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Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy
A Meta-analysis
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JAMA. June 21 2011
"In conclusion, this meta-analysis extends earlier findings of an increased incidence of diabetes with statin therapy by providing evidence of a dose-dependent association."
David Preiss, MRCP Sreenivasa Rao Kondapally Seshasai, MD Paul Welsh, PhD Sabina A. Murphy, MPH Jennifer E. Ho, MD David D. Waters, MD David A. DeMicco, DPharm Philip Barter, MD, PhD Christopher P. Cannon, MD Marc S. Sabatine, MD, MPH Eugene Braunwald, MD John J. P. Kastelein, MD, PhD James A. de Lemos, MD Michael A. Blazing, MD Terje R. Pedersen, MD, PhD Matti J. Tikkanen, MD, PhD Naveed Sattar, MD, PhD Kausik K. Ray, MD
Abstract
Context A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus.
Objective To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy.
Data Sources We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators.
Study Selection We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year.
Data Extraction Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I2 statistic.
Results In 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I2 = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I2 = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.
Conclusion In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.
Statin therapy significantly reduces cardiovascular events among individuals with and without a history of diabetes mellitus compared with placebo.1 ,2 Intensive-dose statin therapy has also been shown to further reduce cardiovascular events compared with moderate-dose statin therapy.1 ,3 A recent meta-analysis of 13 randomized placebo and standard care controlled trials involving 91 140 individuals reported that among patients treated with statins, the risk of developing diabetes was 9% higher (95% confidence interval [CI], 2%-17%) over a 4-year period compared with patients randomized to placebo or standard care.4 Recently, findings of 3 large end-point trials comparing intensive- to moderate-dose statin therapy have suggested an excess risk of incident diabetes among those treated with intensive statin regimens.5,6 However, 2 of these trials used nonstandard diagnostic criteria previously used to define incident diabetes.7 Additionally, published data from a fourth large clinical trial suggested the possibility of a deterioration in glucose control in patients receiving intensive statin therapy,8 and a recent report of 220 patients with hypercholesterolemia treated with placebo or different doses of atorvastatin and followed up for only 2 months found that those receiving the highest dose developed greater insulin resistance, higher insulin levels, and higher hemoglobin A1c levels compared with those receiving the lowest dose or placebo,9 suggesting a potential dose effect. Although no significant relationship was observed between the extent of decreasing low-density lipoprotein (LDL) cholesterol values and new-onset diabetes in the meta-analysis of placebo and standard care controlled trials,4 most of those trials used modest-intensity statins and trial populations also differed greatly, which may have obscured any meaningful association.
Confidence in the observed association between statin therapy and the development of diabetes would be enhanced by providing further large-scale evidence of a dose-dependent association.4 Given the cardiovascular benefits of statins and the likely increasing use of intensive statin regimens, it is important to quantify any potential long-term risks to enable physicians and patients to make informed choices. Furthermore, it would be of value to investigate whether any specific group of patients is at higher risk of diabetes when receiving intensive statin therapy than others. We therefore examined the associations of intensive-dose statin therapy vs moderate-dose therapy with the development of diabetes and the occurrence of major cardiovascular events, respectively, by conducting a collaborative meta-analysis of published and unpublished data from relevant clinical trials.
RESULTS
Five randomized clinical trials provided data on 32 752 nondiabetic participants over a weighted mean (SD) follow-up of 4.9 (1.9) years. During follow-up, 2749 participants (8.4%) developed diabetes (1449 of whom were assigned intensive-dose therapy, 1300 assigned moderate-dose therapy), and 6684 (20.4%) experienced a major cardiovascular event (3134 assigned intensive-dose therapy, 3550 assigned moderate-dose therapy) (Table 1, Table 2, and Figure 2). Of the 2749 diagnoses of diabetes, 2059 (75%) were identified by nonbiochemical methods (ie, commencement of glucose-lowering medication or adverse event reporting), 219 (8%) by elevated FPG values in the trial, and 471 (17%) by more than 1 method. Trials were of high quality with a median Delphi score of 9 (range, 6-9).
