Jeanne M. Dobrzynski

The Effect of Statins on Erectile Dysfunction: A Meta‐Analysis of Randomized Trials

INTRODUCTION Erectile dysfunction (ED) is common in older men, especially those with comorbidities such as diabetes and atherosclerotic disease, conditions where statins are frequently prescribed. AIM To examine the effect of statin therapy on ED using the five-item version of the International Inventory of Erectile Function (IIEF). METHODS We performed a random-effects meta-analysis of studies identified by a systematic search of MEDLINE, Web of Knowledge, the Cochrane Database, and ClinicalTrials.gov. Examination of the 186 retrieved citations resulted in the selection of 11 randomized trials for inclusion in the meta-analysis. MAIN OUTCOME MEASURES Change in the IIEF score. RESULTS IIEF increased by 3.4 points (95% CI 1.7-5.0, P = 0.0001) with statins compared to control. This effect remained statistically significant after multiple sensitivity analyses, including analysis for publication bias, a cumulative meta-analysis, and 11 repeated analyses with each study omitted sequentially. The increase in IIEF with statins was approximately one-third to one-half of that previously reported with phosphodiesterase-5 inhibitors and larger than the effect of lifestyle modification. Metaregression showed an increase in benefit with decreasing lipophilicity. The average age of participants and the degree of LDL cholesterol lowering did not alter the effect on IIEF. CONCLUSION Statins cause a clinically relevant improvement of erectile function as measured by the five-item version of the IIEF.

Prevention of cataracts by statins: a meta-analysis.

Background: Current data indicate a persisting concern about possible cataractogenecity of statins. Objective: To perform a meta-analysis of studies pertaining to statins and cataract. Methods: We identified 363 records by a systematic search of the MedLine, Web of Knowledge, Cochrane database, and ClinicalTrials.gov. After exclusion of duplicates, studies without cataract as an outcome, reviews, and animal or basic science studies, we analyzed 14 studies. Two end points were examined: clinical cataract (requiring extraction or reported by the patient) and lens opacities discovered by slit-lamp examination. Results: Using random effects meta-analysis, a statistically significant decrease in cataracts with statins was observed among studies examining clinical cataract (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.71-0.93, P = .0022). Absolute risk reduction was 1.4% ± 0.015%, 95% CI 1.1%-1.7%, P < .0001, corresponding to 71, 95% CI 59-91, number needed to treat. The effect was larger for the harder end point of cataract extraction (OR 0.66, 95% CI 0.61-0.71, P < .0001). Metaregression indicated an increase in benefit with longer duration of statin use with OR varying from 0.54 for a treatment duration of 14 years to 0.95 for a treatment duration of 6 months. Older age was associated with lower benefit (OR 1.03 for persons in their 70s to OR 0.49 for persons in their 40s), and there were no differences by gender. Several sensitivity analyses confirmed the results. Limitations of this analysis include the combination of randomized and observational studies and imprecise ascertainment of exposure and incomplete adjustment for confounders in several observational studies. Conclusion: This meta-analysis indicates a clinically relevant protective effect of statins in preventing cataracts. The effect is more pronounced in younger patients and with longer duration of follow-up, while there is no difference by gender.

Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid-lowering therapy

BACKGROUND Long-term follow-up of clinical trials with lipid-lowering medications has suggested a continuation of event reduction after study completion. OBJECTIVE To evaluate the persistence of the benefit of lipid-lowering therapy in decreasing mortality after the end of clinical trials, when all patients were advised to take the same open-label lipid-lowering therapy. METHODS Through searches of MEDLINE, the Cochrane Library, the Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov until June 2010 we identified randomized clinical trials of lipid-lowering agents with a second report describing results after the end of the trial. RESULTS Among the 459 trials reviewed, only 8 including 44,255 patients and 8144 deaths qualified for the meta-analysis. All-cause and cardiovascular mortality were lower in the active intervention group during the first phase (0.84, 95% confidence interval [CI] 0.76-0.93; P = .0006 and 0.72, 95% CI 0.63-0.82, P < .0001, respectively) when 71 ± 23% of the patients randomized to receive active therapy actually received it compared with 13 ± 5% of patients who received active therapy although they were randomized to placebo (P = .0001). The lower mortality among those initially randomized to active therapy persisted during the second phase (odds ratio 0.90, 95% CI 0.84-0.97, P = .0035, and 0.82 95% CI 0.73-0.93, P = .0014), when patients in both randomized groups received active therapy in the same proportions (5 ± 2% for both groups). Numerous sensitivity analyses support the conclusions of the paper. CONCLUSION The decrease in mortality with lipid-lowering therapy in clinical trials persists after discontinuation of randomized therapy when patients in the treatment and placebo groups receive active therapy.

