High-dose atorvastatin did not cause diabetes in low-risk patients with existing cardiovascular disease

Atorvastatin molecule

The Diabetes Elf once overheard a respected senior colleague:

“The only treatments that don’t have any side-effects are the ones that don’t work.”

So it turned out with statins, which were recently found to have increased the risk of developing type 2 diabetes.  The questions, of course, is “Are the benefits worth the harms?”  In other words:

  • Is the increased risk of developing diabetes worth the harm from having an increased risk of further cardiovascular disease without statins?
  • Are these risks the same for everyone, or are some people at a higher risk of harm than others?

A recent retrospective meta-analysis of clinical trial data sheds important light on this issue.

Clinical question:

In patients without diabetes receiving statin therapy for secondary prevention of cardiovascular disease, what risk factors affect the balance of risk and benefit between reduced cardiovascular events and harm from increased diabetes?

Methods:

The researchers re-analysed data from two large randomised trials looking at atorvastatin:

  • In the TNT study (n=7,595 without diabetes, median foll0w-up 4.9 years), 10mg atorvastatin was compared with 80mg.
  • The IDEAL study (n=7,461 without diabetes, median foll0w-up 4.8 years) compared 20 to 40mg simvastatin with 80mg atorvastatin.

The researchers categorised the patients in these trials according to whether they had one or more of the following risk factors for developing diabetes:

  1. Fasting blood glucose (FBG) > 100mg/dl
  2. history of hypertension
  3. Body Mass Index (BMI) > 30kg/m2
  4. Fasting triglycerides > 150mg/dl.

They then worked out how many patients had a major cardiovascvular event and how many developed diabetes for each dosage and risk factor combination.

Results

In patients with 0 or 1 of the risk factors:

  • no significant difference was found in the risk of getting diabetes between 80mg atorvastatin and either of the lower dose comparator groups (10mg atorvastatin or simvastatin).  The incidence was 3.22% and 3.35% respectively.
  • the 80mg atorvastatin group had fewer cardiovascular events than the lower dose groups (Hazard Ratio [HR] 0.87; 95% CI 0.755 to 0.995)

In patients with 2 to 4 risk factors,

  • 80mg atorvastatin was associated with an increased risk of developing diabetes (HR 1.24;  95% CI 1.03 to 1.42) compared with the lower dose regimens.  The incidence of diabetes in these groups was 14.32% and 11.86% respectively.
  • the 80mg atorvastatin group had fewer cardiovascular events than the lower dose groups (HR 0.82; 95% CI 0.71 to 0.96).  The incidence was 10.07% and 12.02% respectively.

The researchers concluded that high dose statins increased the risk of new-onset diabetes compared with lower dose regimens only in patients who already had 2 or more risk factors for developing diabetes.

Higher dose statins reduced major cardiovascular events for both groups.

Comments

  • This is a good quality meta-analysis with a restricted data set (no systematic literature review was carried out).  The underlying studies were large-scale, long term randomised trials, suggesting that they had a low risk of bias.  Allocation concealment and intention to treat was not assessed, though.
  • The baseline risk of each outcome would affect the interpretation of this evidence and should be considered along with patient values and preferences.  The trials may have undertestimated the likely incidence of diabetes we would expect to see in practice, for example.
  • These studies were not designed to investigate differential effect of statin dosage on diabetes incidence however.
  • New-onset diabetes was defined as two Fasting Blood Glucose measurements of ≥ 7.0 mmol/l (126 mg/dl) and at least 1 post-baseline glucose 2 mmol/l (36 mg/dl) above baseline.
  • The study did not directly compare the cardiovascular benefits of high dose statins among the low and high risk group.
  • Note that this paper is not about people who already have diabetes.
  • Further research is warranted to clearly establish the balance of benefits and harms in the broader population of people receiving statin therapy for secondary prevention of cardiovascular disease.

Reference:

Waters DD, Ho JE, Boekholdt SM, DeMicco DA, Kastelein JJ, Messig M, Breazna A, Pedersen TR.  Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol. 2013 Jan 15;61(2):148-52. doi: 10.1016/j.jacc.2012.09.042. Epub 2012 Dec 5.

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Badenoch

Badenoch
I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I've been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it.. Ha! Hence The National Elf service.

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