New-Onset Diabetes
In the combined data set, there were 149 more cases of incident diabetes in participants assigned to intensive statin treatment than in those receiving moderate therapy (OR, 1.12; 95% CI, 1.04-1.22) (Figure 2). In absolute terms, there were 2.0 additional cases of diabetes per 1000 patient-years among those receiving intensive-dose therapy (mean [SD] 18.9 [5.2] cases per 1000 patient-years with high-dose statin treatment vs 16.9 [5.5] cases per 1000 patient-years with moderate-dose therapy), corresponding to a number needed to harm of 498 per year. There was no significant heterogeneity between trials for new-onset diabetes (χ2 for heterogeneity = 2.59; P = .60; I2 = 0% [95% CI, 0%-79%]). Likewise, there was no evidence of publication bias (P = .54) (eFigure 2).
Cardiovascular Benefit
In the combined data set, there were 416 fewer patients with cardiovascular events who received intensive-dose therapy (OR, 0.84; 95% CI, 0.75-0.94) (Figure 2). In absolute terms, there were 6.5 fewer first major cardiovascular events per 1000 patient-years among those receiving intensive statin therapy (mean [SD] 44.5 [20.4] cases per 1000 patient-years with high-dose treatment and 51.0 [23.6] cases per 1000 patient-years with moderate-dose therapy), corresponding to a number needed to treat of 155 to prevent 1 cardiovascular event per year. There was significant heterogeneity between trials for major cardiovascular events (χ2 for heterogeneity = 15.04; P = .004; I2 = 74% [95% CI, 36%-90%]). However, there was no evidence of publication bias (P = .70) (eFigure 2). Odds ratios for specific components of the composite cardiovascular end point are provided in Table 3, showing similar associations between intensive statin therapy and each cardiovascular end point component. Intensive-dose therapy was not associated with lower all-cause mortality compared with moderate-dose statin therapy (OR, 0.93; 95% CI, 0.81-1.05; 1318 cases/16 408 patients receiving intensive therapy vs 1360 cases/16 342 patients receiving moderate doses). Intensive statin therapy was not associated with lower rates of noncardiovascular death as compared with moderate-dose statin therapy (OR, 0.98; 95% CI, 0.87-1.10; 559 cases/16 408 patients receiving intensive therapy vs 571 cases/16 342 patients receiving moderate doses). There was no significant heterogeneity between trials for all-cause mortality (χ2 for heterogeneity = 7.06; P = .13; I2 = 43% [95% CI, 0%-79%]) or for noncardiovascular death (χ2 for heterogeneity = 3.41; P = .49; I2 = 0% [95% CI, 0%-79%]).
Subgroup Analyses
Cardiovascular benefit was consistent across all subgroups of participants, including those defined by age, HDL cholesterol level, triglyceride concentration, BMI (assessed in 4 trials5,15 ,16,18 ; n = 29 036; 6192 events), and FPG level (assessed in 3 trials15,16 ,18; n = 16 352; 3436 events) above and below the trial medians at baseline (Figure 3). The odds of developing diabetes among participants receiving intensive compared with moderate statin therapy was also similar for patients differing by age, HDL cholesterol level, BMI (2626 events), and FPG level (1302 events) at baseline but was higher in those with triglyceride concentrations below the median compared with those with higher triglyceride levels. The trial-specific medians of these variables are provided in the eTable.
