- Email: [email protected]
Statins and Diabetes: Current Perspectives and Implications for Clinicians
Accepted Manuscript Statins and Diabetes: Current Perspectives and Implications for Clinicians Charles H. Hennekens, MD, DrPH, Bettina Teng, BA in Biochemistry, Marc A. Pfeffer, MD, PhD PII:
S0002-9343(17)30014-1
DOI:
10.1016/j.amjmed.2016.12.022
Reference:
AJM 13862
To appear in:
The American Journal of Medicine
Received Date: 28 November 2016 Revised Date:
5 December 2016
Accepted Date: 5 December 2016
Please cite this article as: Hennekens CH, Teng B, Pfeffer MA, Statins and Diabetes: Current Perspectives and Implications for Clinicians, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2016.12.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Final Version: November 30, 2016 for resubmission to AJM as a Commentary Word count 1475 Limit 1500
Running Head: Statins and Diabetes Charles H. Hennekens, MD, DrPH (corresponding author)
RI PT
STATINS AND DIABETES: CURRENT PERSPECTIVES AND IMPLICATIONS FOR CLINICIANS
First Sir Richard Doll Professor & Senior Academic Advisor to the Dean
SC
Charles E. Schmidt College of Medicine, Florida Atlantic University 2800 S. Ocean Blvd. PHA
Phone: 561-393-8845 Email: [email protected]
M AN U
Boca Raton, FL 33432.
Bettina Teng, BA in Biochemistry (expected December 19, 2016) Harriet L. Wilkes Honors College at Florida Atlantic University
Jupiter, FL 33458
TE D
5353 Parkside Dr,
Email: [email protected] Marc A. Pfeffer, MD, PhD
EP
Dzau Professor of Medicine Harvard Medical School
AC C
Division of Cardiovascular Medicine Brigham and Women’s Hospital, 75 Francis Street
Boston, MA 02115
Phone: 617-732-5681 Email: [email protected] FUNDING SOURCES: None 1
ACCEPTED MANUSCRIPT
CONFLICT OF INTEREST STATEMENT FOR ALL AUTHORS Professor Hennekens reported that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic University; serves as an independent scientist in an advisory role to
RI PT
investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for
Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, Sanofi, Sunovion and the
SC
Wellcome Foundation; to the United States (U.S.) Food and Drug Administration, UpToDate,
M AN U
and to Pfizer and its legal counsel; receives royalties for authorship or editorship of 3 textbooks and as coinventor on patents for inflammatory markers and CV disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the WestBacon Group within SunTrust Investment Services, which has discretionary investment
device company.
TE D
authority and does not own any common or preferred stock in any pharmaceutical or medical
Ms. Teng reported no disclosures.
EP
Professor Pfeffer reported that he serves as a Consultant for Bayer, Boehringer Ingelheim,
AC C
DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Medicines Company, Merck, Novartis, Novo Nordisk, Relypsa, Sanofi, Teva and Thrasos; research grants from Novartis and Sanofi. Other: Stock options DalCor. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis, with licensing agreement is irrevocably transferred to charity. ALL AUTHORS HAD A ROLE IN WRITING THE MANUSCRIPT
2
ACCEPTED MANUSCRIPT
There is general consensus about the large and persuasive body of evidence that statins are effective and safe in reducing cardiovascular morbidity and mortality in secondary and primary prevention as well as among patients with diabetes. In contrast, there is controversy
RI PT
about real and perceived risks of statins. 1-2 In this Commentary, we address whether there is a valid statistical association between statin use and the risk of developing diabetes3 and, if so, whether a causal judgment is warranted.3 Finally, we address the implications of all these
SC
findings for clinicians.
