statin therapy and incident diabetes · statin therapy for every 54 new cases of diabetes...
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Statin Therapy and Incident Diabetes:Is it a relevant clinical issue for either
primary or secondary prevention?
Paul M Ridker, MD
Eugene Braunwald Professor of Medicine
Harvard Medical School
Director, Center for Cardiovascular Disease Prevention
Brigham and Women’s Hospital, Boston MA
Dr Ridker has received investigator-initiated research support
from the NHLBI, NCI, American Heart Association, Donald W
Reynolds Foundation, Leduc Foundation, Doris Duke Charitable
Foundation, AstraZeneca, Novartis, and SanofiAventis.
Dr Ridker has served as a consultant to Vascular Biogenics,
Merck, ISIS, and Genzyme.
Dr Ridker is listed as a co-inventor on patents held by the
Brigham and Women’s Hospital (BWH) that relate to the use of
inflammatory biomarkers in cardiovascular disease and diabetes
that have been licensed to Seimens and AstraZeneca. Dr. Ridker
and the BWH receive royalties on sales of the hsCRP test.
However, neither Dr. Ridker nor the BWH receives any royalties
attributable to sales of the hsCRP test used in connection with
the CIRT or CANTOS trials.
Rosuvastatin 20 mg (N=8901)MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
4-week
run-in
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
JUPITER
Trial Design
Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Mean LDLC 104 mg/dL, Mean HDLC 50 mg/dL, hsCRP 4 mg/L
JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
Ridker et al NEJM 2008;359:2195-2207
3
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve
In
cid
en
ce
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
Ridker et al NEJM 2008;359:2195-2207
JUPITER
Fatal or Nonfatal Myocardial Infarction
Rosuvastatin
Placebo
- 55 %
0 1 2 3 4
Follow-up Years
0.0
00
0.0
05
0.0
10
0.0
15
0.0
20
0.0
25
0.0
30
Cu
mu
lati
ve
In
cid
en
ce
HR 0.45, 95%CI 0.30-0.70
P < 0.0002
Ridker et al NEJM 2008;359:2195-2207
JUPITER
Fatal or Nonfatal Stroke
Rosuvastatin
Placebo
- 48 %
0 1 2 3 4
Follow-up Years
0.0
00
0.0
05
0.0
10
0.0
15
0.0
20
0.0
25
0.0
30
Cu
mu
lati
ve
In
cid
en
ce
HR 0.52, 95%CI 0.34-0.79
P = 0.002
Ridker et al NEJM 2008;359:2195-2207
JUPITER
Arterial Revascularization / Unstable Angina
Placebo (N = 143)
Rosuvastatin (N = 76)
HR 0.53, 95%CI 0.40-0.70
P < 0.00001
- 47 %
0 1 2 3 4
0.0
00
.01
0.0
20
.03
0.0
40.0
50.0
6
Cu
mu
lati
ve
In
cid
en
ce
Number at RiskFollow-up (years)
Rosuvastatin
Placebo
8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158
8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176
Ridker et al NEJM 2008;359:2195-2207
JUPITER
Secondary Endpoint – All Cause Mortality
Placebo 247 / 8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
- 20 %
0 1 2 3 4
0.0
00
.01
0.0
20
.03
0.0
40
.05
0.0
6
Cu
mu
lati
ve
In
cid
en
ce
Number at RiskFollow-up (years)
Rosuvastatin
Placebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
NEJM 2008;359:2195-2207
JUPITERPrimary Endpoint – Understudied or “Low Risk” Subgroups
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Women
Age > 70
Framingham Risk < 10 %
Black, Hispanic, Other
No Hypertension
All Participants
N HR (95%CI)
6,801 0.54 (0.37-0.80)
5,695 0.61 (0.46-0.82)
8,882 0.56 (0.38-0.83)
5,117 0.63 (0.41-0.98)
7,586 0.62 (0.44-0.87)
17,802 0.56 (0.46-0.69)
BMI < 25 mg/m2 4,073 0.59 (0.40-0.87)
No metabolic Syndrome 10,296 0.49 (0.37-0.65)
Understudied Subgroups
“Low Risk” Subgroups
Ridker et al NEJM 2008;359:2195-2207
9
CRP, IL-6 and the Risk for Developing
Type-2 Diabetes in the Women’s Health Study
Pradhan et al JAMA 2001; 286:327-34
0
2
4
6
8
10
12
14
16
1 2 3 4
0
2
4
6
8
10
12
