simvastatin

Atorvastatin, Rosuvastatin, and Simvastatin Are Associated with Excess Risk for Diabetes.

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Using low doses of these drugs might mitigate the risk.

Studies in people and in animal models suggest that atorvastatin, rosuvastatin (Crestor), and simvastatin are associated with elevated risk for diabetes, whereas pravastatin is associated with lower risk. In this population-based cohort study, investigators in Canada used administrative databases to assess incident diabetes between 1997 and 2010 in 471,000 older patients (age, 66) who were newly treated with statins (median age at treatment onset, 73).

After adjustment for multiple confounders, with pravastatin as the reference drug, risk for new diabetes was 10%, 18%, and 22% higher in participants who received simvastatin, rosuvastatin, and atorvastatin, respectively. Corresponding numbers needed to harm were 363 (simvastatin), 210 (rosuvastatin), and 172 (atorvastatin). Fluvastatin and lovastatin were not associated with excess risk. Compared with low statin doses (pravastatin, fluvastatin, and lovastatin at all doses; atorvastatin, <20 mg; rosuvastatin, <10 mg; simvastatin, <80 mg), moderate and high statin doses were associated with higher diabetes risk.

Comment: In this study, compared with pravastatin, moderate- and high-potency statins (simvastatin, rosuvastatin, and atorvastatin) were associated with higher risk for incident diabetes. Using low doses of these drugs or low-potency statins (fluvastatin and lovastatin) might mitigate this risk. Notably, these results are biologically plausible: Simvastatin diminishes insulin secretion, whereas pravastatin improves insulin sensitivity and inhibits gluconeogenesis. An editorialist recommends: “When total cardiovascular risk favours statin treatment, a low dose, low potency agent should be used to begin with.” However, some readers will disagree and will argue that, for some high-risk patients, benefits of high-potency statins outweigh the small absolute risk for incident diabetes.

 

Source: Journal Watch General Medicine

Risk of incident diabetes among patients treated with statins: population based study.

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Abstract

Objective To examine the risk of new onset diabetes among patients treated with different HMG-CoA reductase inhibitors (statins).

Design Population based cohort study with time to event analyses to estimate the relation between use of particular statins and incident diabetes. Hazard ratios were calculated to determine the effect of dose and type of statin on the risk of incident diabetes.

Setting Ontario, Canada.

Participants All patients aged 66 or older without diabetes who started treatment with statins from 1 August 1997 to 31 March 2010. The analysis was restricted to new users who had not been prescribed a statin in at least the preceding year. Patients with established diabetes before the start of treatment were excluded.

Interventions Treatment with statins.

Main outcome measure Incident diabetes.

Results Compared with pravastatin (the reference drug in all analyses), there was an increased risk of incident diabetes with atorvastatin (adjusted hazard ratio 1.22, 95% confidence interval 1.15 to 1.29), rosuvastatin (1.18, 1.10 to 1.26), and simvastatin (1.10, 1.04 to 1.17). There was no significantly increased risk among people who received fluvastatin (0.95, 0.81 to 1.11) or lovastatin (0.99, 0.86 to 1.14). The absolute risk for incident diabetes was about 31 and 34 events per 1000 person years for atorvastatin and rosuvastatin, respectively. There was a slightly lower absolute risk with simvastatin (26 outcomes per 1000 person years) compared with pravastatin (23 outcomes per 1000 person years). Our findings were consistent regardless of whether statins were used for primary or secondary prevention of cardiovascular disease. Although similar results were observed when statins were grouped by potency, the risk of incident diabetes associated with use of rosuvastatin became non-significant (adjusted hazard ratio 1.01, 0.94 to 1.09) when dose was taken into account.

Conclusions Compared with pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, might be associated with an increased risk of new onset diabetes.

Discussion

In this population based study, we found that patients treated with atorvastatin, rosuvastatin, or simvastatin were at increased risk of new onset diabetes compared with those treated with pravastatin. No such risk was evident with fluvastatin or lovastatin. The risk associated with rosuvastatin could depend on dose and duration of treatment. The risk of incident diabetes was similar whether statins were being used for primary or secondary prevention.

