Beyond LDL Cholesterol: Do Statins Have Other Roles?

November 8 - 12, 2008, New Orleans, Louisiana

Linda Brookes, MSc

February 16, 2009

Introduction

The question continues... do statins have "pleiotropic" benefits in addition to their principal action of inhibiting 2-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis? Three reports at the American Heart Association (AHA) 2008 Scientific Sessions in New Orleans, Louisiana, sought to elucidate the potential therapeutic effects mediated by these putative pleiotropic actions, addressing the questions:

Whether statins have potential benefits in apparently healthy people with normal or even "healthy" low-density lipoprotein cholesterol (LDL-C) levels?
Whether, following the disappointing results of the first 2 outcomes studies with rosuvastatin in patients with heart failure -- CORONA (COntrolled ROsuvastatin multiNAtional trial in heart failure) and GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico--Heart Failure) -- there might be a subgroup of patients with heart failure who may benefit from statin treatment?
Whether statins may protect against, or even induce, new-onset diabetes?

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Table 1. JUPITER: Primary and Secondary Endpoints
Endpoint	Event Rate*		HR (95% CI)	P Value
Endpoint	Placebo	Rosuvastatin
Primary endpoint	1.36	0.77	0.56 (0.46-0.69)	< .00001
Secondary endpoint
Nonfatal MI	0.33	0.12	0.35 (0.22-0.58)	< .00001
Any MI	0.37	0.17	0.46 (0.30-0.70)	.0002
Nonfatal stroke	0.34	0.16	0.52 (0.33-0.80)	.003
Any stroke	0.34	0.18	0.52 (0.34-0.79)	.002
Revascularization or unstable angina	0.77	0.41	0.53 (0.40-0.70)	< .00001
MI, stroke, or death from cardiovascular cause	0.85	0.45	0.53 (0.40-0.69)	< .00001
All-cause mortality	1.25	1.00	0.80 (0.67-0.97)	.02

HR = hazard ratio; 95% CI = 95% confidence interval; MI = myocardial infarction
*Number of events per 100 person-years

Table 2. JUPITER: Adverse Events
Event	Placebo	Rosuvastatin	P Value
Any serious adverse event (%)	15.5	15.2	.60
Muscle weakness (%)	15.4	16.0	.34
Myopathy (%)	0.1	0.1	.82
Rhabdomyolysis (%)	0.1	0.01	-
Incident cancer (%)	3.5	3.4	.51
Cancer deaths (%)	0.7	0.4	.02
Hemorrhagic stroke (%)	0.1	0.1	.44
New-onset diabetes (%)	2.4	3.0	.01

Table 3. JUPITER: Laboratory Values
Parameter	Placebo	Rosuvastatin	P Value
Glomerular filtration rate at 12 mo (mL/min/1.73 m²)	66.6 (58.8-76.2)	66.8 (59.1-76.5)	.02
ALT >3 × ULN (%)	17	23	.34
Fasting glucose at 24 mo (mg/dL)	98 (90-106)	98 (91-107)	.12
Glycated hemoglobin at 24 mo (mg/dL)	5.8 (5.6-6.1)	5.9 (5.7-6.1)	.001
Glucosuria at 12 mo (%)	32	36	.64

ALT = alanine aminotransferase; ULN = upper limit of normal; Values = median (interquartile range)

Table 2. JUPITER: Adverse Events
Event	Placebo	Rosuvastatin	P Value
Any serious adverse event (%)	15.5	15.2	.60
Muscle weakness (%)	15.4	16.0	.34
Myopathy (%)	0.1	0.1	.82
Rhabdomyolysis (%)	0.1	0.01	-
Incident cancer (%)	3.5	3.4	.51
Cancer deaths (%)	0.7	0.4	.02
Hemorrhagic stroke (%)	0.1	0.1	.44
New-onset diabetes (%)	2.4	3.0	.01

Table 4. Prespecified and Post Hoc Endpoints
	Event Rate^*		HR (95% CI)**	P Value^†
	Placebo	Rosuvastatin
Primary endpoint
hsCRP < 2.0	8.9	9.8	1.08 (0.88-1.32)	.062
hsCRP ≥ 2.0	14.0	12.2	0.87 (0.77-0.98)	.062
Coronary endpoint
hsCRP < 2.0	7.5	8.7	1.14 (0.91-1.43)	.023
hsCRP ≥ 2.0	11.3	9.6	0.85 (0.74-0.97)	.023
All-cause mortality
hsCRP < 2.0	8.3	9.7	1.16 (0.94-1.42)	.026
hsCRP ≥ 2.0	14.1	12.6	0.89 (0.79-1.00)	.026
All-cause mortality/heart failure hospitalization^†
hsCRP < 2.0	13.9	19.6	1.10 (0.93-1.30)	.011
hsCRP ≥ 2.0	24.1	20.8	0.87 (0.79-0.96)	.011