Statin Type and Trial Population
The difference in relative LDL cholesterol reduction between the more- and less-intensive statin groups was 12% to 15% in the 2 trials (n = 14 301)5 ,17 that studied simvastatin 80 mg and 16% to 22% in the 3 trials (n = 18 451)15 ,16,18 that studied atorvastatin 80 mg. The odds of developing diabetes was comparable with simvastatin 80 mg (OR, 1.13; 95% CI, 0.93-1.38; I2 = 0%; 690 cases/7166 patients receiving simvastatin 80 mg vs 634 cases/7135 patients with moderate-dose statins) and atorvastatin 80 mg (OR, 1.15; 95% CI, 1.03-1.28; I2 = 0%; 759 cases/9242 patients with atorvastatin 80 mg vs 666 cases/9209 patients with moderate-dose statin) (P = .56 for interaction) (eFigure 3). In contrast, there was no significant cardiovascular benefit over moderate-dose therapy in the trials of simvastatin 80 mg (OR, 0.95; 95% CI, 0.88-1.03; I2 = 0%; 1396 events/7166 patients with simvastatin 80 mg vs 1448 cases/7135 patients with moderate-dose statin therapy), whereas there was a significant benefit for atorvastatin 80 mg (OR, 0.78; 95% CI, 0.73-0.85; I2 = 14%; 1738 events/9242 patients with atorvastatin 80 mg vs 2102 events/9209 patients with moderate-dose statin therapy) (P < .001 for interaction). Three trials were conducted in patients with stable coronary heart disease (n = 25 853)5,15 ,16 and 2 in patients following recent ACS (n = 6899).17 ,18 Intensive statin therapy was associated with higher odds of incident diabetes following ACS (OR, 1.15; 95% CI, 0.85-1.54; 166 cases/3475 patients with intensive therapy vs 146 cases/3424 patients with moderate-dose therapy) and in stable coronary heart disease (OR, 1.12; 95% CI, 1.03-1.22; 1283 cases/12 933 patients with intensive therapy vs 1154 cases/12 920 patients with moderate-dose therapy), while cardiovascular events were lower in both conditions (OR, 0.86; 95% CI, 0.76-0.98; 527 events/3475 patients vs 589 events/3424 patients; and OR, 0.83; 95% CI, 0.70-0.98; 2607 events/12 933 patients vs 2961/12 920 patients, respectively) (eFigure 4); there was no significant heterogeneity for these outcomes by study cohort.
Sensitivity Analyses
In sensitivity analyses, the overall risk of developing diabetes (assessed in 3 trials5 ,15,16 ) and the reduction in cardiovascular events (assessed in 5 trials), calculated by combining trial-specific hazard ratios, produced similar results to the primary analysis (eFigure 5). The risk of developing diabetes for patients receiving intensive statin therapy using nonstandard diagnostic criteria in 2 trials, namely TNT15 and IDEAL,16 was also qualitatively similar to the primary analysis in which standard diagnostic criteria were used (OR, 1.11; 95% CI, 1.03-1.21) (eFigure 6). Fixed-effects model meta-analysis produced similar results to random-effects model meta-analysis for new-onset diabetes when pooling data from the 5 trials.