Overall, we observed a 10-22% increased risk of diabetes for some statins that is consistent with findings from previously published meta-analyses of clinical trials. The increased risk with rosuvastatin significantly decreased after covariate adjustment and became non-significant once dose was taken into consideration. This could possibly represent greater use of rosuvastatin in patients with lower cardiovascular risk.3 In 2009, an analysis of five placebo controlled trials (n=57 593) found a 13% (relative risk 1.13, 95% confidence interval 1.03 to 1.23) increased incidence of diabetes in people taking statins compared with placebo over an average 3.9 years of follow-up,9 with a subsequent analysis of 13 placebo controlled trials (n=91 140) showing a 9% (odds ratio 1.09, 95% confidence interval 1.02 to 1.17) increased incidence of diabetes over four years of follow-up.10 More recently, two meta-analyses have suggested a dose dependent effect for patients receiving high dose atorvastatin or simvastatin treatment versus moderate dose treatment (odds ratio 1.12, 95% confidence interval 1.04 to 1.22) and when considering only atorvastatin trials.11 12 Our results differ from those of the Women’s Health Initiative study, which showed a nearly 50% increase in new onset diabetes with statins compared with placebo (hazard ratio 1.48, 95% confidence interval 1.38 to 1.59), with no differential risk among low potency (fluvastatin, lovastatin, pravastatin) and high potency (simvastatin, atorvastatin) statins.14 Our findings, however, are consistent with the findings of Zaharan and colleagues in 2012, who found an increased risk with atorvastatin (hazard ratio 1.25, 1.21 to 1.28), rosuvastatin (1.42, 1.33 to 1.52), and simvastatin (1.14, 1.06 to 1.23).30 Our population based assessment adds to the discussion of risk when doctors are considering starting statin treatment in a patient for primary versus secondary prevention.

Possible mechanisms

Several factors could explain the increased risk of new onset diabetes among patients receiving certain statins.2 7 15 The increased production of plasma derived low density lipoprotein (LDL) cholesterol as a compensatory response to de novo cholesterol synthesis inhibition might result in direct inflammation and oxidation within the β cell. Consequently, the functional and structural integrity of β cells is compromized, impairing insulin secretion as a result of cellular apoptosis.15Additionally, metabolic receptor effects interfere with cellular glucose uptake, energy production, and insulin secretion.2 7 15 16 Statins can also inhibit calcium mediated pancreatic insulin release and decrease expression of the β cell glucose transporters GLUT-2 and GLUT-4.15 Finally, statins are also known to interfere with the synthesis of ubiquinone (CoQ10), which could independently alter insulin secretion.15 16 The degree to which statins are involved in these respective mechanisms of diabetes onset is variable and supports why some statins pose a higher risk than pravastatin.7 As shown in our dose and potency analyses, the risk could be greater for atorvastatin and simvastatin, regardless of the dose prescribed.

Limitations and strengths

Some limitations of our study merit emphasis. We could not identify and account for potentially important risk factors for diabetes such as weight, ethnicity, and family history. Newer statins might be preferentially used in patients at higher risk of diabetes, though the characteristics of patients in our study were highly similar across study groups. Secondly, data on blood lipids, hemoglobin A1C concentration, or triglyceride concentrations were unavailable, and therefore we could not use these measures for risk stratification or diagnostic purposes. The ODD, however, has been shown to be both sensitive (86-90%) and specific (92-97%).19 Furthermore, we had no data on marketing or promotional efforts nor did we have data on physicians’ preferences for particular statins. Although the statin groups were well balanced with respect to a wide variety of demographic and clinical variables, we cannot exclude the possibility of residual confounding.

Our study also had several strengths including a large sample size, use of pravastatin as an active comparator reference group, and a population based design. Our findings suggest that older patients treated with certain statins are at increased risk for incident diabetes, regardless of dose or whether treatment is used for primary or secondary prevention. The risk seems to be greatest with atorvastatin, rosuvastatin, and simvastatin. After adjustment for dose, however, the risk did not seem to persist among rosuvastatin users. Clinicians should consider this risk when they are contemplating statin treatment for individual patients. Preferential use of pravastatin, and potentially fluvastatin or lovastatin, while recognizing the limited efficacy data and increased risk of drug interactions with these two agents, might be warranted. Pravastatin might have a preferential benefit among primary prevention patients at high risk of diabetes.

What is already known on this topic

  • Given the widespread use of statins to manage hypercholesterolemia, small effects in their efficacy and safety profiles can have important population impact.
  • Statins have previously been associated with an increased risk of incident diabetes, though there is controversy around whether this risk differs among drugs
  • When compared with pravastatin, atorvastatin, rosuvastatin, and simvastatin are associated with a greater risk of new onset diabetes, regardless of their use for primary or secondary prevention of cardiovascular events
  • The risk for rosuvastatin users might depend on the dose prescribed

What this study adds

 

 

Source: BMJ

 

HPS2-THRIVE: Niacin therapy not beneficial for vascular disease.