M AN U
By 2012, of 27 published trials, none of which was designed a priori to test the hypothesis, only 6 (22%) even mentioned newly diagnosed diabetes. Thus, any findings on statins and diabetes from any such individual trials or their meta-analyses, should be considered hypothesis generating, not testing.4 Two of the individual trials reported statistically significant findings and four did not. Of the two, the results were in opposite directions. The first, the West
TE D
of Scotland Coronary Prevention Study (WOSCOPS), concluded that there was “evidence for a protective treatment effect” of pravastatin on diabetes.5 Specifically, there was a statistically significant 30% decreased risk of newly diagnosed diabetes (relative risk (RR) 0.70, 95%
EP
confidence interval (CI) 0.50-0.98, p=0.036) among those assigned at random to the statin. The second, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial with
AC C
Rosuvastatin (JUPITER) trial, 6 reported an unexpected statistically significant 25% positive association between rosuvastatin and newly diagnosed diabetes (RR 1.25, 95% CI 1.05-1.49, p=0.01). This finding was unexpected because, based on the WOSCOP findings, a benefit had been hypothesized a priori. In addition, the trial was terminated early, after 1.9 years, due to the emergence of a statistically extreme 44% benefit on the primary combined cardiovascular disease endpoint and a statistically significant 20% benefit on total mortality, so any findings on
3
ACCEPTED MANUSCRIPT
secondary endpoints, such as diabetes, are less reliable. In contrast, the recent and large Heart Outcomes Prevention Evaluation (HOPE-3) trial continued to its scheduled termination of 5.6
RI PT
years and reported no statistically significant association between rosuvastatin and diabetes.7 In 2010, 13 individual trials, none designed a priori to test the hypothesis of statins and diabetes, were included in a meta-analysis. Of the 13, 11 reported no statistically significant association and 4 were in the direction of a protective effect. In this meta-analysis, the authors
SC
reported a small but statistically significant 9% association between statins and diabetes
M AN U
(RR=1.09, CI 1.02-1.17). The range of the confidence interval suggests that any risk is likely to be as low as 2% and no higher than 17%. The authors noted that, even assuming that the findings were real, 255 patients would have to be treated with a statin for four years before even one patient would be diagnosed with diabetes. In these same 255 patients, 9 major nonfatal and fatal vascular events would have been prevented. Thus, the authors concluded that, even
TE D
assuming causality, the benefits of statins far exceed the potential risk of diabetes.8 In 2011, 5 individual trials were included in a subsequent meta-analysis of more versus less intensive statin therapy which had been designed a priori to test clinical cardiovascular events, but not diabetes.
EP
Of the 5, 4 did not achieve statistical significance. In the meta-analysis, the authors reported a
AC C
small but statistically significant 12% increase in risk (RR=1.12, 95% CI 1.04-1.22).9 The Cholesterol Treatment Trialists’ (CTT) Collaboration published several worldwide
comprehensive meta-analysis of trials designed a priori to test the hypothesis of benefits of statins on vascular events, but not diabetes, using individual patient data. The CTT investigators concluded that on the assumption of causality, the net absolute benefit observed with statin therapy in such individuals is more than 50 times larger than any putative effect on diabetes. Specifically, there are 11 fewer major vascular events per 1,000 treated over 5 years per 1.0 4
ACCEPTED MANUSCRIPT
millimoles per liter (mmol/L), or 39 milligrams per deciliter (mg/dL) reduction in low density lipoprotein cholesterol (LDL-C). Moreover, long-term follow-up of statin trials has shown that the absolute reductions in major vascular events increase while the statin treatment is continued,
evidence of any adverse effects emerging with extended follow-up
RI PT
and that these benefits persist for at least 5 years after the treatment has stopped, with no
SC
We believe that the totality of evidence regarding statins and newly diagnosed diabetes should be viewed as hypothesis-formulating, not hypothesis testing. First, there should be
M AN U
substantial differences between how trial evidence is interpreted for any pre-specified main effects in contrast to any somewhat unexpected side-effects. Every adverse event that reaches a level of statistical significance of p ≤.01, especially those generated from small trials not designed a priori to test a hypothesis or their meta-analyses, should not be accepted as real. If that were to occur then, many drugs of lifesaving benefit would be mistakenly labeled as
TE D
hazardous, and any real side-effects might be obscured by a mass of unreal ones. Second, it is also plausible that differential follow-up times between the statin-treated patients who achieve clinical vascular disease endpoints and the comparison groups who achieve these endpoints at
EP
higher rates earlier, and thus have shorter durations of follow-up, may lead to a higher but biased
AC C
ascertainment rates of newly diagnosed diabetes in the statin group. Third, exclusion of chance as a plausible alternative explanation is a necessary, but not sufficient, basis upon which to conclude the presence of a valid statistical association, let alone a judgment of causality 3,4 Clinicians should also consider that, even if the current insufficient totality of evidence
were judged to be causal, the possible but unproven small risks of statins and newly diagnosed diabetes pale in comparison to the clear and conclusive benefits of statins on vascular disease outcomes, especially in subjects with diabetes or at high risk of being diagnosed with diabetes 5
ACCEPTED MANUSCRIPT
The totality of evidence is large and persuasive that clinicians should more widely prescribe statins in the treatment and prevention of cardiovascular disease in women and men in secondary and primary prevention including those at high as well as low risk. This is because
RI PT
the large and persuasive current totality of evidence indicates the need for more widespread and appropriate utilization of statins, as first line drugs of choice as adjuncts, not alternatives to therapeutic lifestyle changes. Further, there is evidence for benefits of statins even among
SC
subjects who are unwilling or unable to adopt therapeutic lifestyle changes.