14
16
1 2 3 4
Relative Risk
IL-6
Relative Risk
hs-CRP
Quartile of IL-6 Quartile of hs-CRP
Fully adjusted BMI-adjusted Crude
0 2 4 6 8
Years of Follow-Up
0.95
0.96
0.97
0.98
0.99
1.00C
VD
Eve
nt-
Fre
e
Su
rviv
al
Pro
ba
bilit
y
CRP < 1 mg/L
CRP 1-3 mg/L
CRP >3 mg/L
CRP adds to the ATP-III Definition of the Metabolic Syndrome
(N = 3,097 with ATP-III Metabolic Syndrome)
Ridker et al
Circulation 2003;107:391-7
JUPITER
Adverse Events and Measured Safety Parameters
Event Rosuvastatin Placebo P
Any SAE 1,352 (15.2) 1,337 (15.5) 0.60
Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy 10 (0.1) 9 (0.1) 0.82
Rhabdomyolysis 1 (0.01)* 0 (0.0) --
Incident Cancer 298 (3.4) 314 (3.5) 0.51
Cancer Deaths 35 (0.4) 58 (0.7) 0.02
Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02
ALT > 3xULN 23 (0.3) 17 (0.2) 0.34
Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12
HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01
Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64
Incident Diabetes** 270 (3.0) 216 (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)
**Physician reported
JUPITER
Statins and the Development of Diabetes
0.25 0.5 1.0 2 4
WOSCOPS Pravastatin
HPS Simvastatin
ASCOT-LLA Atorvastatin
JUPITER Rosuvastatin
PROVE-IT AtorvastatinVS
Pravastatin
0.70 (0.50–0.98)
1.20 (0.98–1.35)
1.20 (0.91–1.44)
1.11 (0.67–1.83)
1.25 (1.05–1.54)
Statin Better Statin Worse
HR (95% CI)
PROSPER Pravastatin 1.34 (1.06–1.68)
LIPID Pravastatin 0.91 (0.72–1.18)
CORONA Rosuvastatin 1.13 (0.86–1.50)
(Hypothesis Testing Trials) 1.12 (1.04–1.30)
(Hypothesis Generating Trial)
Rajpathak et al, Diabetes Care 2009;32:1924-29
Meta-regression p-value=0.102
Sattar et al, Lancet 2010;375:735-42
Statin-Associated New Onset DMRelationship to LDL-C Lowering
Vascular benefits in secondary prevention greatly exceed risks, no implication
for practice other than increased vigilence.
Statin-Associated New Onset DMMeta-Analysis of Intensive-Dose vs. Moderate-Dose Statin Therapy
80A vs 40P40-80S vs P-40S80A vs 10A80A vs 20S or 40S80S vs 20S
22%15%22%16%12%
DLDL ↓
CVD defined as first MI, stroke, coronary revascularization, or cardiovascular death
Preiss D et al, JAMA 2011;305:2556-2564
Treatment Arms
Statin-Associated New Onset DMIntensive vs. Moderate Dose, Relationship to LDL-C Lowering
LDL reduction 16-22%
LDL reduction 12-15%
Main Conclusions
When comparator was lower dose statin, trends toward increased risk were not statistically significant.
44% increase in NODM associated with 80 mg atorvastatin vs. placebo
Baseline fasting glucose and features of the metabolic syndrome associate with NODM across all three trials.
Three Large RCTs of Atorvastatin
TNT (Treating to New Targets); 80 vs. 10 Atorva
IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering); 80 Atorva vs. 20 Simva
SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels); 80 Atorva vs. Placebo
Statin-Associated NODMClinical Predictors of NODM in Primary Prevention
Waters et al, JACC 2011;57:1535-45
SPARCL
Risk Factor Present
Risk Factor Absent
HR 2.8
HR 2.4
HR 2.4
HR 1.9
NOD Versus CV Event ReductionEffect of Baseline Risk Factors for DM in TNT and IDEAL
Waters D et al, JACC 2013:61;148-52
“We are overdosing on cholesterol-lowering statins,
and the consequence could be a sharp increase in the
incidence of Type 2 diabetes”.
“In the vast majority of people who take statins – those
who never had any heart disease – there should be a
careful review of whether the statin is necessary, in
light of the risk of diabetes and the relatively small
benefit that can be derived. Beyond that, a dose
reduction or use of a less potent statin should be
considered on an individual basis”.