Response to Letter on “Statins Use and Risk of Cataracts Firm Conclusions Are Still Far Off”

We appreciate the careful reading of our meta-analysis on prevention of cataracts by statins by Macias Saint-Gerons and associates and understand that there are data on both sides on the relationship between statins and cataract. The antiinflammatory and antioxidant effects of statins may mediate a decrease in the rate of cataract formation, while bidirectional effects of statins on oxidation and inhibition of appropriate epithelial cell development within the crystalline lens may increase the chance of developing cataract. We have proposed that a well-powered prospective randomized clinical trial be performed in order to confirm the positive or negative relationship of statins to cataract. A protective effect may help increase adherence to statin therapy, while an increased risk of cataract may be balanced by the marked benefits of statins in decreasing cardiovascular events. We have acknowledged the limitations of our article including the lack of significant effect in randomized trials and the other limitations of meta-analyses. The article by Professor Blumenthal’s group published about 6 months after our metaanalysis agrees with our findings and recommendations. The reason we did not use the 2010 article from the QResearch database by Hippisley-Cox and Coupland is that we used a later publication from the same database (2012) by Collins and Altman. Repeating our search strategies of MedLine, Web of Science, and the Cochrane library for the intersection of the terms statin and cataract did not retrieve the Waudby reference. Waudby and associates showed an increase in agespecific cataract rate but apparently did not have an internal control group. We repeated our meta-analysis by including the data from the abstract and table 1 of the Waudby article. The overall effect as shown in figure 2 of our meta-analysis remained statistically significant with a higher P value (P 1⁄4 .0467 vs P 1⁄4 .0009). The effect on cataract extraction (figure 5) was not statistically significant (P 1⁄4 .7391 vs P < .0001), while the overall effect remained nearly unchanged (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.81-0.88, P < .0001 vs OR 0.08, 95% CI 0.77-0.83, P < .0001). The data of Machan et al were described in the introduction of our article. They were not included in the meta-analysis since they derive from the Waterloo Eye Study database, where the prevalence of cataract was very high (above the age of 60 varying between 98.2% and 100% in the 70-79 group, 98.9%-100% in the 80þ group, and 80.4%-93.5% among those aged 6069), rather than the population at large. The observational studies by Leuschen et al and Lai et al are discussed in our letter to the editor in JAMA Ophthalmology and the related commentary. We have addressed the issue of statins, cataracts, age, and duration of treatment in our metaanalysis and in a review article where we stated that the data on the relationship of statin therapy to the development of cataract are not consistent and that there appears to be an age effect in that statins may prevent cataract among younger individuals with long duration of exposure. In summary, the issue of the relationship of statin use and cataracts is not definitely settled, may be confounded by age and may be resolved by a well-powered prospective randomized clinical trial as we have proposed. Depending on the age at randomization and the end point selected (slit lamp examination and cataract extraction), such a study may be too long and/or too expensive to carry out. Incorporation of cataract as a secondary end point in clinical trials of statins and possibly of Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies may yield useful information. Also, cataract may be incorporated in large epidemiologic studies such as the Framingham Heart Study, the Atherosclerosis Risk in Communities Study, and so on. A protective effect of statins may help increase adherence to statin therapy, while an increased risk of cataract may be balanced by the marked benefits of statins in decreasing cardiovascular events.