COMMENT
This study demonstrates that use of intensive-dose statin therapy compared with moderate-dose statin therapy was associated with a higher incidence of new-onset diabetes (OR, 1.12). However, intensive statin therapy was associated with fewer major cardiovascular events (OR, 0.84). In this combined trial population, although the risk of new-onset diabetes and the benefit of cardiovascular event reduction for patients receiving intensive therapy were similar in relative terms, when expressed in absolute terms there was 1 additional case of diabetes for every 498 patients treated for 1 year compared with 1 fewer patient experiencing a cardiovascular event for every 155 patients treated for 1 year. The cardiovascular benefit described here may be a conservative estimate because 3 trials have demonstrated that intensive statin therapy also reduces multiple cardiovascular events if intensive statin therapy is continued.22,23 ,24 These findings complement the recent observation of excess risk of developing diabetes among patients treated with statins compared with those receiving placebo.4
The benefits of statin therapy were consistent across all subgroups and for each component of the primary efficacy end point, including cardiovascular death. Analyses of all-cause mortality were consistent with observations for cardiovascular death, although the generalizability of these findings to other populations is less clear because these depend on the relative contributions of cardiovascular death (modified by statins) and noncardiovascular death (nonmodifiable by statins) in those populations. For new-onset diabetes, however, there was some evidence that the odds of new-onset diabetes was higher among individuals with triglyceride concentrations below the median level of distribution with intensive statin treatment, which, in the absence of a biologically plausible mechanism, may be a chance finding given the modest statistical significance in the context of multiple statistical tests. The higher incidence of new-onset diabetes and lower incidence of cardiovascular events were similar in patients following recent ACS and those with stable coronary disease. In the trials we studied whose control groups were different but comparable, the relative LDL-cholesterol reduction was greater in those that used atorvastatin 80 mg than in those that used simvastatin 80 mg.25 Whereas the odds of developing diabetes was similar on both, there was a significantly lower odds of cardiovascular events in the trials with high-dose atorvastatin but not with high-dose simvastatin.1
Important questions remain. First, a potential mechanism to explain the findings of a higher incidence of diabetes with statin therapy compared with placebo, and intensive-dose therapy compared with moderate-dose therapy, has not been identified. Possibilities include a direct and off-target effect. For example, statins may influence muscle or liver insulin action directly, resulting in higher diabetes risk. Data from an animal model suggest that statin-induced myopathy is associated with the development of muscle insulin resistance, providing a potential mechanism.26 Second, it remains unclear whether statin therapy is associated with a generalized tendency for an increase in diabetes risk in many who take statins or whether there is a specific group of individuals at particular risk. Analysis of data from subgroups did not provide conclusive data. Third, although statin therapy is associated with a higher incidence of diabetes, to what extent this may carry with it the important associated long-term risks of developing microvascular disease is unknown. To date, no large clinical studies have examined the associations of statin therapy with microvascular disease. In contrast, fibrate therapy is associated with lower rates of microvascular complications.27 ,28 We hypothesize that given that cardiovascular risk from diabetes is modest in the first decade after diagnosis,29 and as the benefit of statin therapy increases over time and in absolute terms with increasing age,30 net cardiovascular benefit in high-risk individuals will still strongly favor statin therapy. Finally, it would be of interest to investigate the impact of intensive statin therapy on glycemic control and treatment requirements in patients with established diabetes. One consideration to help quantify potential concerns is the establishment of a registry to examine these issues of long-term risk. Our findings suggest that clinicians should be vigilant for the development of diabetes in patients receiving intensive statin therapy.
Strengths of this meta-analysis include the following: first, we were able to include data from all the relevant clinical trials and thereby provide adequate power to detect potentially modest effects. Second, access to trial data allowed relevant subgroup analyses. And third, it was possible to provide a comparison of the potential risk of new-onset diabetes with cardiovascular benefit, thereby providing clinically useful information. Potential weaknesses include the following: first, different methods for diagnosing diabetes were available for the 5 trials, and the trials were not designed to assess new-onset diabetes. However, the low heterogeneity in new-onset diabetes as well as the very similar sensitivity analysis using the nonstandard criteria in 2 trials provides confidence in the results obtained. Second, analyses of incident diabetes were not prespecified in the trial designs and only 1 trial (TNT15 ) included regular measurement of FPG as a consequence. Because undiagnosed diabetes is relatively common,31 it is possible that we may have somewhat underestimated the risk of incident diabetes in the trial participants. Third, because all 5 trials specifically included participants with established coronary disease at high risk of future cardiovascular events rather than diabetes, our findings may not necessarily be generalizable to populations at higher risk of incident diabetes. Fourth, analyses were conducted without access to individual participant data. Fifth, we cannot exclude the possibility that intensive statin therapy may have caused more adverse effects and therefore led to differences in routine clinical care between those treated with intensive- and moderate-dose regimens, resulting in detection bias.
In conclusion, this meta-analysis extends earlier findings of an increased incidence of diabetes with statin therapy by providing evidence of a dose-dependent association.
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