From the perspective of the health of the general public, there is underutilization of
M AN U
statins in the United States in secondary and primary prevention. 10 Many premature deaths will occur needlessly if patients for whom statins should be prescribed do not agree to take the drug or if patients prescribed statins stop taking the drug as a result of misplaced concerns about the risk of diabetes. These public health issues are particularly alarming in women, for whom
TE D
cardiovascular disease is also, far and away, the leading cause of death, and for whom there is
AC C
EP
more underutilization of statins than for men. 2
6
ACCEPTED MANUSCRIPT
REFERENCES 1.
Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al.
RI PT
Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016. 2.
Hennekens CH, Lieberman E, Rubenstein M, Hebert P, DeMets D, Pfeffer M. Lipid modification in the treatment and prevention of cardiovascular diseases: Emerging
SC
clinical and public health challenges. In Handbook of Cholesterol. Ed. Watson RR.
3.
M AN U
AOCS Press, Urbana, IL., 2016, Chapter 9: 155-181.
Hennekens CH, DeMets D. Statistical association and causation: contributions of different types of evidence. JAMA 2011; 305: 1134-5.
4.
Hennekens CH, DeMets D. The need for large-scale randomized evidence without undue
5.
TE D
emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009; 302: 2361-2. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West
6.
EP
of Scotland Coronary Prevention Study. Circulation 2001; 103: 357-62. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al.
AC C
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-207.
7.
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: 202131. 8. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: collaborative meta-analysis of randomized trials. Lancet. 2010; 375:735-42. 7
a
ACCEPTED MANUSCRIPT
9.
Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy – A meta-analysis. JAMA. 2011;305(24): 2556-64.
RI PT
10. Hennekens CH, Pfeffer M. Guidelines and guidance in lipid modification. Trends in CV Med, 2015, published online ahead of print
SC
ACKNOWLEDGMENT
AC C
EP
TE D
M AN U
We are indebted to Angela Moscaritolo for her expert technical assistance.
8
S0002-9343(17)30014-1
DOI:
10.1016/j.amjmed.2016.12.022
Reference:
AJM 13862
To appear in:
The American Journal of Medicine
Received Date: 28 November 2016 Revised Date:
5 December 2016
Accepted Date: 5 December 2016
Please cite this article as: Hennekens CH, Teng B, Pfeffer MA, Statins and Diabetes: Current Perspectives and Implications for Clinicians, The American Journal of Medicine (2017), doi: 10.1016/ j.amjmed.2016.12.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Final Version: November 30, 2016 for resubmission to AJM as a Commentary Word count 1475 Limit 1500
Running Head: Statins and Diabetes Charles H. Hennekens, MD, DrPH (corresponding author)
RI PT
STATINS AND DIABETES: CURRENT PERSPECTIVES AND IMPLICATIONS FOR CLINICIANS
First Sir Richard Doll Professor & Senior Academic Advisor to the Dean
SC
Charles E. Schmidt College of Medicine, Florida Atlantic University 2800 S. Ocean Blvd. PHA
Phone: 561-393-8845 Email: [email protected]
M AN U
Boca Raton, FL 33432.
Bettina Teng, BA in Biochemistry (expected December 19, 2016) Harriet L. Wilkes Honors College at Florida Atlantic University
Jupiter, FL 33458
TE D
5353 Parkside Dr,
Email: [email protected] Marc A. Pfeffer, MD, PhD
EP
Dzau Professor of Medicine Harvard Medical School
AC C
Division of Cardiovascular Medicine Brigham and Women’s Hospital, 75 Francis Street
Boston, MA 02115
Phone: 617-732-5681 Email: [email protected] FUNDING SOURCES: None 1
ACCEPTED MANUSCRIPT
CONFLICT OF INTEREST STATEMENT FOR ALL AUTHORS Professor Hennekens reported that he is funded by the Charles E. Schmidt College of Medicine of Florida Atlantic University; serves as an independent scientist in an advisory role to
RI PT
investigators and sponsors as Chair or Member of Data and Safety Monitoring Boards for
Amgen, AstraZeneca, Bayer, Bristol Myers-Squibb, British Heart Foundation, Cadila, Canadian Institutes of Health Research, DalCor, Genzyme, Lilly, Regeneron, Sanofi, Sunovion and the
SC
Wellcome Foundation; to the United States (U.S.) Food and Drug Administration, UpToDate,
M AN U
and to Pfizer and its legal counsel; receives royalties for authorship or editorship of 3 textbooks and as coinventor on patents for inflammatory markers and CV disease that are held by Brigham and Women’s Hospital; has an investment management relationship with the WestBacon Group within SunTrust Investment Services, which has discretionary investment
device company.