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Niacin, in combination with laropiprant, appears to provide no benefit and may have harmful effects in patients with vascular disease, researchers reported.

The 4-year HPS2-THRIVE study tested a combination of extended-release niacin 2 g plus laropiprant 40 mg (Tredaptive, Merck) compared with placebo in 25,673 patients at risk for CV events. In addition, all patients received simvastatin (Zocor, Merck), with or without ezetimibe (Zetia, Merck).

According to results presented at a late-breaking clinical trials session, the study did not meet the primary endpoint of reducing risk for a major vascular event, defined as a composite of nonfatal MI or CV-related death, stroke, or need for angioplasty or bypass surgery. Patients assigned extended-release niacin/laropiprant had a similar number of major vascular events compared with patients assigned placebo (13.2% vs. 13.7%; P=.29).

The extended-release niacin/laropiprant had increased rates of excess bleeding (2.5% vs. 1.9%) and infections (8% vs. 6.6%). In addition, serious adverse events were more prevalent with combination therapy, including new-onset diabetes (9.1% vs. 7.3%), diabetic complications (11.1% vs. 7.5%), indigestion and diarrhea (4.8% vs. 3.8%) and rashes (0.7% vs. 0.4%).

Data by the HPS2-THRIVE Collaborative Group published in European Heart Journal in early March revealed that by the end of the study 25% of patients assigned combination therapy had stopped treatment compared with 17% of patients assigned placebo.

“A striking finding from the study was a significant excess [in adverse events] among people who were allocated the niacin preparation. The excess represents a 3% absolute excess, which means 30 patients for every 1,000 treated patients had at least one side effect,” Jane Armitage, FFPH, FRCP,professor at the University of Oxford, United Kingdom, said at a press conference.

“It was a disappointing result but, nevertheless, these are clear and reliable results from a large study.”

 

PERSPECTIVE

 

Christie M. Ballantyne

  • We confirmed that using niacin in well-treated patients on statins with low LDL does not have a benefit. That was a very common use for this medicine. The other important point this study nails down is that the adverse effects of niacin in extended release were considerable. If we are going to use the drug in patients with high LDL, we have to think about the modest benefits and risks.
  • Christie M. Ballantyne, MD
  • Professor of Medicine
    Baylor College of Medicine

    • Source: Endocrine Today.

 

Stronger statins associated with muscle problems.

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Among patients taking statins, those who reported experiencing muscle problems were prescribed a stronger or more potent statin, according to study results recently published in PLoS One.

Researchers analyzed 147,789 case reports from the FDA Adverse Event Reporting System (AERS) database linking muscle-related adverse events to statin use from July 2005 to March 2011. Statins selected for analysis included: atorvastatin (Lipitor, Pfizer), simvastatin (Zocor, Merck), lovastatin (Mevacor, Merck), pravastatin (Pravachol, Bristol-Myers Squibb), rosuvastatin (Crestor, AstraZeneca), fluvastatin (Lescol, Novartis) and generic equivalents and foreign designations. Death, disability and hospitalization were collected as outcome measures for the main adverse event categories, which included joints and tendons, muscle atrophy and injury, and muscle coordination and weakness.

Overall, researchers found that relative risk rates were consistently higher for rosuvastatin and fluvastatin, intermediate for atorvastatin and simvastatin and low for pravastatin and lovastatin. When all muscle categories were incorporated, study results showed that rosuvastatin had the highest ranked risk, followed by atorvastatin (55%), simvastatin (26%), pravastatin (17%) and lovastatin (7.5%).

“These findings underscore that stronger statins bear higher risk — and should be used with greater caution and circumspection,” Beatrice Golomb, MD, PhD, professor in the departments of medicine and family and preventative medicine at the University of California, San Diego, said in a press release. “These rankings closely match the individual potencies of each statin. Thus, the strength of the statin drug appears to be a dominant factor in determining how likely muscle problems are to occur.”

Source: Endocrine Today.

 

 

Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20 536 high-risk individuals: a randomised controlled trial.

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Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods.
METHODS: 20 536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5.3 years (SD 1.2), and post-trial follow-up of surviving patients yielded a mean total duration of 11.0 years (SD 0.6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393.
FINDINGS: During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1.0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19-28; p<0.0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0.95 [0.89-1.02]) or vascular mortality (0.98 [0.90-1.07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0.98 [0.92-1.05]) or any particular site, or in mortality attributed to cancer (1.01 [0.92-1.11]) or to non-vascular causes (0.96 [0.89-1.03]).
INTERPRETATION: More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment.

Source:Lancet.