EFFECT OF STATINS ON ERECTILE FUNCTION

Erectile dysfunction (ED) is common in older men, especially those with comorbidities such as diabetes and atherosclerotic disease, where statins are frequently prescribed. We performed a meta-analysis of all trials of the effect of statin therapy on ED as evaluated by the International Inventory

Statins and Erectile Dysfunction

of men and erectile dysfunction affects other dimensions of the individual including depression, sexual performance, and self worth. At age 40, approximately 40% of men are affected by erectile dysfunction. The rate increases to nearly 70% in men aged 70 years [1]. This problem has become magnified because of the current aging of the population after the control of communicable diseases. In addition to age, erectile dysfunction is associated with cardiovascular disease since the two conditions share similar risk factors, such as diabetes, metabolic syndrome, sedentary lifestyle, smoking, injuries, or surgery to the pelvic area or spinal cord, obesity, hypertension, hyperlipidemia, and depression [2]. Thus, the treatment of erectile dysfunction depends on the underlying etiology. Attention and amelioration to the extent possible of the conditions mentioned above is the first therapeutic approach. In the large majority of older persons with erectile dysfunction, phosphodiesterase isoenzyme 5 inhibitors are indicated and have been proven to be effective, welltolerated and may have additional benefits in idiopathic pulmonary hypertension, heart failure, and coronary heart disease. A common instrument for the evaluation of sexual function in men is the International Index of Erectile Function (IIEF), a validated self-administered questionnaire that has been psychometrically sound and linguistically validated in ten languages. This instrument ranks on a scale of one to five, five dimensions of sexual function (erection, orgasm, desire, intercourse satisfaction, and overall satisfaction) [3]. The coexistence of erectile dysfunction with cardiovascular disease and especially coronary heart disease stemming from the commonality of risk factors mentioned above has resulted in increasing use of statins in patients with erectile dysfunction. Also, patients without erectile dysfunction who qualify for statin therapy need to be reassured regarding the relationship of statin therapy with erectile dysfunction. Lifestyle modification is important for both cardiovascular health and improvement of erectile function. In some instances, it may be sufficient to reverse pre-existing abnormalities in function as well as structure. In all cases, lifestyle change is a necessary adjunct to pharmacologic therapy. Reducing body weight with caloric restriction and regular exercise, as well as avoidance of smoking, are important in reducing the risk of coronary heart disease and erectile dysfunction. Randomized studies of pharmacologic agents to reduce cholesterol were performed on background non-pharmacologic therapy and specific pharmacologic therapy for co-morbidities such as hypertension diabetes, etc. discussed above. The effect of lifestyle changes on erectile dysfunction was examined in a randomized control trial of 110 obese men aged 35 to 55 years with body mass index ≥30 kg/m. In this study, non-pharmacologic

Statin Use and Risk of Cataract Response to Letter

We are happy to clarify the issue raised by professor HippisleyCox in identifying a mistake in our letter to the editor regarding statin use and risk of cataracts: firm conclusions are still off. We performed a new meta-analysis including both the Collins and Altman and the Hippisley-Cox and Coupland articles using data from table 4 of the Hippisley-Cox and Coupland article. In this analysis, the odds ratio (OR) is closer to 1, the confidence interval (CI) is wider, and the P value is higher than .05 (OR 0.86 95% CI 0.68-1.07, P 1⁄4 .1744) compared to our previous report (OR 0.82 95% CI 0.72-0.92, P 1⁄4 .0011). This was expected from the directionally opposite statistically significant effects of the Collins and Altman article (OR 0.83, 95% CI 0.80-0.87, P < .0001) compared to the HippisleyCox and Coupland article (OR 1.31, 95% CI 1.27-1.36, P < .0001). We had questions about the article of Collins and Altman and tried to obtain clarification via e-mail. In addition, a reviewer of our original submission commented on the skewed distribution of the numbers of participants included in the meta-analysis (Collins et al, over 2 million persons; data from all other studies ranged from 58 to 105 454 participants). For these reasons, we performed an additional meta-analysis excluding the data of Collins. This analysis showed a significant protective effect of statins (OR 0.81, 95% CI 0.69-0.95, P 1⁄4 .0105). As we stated in our letter, the issue of the relationship of statin use and cataracts is not definitely settled, may be confounded by age, and may be resolved by a well-powered prospective randomized clinical trial as we proposed previously.