In reply: Sex, statins, and diabetes

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.

In Reply: As Dr. Thacker notes, women are underrepresented in statin clinical trials. This, in addition to the fact that the metaanalyses reviewed did not generally stratify results by sex, makes a detailed discussion of sex-based differences on diabetes incidence and comparative outcomes difficult.

In terms of outcomes, some metaanalyses have found similar reductions of cardiovascular events with statin treatment in men and women, particularly in secondary-prevention populations.^1–3 Even though the cited report from Gutierrez et al⁴ may not have been as inclusive as some other studies, it also demonstrated similar reductions in myocardial infarction, need for intervention, and coronary mortality rates compared with men. The lack of significant reduction in rates of cerebrovascular accidents and all-cause mortality in this study may be a function of the low percentage of women in the analysis (20.6%), the low number of events, and the lack of power. However, the results did trend in a positive direction.

It is true that outcome benefits are harder to demonstrate in primary-prevention populations. However, a meta-analysis by Brugts et al⁵ in 2009 examined 10 placebocontrolled statin trials, including at least 80% of individuals without cardiovascular disease or whose data were reported from a sole primary prevention group. Thirty-four percent of the participants were women. Overall, there was a 12% reduction in mortality, 30% reduction in coronary events, and 19% reduction in cerebrovascular events. Although sex-specific analysis did not show significant reductions in women alone, the directional trends were similar to those in men, and subgroup analysis revealed no heterogeneity in treatment effect by sex, age, or diabetes status.

The meta-analysis from the Cholesterol Treatment Trialists cited in this review included 27 controlled trials and stratified patients by estimated 5-year major vascular event risk⁶; 29% of the patients were women. As expected, annual event rates increased with increasing estimate of risk. Rates of major vascular and major coronary events were reduced by 21% and 30%, respectively. Similar significant proportional reductions were noted in all risk groups, including the lowest two risk groups (< 5% and 5 to < 10%). Although analysis was not stratified by sex, there was a proportionately higher percentage of women (54%) represented in the lowest-risk group, which had a similar relative risk reduction. In the primary-prevention trial JUPITER⁷ in patients with elevated C-reactive protein and low low-density lipoprotein cholesterol levels, rosuvastatin significantly reduced the primary composite end point in women (38% of the study group) by 46%, which was similar to that in the men.^7,8 In the same paper, an additional meta-analysis of exclusively primary prevention trials reported a significant 37% reduction in cardiovascular events.

As for comparable diabetes incidence on statins, it is not accurate to imply that women have a higher risk of developing diabetes than men based only on the Women’s Health Initiative observational analysis—an all-female study with no male comparison arm, without randomization to statins, and in which only 7% of participants at entry were taking the drug in question.

The use of statins in low-risk individuals and in women in particular does remain controversial, partially because of the lack of controlled data and sufficiently powered studies with women. It was not my intent to “promulgate a fiction” that statins should be used in primary prevention in all women, but rather to recommend the use of statins appropriately in at-risk patients after weighing the treatment risks. All therapies, including statin therapy, should be directed toward those who would have the best benefit-risk ratio. To lump together all primary-prevention women, however, is overly simplistic and may result in denying therapy to a patient who may benefit from the intervention. In women as in men, the available data (although imperfect) support statin use with an acceptable risk profile in those at moderate to high risk of subsequent cardiovascular events. Some of these patients would be in the primary prevention classification. Every decision to treat needs to factor in the patient’s overall cardiovascular risk, the likelihood of adverse effects including diabetes, and the patient’s sex.