HR = Cox-adjusted hazard ratio; CI = confidence interval
^* Number of events per 100 patient-years of follow-up
**Interaction by treatment
^†Post hoc endpoint

Table 4. Prespecified and Post Hoc Endpoints
	Event Rate^*		HR (95% CI)**	P Value^†
	Placebo	Rosuvastatin
Primary endpoint
hsCRP < 2.0	8.9	9.8	1.08 (0.88-1.32)	.062
hsCRP ≥ 2.0	14.0	12.2	0.87 (0.77-0.98)	.062
Coronary endpoint
hsCRP < 2.0	7.5	8.7	1.14 (0.91-1.43)	.023
hsCRP ≥ 2.0	11.3	9.6	0.85 (0.74-0.97)	.023
All-cause mortality
hsCRP < 2.0	8.3	9.7	1.16 (0.94-1.42)	.026
hsCRP ≥ 2.0	14.1	12.6	0.89 (0.79-1.00)	.026
All-cause mortality/heart failure hospitalization^†
hsCRP < 2.0	13.9	19.6	1.10 (0.93-1.30)	.011
hsCRP ≥ 2.0	24.1	20.8	0.87 (0.79-0.96)	.011

HR = Cox-adjusted hazard ratio; CI = confidence interval
^* Number of events per 100 patient-years of follow-up
**Interaction by treatment
^†Post hoc endpoint

Table 5. Logistic Regression: Statin Use
Statin Use	n (%)	P Value	OR (95% CI)
None	3044 (29.0)	< .001	1.561 (1.389-1.755)
1%-25%	234 (2.2)	.324	0.885 (0.695-1.128)
26%-75%	1086 (10.3)	.004	0.808 (0.698-0.936)
> 75%	6146 (58.5)	.040	0.895 (0.805-0.995)

OR = odds ratio

Table 6. Logistic Regression: Statin Use Initiated After Heart Failure
Statin Use	n (%)	P Value	OR (95% CI)
None	3044 (57.6)	< .001	1.543 (1.328-1.793)
1%-25%	135 (2.6)	.969	1.006 (0.73-1.388)
26%-75%	355 (6.7)	.040	0.779 (0.616-0.989)
> 75%	1748 (33.1)	.020	0.826 (0.704-0.970)

Table 7. Logistic Regression: Statin Use In Ischemic Heart Failure
Statin Use	n (%)	P Value	OR (95% CI)
None	1821 (17.2)	< .001	1.588 (1.395-1.806)
1%-25%	189 (1.8)	.230	0.851 (0.654-1.108)
26%-75%	920 (6.7)	.012	0.817 (0.698-0.956)
> 75%	5373 (51.1)	.041	0.906 (0.808-0.986)

Table 8. Logistic Regression: Statin Use in Nonischemic Heart Failure
Statin Use	n (%)	P Value	OR (95% CI)
None	1223 (11.6)	.020	1.383 (1.052-1.819)
1%-25%	45 (0.4)	.926	1.029 (0.569-1.860)
26%-75%	166 (1.6)	.300	0.809 (0.542-1.208)
> 75%	773 (7.4)	.315	0.869 (0.660-1.143

Table 9. Risk for New-onset Diabetes in 5 Clinical Trials (Statin vs Placebo)
Study	RR	95% CI	% Weight
All statins	1.01	0.86-1.19	-
ASCOT	1.14	0.91-1.44	18.3
CORONA	1.13	0.85-1.40	12.0
HPS	1.14	0.98-1.33	39.8
LIPID	0.91	0.72-1.16	18.7
WOSCOPS	0.69	0.49-0.96	11.2

RR = risk ratio; 95% CI = 95% confidence interval

Table 10. Risk for New-onset Diabetes According to Statin Dose
Statin Dose	RR	95% CI
Low-dose (2 trials)	1.14	0.95-1.35
High-dose (3 trials)	0.93	0.71-1.22

RR = risk ratio. 95% CI = 95% confidence interval

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Beyond LDL Cholesterol: Do Statins Have Other Roles?

November 8 - 12, 2008, New Orleans, Louisiana

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