TE D
authority and does not own any common or preferred stock in any pharmaceutical or medical
Ms. Teng reported no disclosures.
EP
Professor Pfeffer reported that he serves as a Consultant for Bayer, Boehringer Ingelheim,
AC C
DalCor, Genzyme, Gilead, GlaxoSmithKline, Janssen, Lilly, Medicines Company, Merck, Novartis, Novo Nordisk, Relypsa, Sanofi, Teva and Thrasos; research grants from Novartis and Sanofi. Other: Stock options DalCor. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis, with licensing agreement is irrevocably transferred to charity. ALL AUTHORS HAD A ROLE IN WRITING THE MANUSCRIPT
2
ACCEPTED MANUSCRIPT
There is general consensus about the large and persuasive body of evidence that statins are effective and safe in reducing cardiovascular morbidity and mortality in secondary and primary prevention as well as among patients with diabetes. In contrast, there is controversy
RI PT
about real and perceived risks of statins. 1-2 In this Commentary, we address whether there is a valid statistical association between statin use and the risk of developing diabetes3 and, if so, whether a causal judgment is warranted.3 Finally, we address the implications of all these
SC
findings for clinicians.
M AN U
By 2012, of 27 published trials, none of which was designed a priori to test the hypothesis, only 6 (22%) even mentioned newly diagnosed diabetes. Thus, any findings on statins and diabetes from any such individual trials or their meta-analyses, should be considered hypothesis generating, not testing.4 Two of the individual trials reported statistically significant findings and four did not. Of the two, the results were in opposite directions. The first, the West
TE D
of Scotland Coronary Prevention Study (WOSCOPS), concluded that there was “evidence for a protective treatment effect” of pravastatin on diabetes.5 Specifically, there was a statistically significant 30% decreased risk of newly diagnosed diabetes (relative risk (RR) 0.70, 95%
EP
confidence interval (CI) 0.50-0.98, p=0.036) among those assigned at random to the statin. The second, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial with
AC C
Rosuvastatin (JUPITER) trial, 6 reported an unexpected statistically significant 25% positive association between rosuvastatin and newly diagnosed diabetes (RR 1.25, 95% CI 1.05-1.49, p=0.01). This finding was unexpected because, based on the WOSCOP findings, a benefit had been hypothesized a priori. In addition, the trial was terminated early, after 1.9 years, due to the emergence of a statistically extreme 44% benefit on the primary combined cardiovascular disease endpoint and a statistically significant 20% benefit on total mortality, so any findings on
3
ACCEPTED MANUSCRIPT
secondary endpoints, such as diabetes, are less reliable. In contrast, the recent and large Heart Outcomes Prevention Evaluation (HOPE-3) trial continued to its scheduled termination of 5.6
RI PT
years and reported no statistically significant association between rosuvastatin and diabetes.7 In 2010, 13 individual trials, none designed a priori to test the hypothesis of statins and diabetes, were included in a meta-analysis. Of the 13, 11 reported no statistically significant association and 4 were in the direction of a protective effect. In this meta-analysis, the authors
SC
reported a small but statistically significant 9% association between statins and diabetes
M AN U
(RR=1.09, CI 1.02-1.17). The range of the confidence interval suggests that any risk is likely to be as low as 2% and no higher than 17%. The authors noted that, even assuming that the findings were real, 255 patients would have to be treated with a statin for four years before even one patient would be diagnosed with diabetes. In these same 255 patients, 9 major nonfatal and fatal vascular events would have been prevented. Thus, the authors concluded that, even
TE D
assuming causality, the benefits of statins far exceed the potential risk of diabetes.8 In 2011, 5 individual trials were included in a subsequent meta-analysis of more versus less intensive statin therapy which had been designed a priori to test clinical cardiovascular events, but not diabetes.