- Eric Topol, NY Times Op-Ed, March 4, 2012
February 28, 2012, FDA approves safety change for statins as a class:
Statin-Associated New Onset DMFDA Safety Announcement
Addition of information about the potential
for generally non-serious and reversible
cognitive side effects and reports of
increased blood sugar and HbA1c
JUPITERIncident Diabetes Limited to Those With Impaired Fasting Glucose
(51) (62) (18)
(43)
(39) (38)
(34)
(53)
(34) (29)
(39)
(45)
Fasting Glucose Level (mg/dL)
0
2
4
6
8
10
12
14
<100 100-104 105-109 110-114 115-119 120-125
Inc
ide
nc
e R
ate
(p
er
10
0 p
ers
on
ye
ars
)
Placebo
Rosuvastatin
Ridker et al Lancet 2012;380:
JUPITER
Statin Highly Effective in All Patients – Primary Endpoint
HR 0.51, 95% CI 0.40-0.67
Normal Fasting Glucose
HR 0.69, 95% CI 0.49-0.98
Impaired Fasting Glucose
0 1 2 3 4
Follow-up Years
0.0
00
.02
0.0
40
.06
0.0
80
.10
Cu
mu
lati
ve
In
cid
en
ce
0 1 2 3 4
Follow-up Years
Rosuvastatin
Rosuvastatin
PlaceboPlacebo
Ridker et al Lancet 2012
JUPITERCardiovascular Benefits of Statin Therapy In All High Risk Groups for Diabetes
0.20 0.5 1.0 2.0
Nonfatal MI+ Stroke
RosuvastatinSuperior Inferior
Metabolic
Syndrome
Y
N
FG >100 mg/dL_ Y
N
BMI > 30 kg/m2_ Y
N
HbA1c >6 % Y
N
Any Risk Factor Y
N
N
7,316
10,278
5,504
12,170
6,637
11,042
3,008
14,615
11,508
6,095
0.20 0.5 1.0 2.0
Revascularization +Unstable Angina
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
VTE
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
Mortality
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
Diabetes
RosuvastatinSuperior Inferior
Ridker et al Lancet 2012
Cardiovascular Benefits and Diabetes Risks of Statin
Therapy in Primary Prevention: The JUPITER Trial
• In absolute terms for those without a major diabetes risk factor, 86 vascular events or death were avoided by statin therapy with no excess cases of diabetes diagnosed.
• In absolute terms for those with a major diabetes risk factor, 134 vascular events or deaths were avoided by statin therapy for every 54 new cases of diabetes diagnosed.
• Statin therapy increased the time to diagnosis of diabetes by 5.4 weeks.
• Conclusion: In primary prevention, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including among individuals at high risk for developing diabetes. Long-term microvascular effects unknown.
Decreased insulin secretion, due to reduced ubiquinone and delayed ATP production
Apoptosis, islet inflammation
b-cell dysfunction
Statin-induced myopathy and ensuing peripheral insulin resistance, diminished glucose uptake
Hepatic insulin resistance
Insulin Resistance
Isoprenoid depletion causing reduced glucose uptake in adipocytes
Decreased adiponectin levels with some but not all statins
Adipocyte Signaling and Function
Increase total adiposity
Increase in visceral fat
Change in Body Composition
Potential MechanismsPreviously Examined with Inconsistent Results
Statins in patients with diabetes: CTT Collaborators meta-analysis
CTT Collaborators Lancet 2008;371:117
Major Coronary Event
Diabetes 0.78 (0.69-0.87)
No diabetes 0.77 (0.73-0.81)
Coronary Revascularization
Diabetes 0.75 (0.64-0.88)
No diabetes 0.76 (0.72-0.81)
Stroke
Diabetes 0.79 (0.67-0.93)
No diabetes 0.84 (0.76-0.93)
Major vascular event
Diabetes 0.79 (0.72-0.86)
No diabetes 0.79 (0.76-0.82)
Intensive glucose reduction and CVD:
Meta-analysis All-cause mortality:OR 1.02 (0.87-1.19)
Ray et al. Lancet 2009;373:1765
Number of cardiovascular events prevented by treating glucose, SBP, and LDL-C
• Treating 200 patients with diabetes for 5 years
– Focusing on HbA1c reduction leads to relative modest event reductions
– Reductions more substantial with SBP or LDL-C reductions
Sattar N. Diabetologia. 2013;56:686