Autonomic Dysfunc-on on Mortality Risk in the Ac-on to Control Cardiovascular Risk in Diabetes (ACCORD) Trial
Diabetes Care. 2010 Jul;33(7):1578-‐84. Epub 2010 Mar 9.
Platelet Dysfunc-on
The following seem to be specific to Type 2 diabetes: – increased sensi-vity to aggrega-on – increased glycosyla-on – decreased concentra-on of Cyclic AMP
These result in increased platelet s-ckiness Therefore ALL pa-ents with Type 2 diabetes should be on aspirin therapy (75-‐150mg per day) from -me of
diagnosis
Unless Contraindicated!
UKPDS found that metformin reduces risk of macrovascular complications
death
0 5
10 15 20 25 30 35 40 45
P=0.0023 P=0.02
P=0.010
P=0.017
P=0.011
Diabetes
50
Metformin in overweight patients.
% ri
sk re
duct
ion
related
Any Macrovascular diabetes
Myocardial infarction related
All cause mortality
UKPDS 34. Lancet 1998;352:854–865