EP
Of the 5, 4 did not achieve statistical significance. In the meta-analysis, the authors reported a
AC C
small but statistically significant 12% increase in risk (RR=1.12, 95% CI 1.04-1.22).9 The Cholesterol Treatment Trialists’ (CTT) Collaboration published several worldwide
comprehensive meta-analysis of trials designed a priori to test the hypothesis of benefits of statins on vascular events, but not diabetes, using individual patient data. The CTT investigators concluded that on the assumption of causality, the net absolute benefit observed with statin therapy in such individuals is more than 50 times larger than any putative effect on diabetes. Specifically, there are 11 fewer major vascular events per 1,000 treated over 5 years per 1.0 4
ACCEPTED MANUSCRIPT
millimoles per liter (mmol/L), or 39 milligrams per deciliter (mg/dL) reduction in low density lipoprotein cholesterol (LDL-C). Moreover, long-term follow-up of statin trials has shown that the absolute reductions in major vascular events increase while the statin treatment is continued,
evidence of any adverse effects emerging with extended follow-up
RI PT
and that these benefits persist for at least 5 years after the treatment has stopped, with no
SC
We believe that the totality of evidence regarding statins and newly diagnosed diabetes should be viewed as hypothesis-formulating, not hypothesis testing. First, there should be
M AN U
substantial differences between how trial evidence is interpreted for any pre-specified main effects in contrast to any somewhat unexpected side-effects. Every adverse event that reaches a level of statistical significance of p ≤.01, especially those generated from small trials not designed a priori to test a hypothesis or their meta-analyses, should not be accepted as real. If that were to occur then, many drugs of lifesaving benefit would be mistakenly labeled as
TE D
hazardous, and any real side-effects might be obscured by a mass of unreal ones. Second, it is also plausible that differential follow-up times between the statin-treated patients who achieve clinical vascular disease endpoints and the comparison groups who achieve these endpoints at
EP
higher rates earlier, and thus have shorter durations of follow-up, may lead to a higher but biased
AC C
ascertainment rates of newly diagnosed diabetes in the statin group. Third, exclusion of chance as a plausible alternative explanation is a necessary, but not sufficient, basis upon which to conclude the presence of a valid statistical association, let alone a judgment of causality 3,4 Clinicians should also consider that, even if the current insufficient totality of evidence
were judged to be causal, the possible but unproven small risks of statins and newly diagnosed diabetes pale in comparison to the clear and conclusive benefits of statins on vascular disease outcomes, especially in subjects with diabetes or at high risk of being diagnosed with diabetes 5
ACCEPTED MANUSCRIPT
The totality of evidence is large and persuasive that clinicians should more widely prescribe statins in the treatment and prevention of cardiovascular disease in women and men in secondary and primary prevention including those at high as well as low risk. This is because
RI PT
the large and persuasive current totality of evidence indicates the need for more widespread and appropriate utilization of statins, as first line drugs of choice as adjuncts, not alternatives to therapeutic lifestyle changes. Further, there is evidence for benefits of statins even among
SC
subjects who are unwilling or unable to adopt therapeutic lifestyle changes.
From the perspective of the health of the general public, there is underutilization of
M AN U
statins in the United States in secondary and primary prevention. 10 Many premature deaths will occur needlessly if patients for whom statins should be prescribed do not agree to take the drug or if patients prescribed statins stop taking the drug as a result of misplaced concerns about the risk of diabetes. These public health issues are particularly alarming in women, for whom
TE D
cardiovascular disease is also, far and away, the leading cause of death, and for whom there is
AC C
EP
more underutilization of statins than for men. 2
6
ACCEPTED MANUSCRIPT
REFERENCES 1.
Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, et al.
RI PT
Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016. 2.
Hennekens CH, Lieberman E, Rubenstein M, Hebert P, DeMets D, Pfeffer M. Lipid modification in the treatment and prevention of cardiovascular diseases: Emerging
SC
clinical and public health challenges. In Handbook of Cholesterol. Ed. Watson RR.
3.
M AN U
AOCS Press, Urbana, IL., 2016, Chapter 9: 155-181.
Hennekens CH, DeMets D. Statistical association and causation: contributions of different types of evidence. JAMA 2011; 305: 1134-5.
4.
Hennekens CH, DeMets D. The need for large-scale randomized evidence without undue
5.
TE D
emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009; 302: 2361-2. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West
6.
EP
of Scotland Coronary Prevention Study. Circulation 2001; 103: 357-62. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al.
AC C
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359: 2195-207.
7.
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: 202131. 8. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: collaborative meta-analysis of randomized trials. Lancet. 2010; 375:735-42. 7
a
ACCEPTED MANUSCRIPT
9.
Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy – A meta-analysis. JAMA. 2011;305(24): 2556-64.
RI PT
10. Hennekens CH, Pfeffer M. Guidelines and guidance in lipid modification. Trends in CV Med, 2015, published online ahead of print
SC
ACKNOWLEDGMENT
AC C
EP
TE D
M AN U
We are indebted to Angela Moscaritolo for her expert technical assistance.
8