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Statin use before a diabetes diagnosis was not associated with an increased risk for microvascular complications and appeared to be slightly protective against diabetic eye and nerve damage in a nationwide study from Denmark.

Using data from national clinical registries, the researchers identified all patients ages 40 and older in the country diagnosed with incident diabetes from 1996 through 2009.

Compared with nonstatin users, statin users had a lower cumulative incidence of diabetic retinopathy (hazard radio 0.60, 95% CI 0.54-0.66; P<0.0001), diabetic neuropathy (HR 0.66, 95% CI 0.57-0.75; P<0.0001), and gangrene of the foot (HR 0.88, 95% CI 0.80-0.97; P=0.010), but not diabetic nephropathy (HR 0.97, 95% CI 0.85-1.10; P=0.62), researchers , and of Herlev Hospital, Copenhagen, wrote in the Sept. 10 issue of

'Microvascular Findings Not Conclusive'

In 2012, Nielsen, Nordestgaard, and colleagues reported that statin use appeared to reduce the risk of death in cancer patients, based on findings from another nationwide clinical registry study.

Their latest work should be viewed as reassuring, but not definitive evidence that statin use is not associated with an increased risk for common microvascular complications in patients with diabetes, said of the University of Glasgow, who is a diabetes researcher and senior lecturer in metabolic medicine.

A of five large statin trials by Preiss and colleagues suggested that intensive-dose statin therapy may be associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

"The study from Denmark should be considered hypothesis generating, but not conclusive," Preiss told MedPage Today. "No large-scale randomized trials have been done to examine this issue, and there are not likely to be any since it would be difficult to ethically randomize people with diabetes to a placebo group."

Study Captured All Diabetes Patients

Myocardial infarction and stroke are the leading killers of people with diabetes, and statins have been shown to significantly reduce the risk for these cardiovascular events in this population.

But it has been suggested that statins can also increase glucose levels and increase diabetes risk in people with one or more metabolic risk factors.

"Whether statin use affects the development of microvascular disease in individuals with diabetes is presently unknown," Nielsen and Nordestgaard wrote. "We aimed to test the hypothesis that statin use amplifies the risk of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and gangrene of the foot in individuals in the general population with diabetes."

The study included data from the Danish Civil Registration System, a nationwide database that records all birth, immigrations, emigrations, and deaths in Denmark and is 100% complete. Diabetes cases were identified from the Danish Patient Registry or the Danish Registry of Medical Product Statistics, and median follow-up was 2.7 years (range 0-13 years).

To address potential biases between statin users and nonstatin users, the researchers made adjustments to their analysis with propensity score and with other measures.

Between Jan. 1 of 1996 and Dec. 31 of 2009, 213,974 people ages 40 and older in Denmark were diagnosed with any form of diabetes. A total of 62,716 people were randomly selected for the present study, including 15,679 statin users and 47,037 nonstatin users. During 215,725 person-years of follow-up, diabetic retinopathy was recorded in 2,866 patients, diabetic neuropathy in 1,406, diabetic nephropathy in 1,248, and gangrene of the foot in 2,392.

The analysis revealed that:

• Compared with nonstatin users, the cumulative incidence of diabetic retinopathy was lower for statin users, and the corresponding multivariable adjusted hazard ratio was 0.60 (95% CI 0.54-0.66; P<0.0001).
• The results were similar for diabetic neuropathy (0.66, 95% CI 0.57-0.75; P<0.0001) and gangrene (0.88, 95% CI 0.80-0.97; P=0.010). The cumulative incidence of diabetic nephropathy was similar between groups (0.97, 95% CI 0.85-1.10; P=0.62).
• In an analysis adjusted for propensity score and a nested analysis adjusted for potentially earlier diabetes diagnosis, results were similar to the initial analysis. Post-hoc analyses that adjusted for previous use of antihypertensive medications during the 2 years before a diabetes diagnosis or for irregular statin use also had similar findings.

Study strengths included the large size and comprehensive nature of the analysis, which included everyone with incident diabetes in Denmark over a 13-year period.

Study limitations included incomplete registry information on how diabetes was controlled after diagnosis and blood pressure. The researchers noted that statin use could also be a marker for atherosclerosis, enhanced health awareness, or increased frequency of doctor visits.

The researchers wrote that the similar findings in the primary and secondary analyses suggest that the results were not distorted by competing risks such as all-cause mortality, CVD death, or more frequent visits to the doctor.

Findings Are Reassuring, But More Study Needed

"We found no evidence that statin use is associated with an increased risk of microvascular disease; this result is important and clinically reassuring on its own," the researchers wrote.

They added that additional research will be needed to determine whether statins are protective against some forms of microvascular disease, which their data suggest.

Since large, placebo-controlled trials are unlikely, they proposed Mendelian randomization studies that include genetic variants associated with lifelong reduced LDL cholesterol.

In an editorial published with the analysis, Preiss wrote this type of investigation would likely involve assessment of microvascular complications in those with polymorphisms in the HMGCR gene, which are proxies for statin treatment.

"Such studies will need huge populations with robust recording of diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy outcomes, but suitable studies are developing," he wrote. "A further possibility is to gather information about laser treatment for diabetic retinopathy across all major statin trials. For now, any benefits of statins on microvascular complications remains unproven."

Statins act by inhibiting HMGCR which leads to upregulation of hepatic LDL cholesterol receptors and subsequent reduction in circulating concentrations of LDL, and, to a lesser extent, triglycerides.

Preiss wrote that if statins do protect against microvascular complications of diabetes, this action may have little to do with its primary role of lipid modification.

He told MedPage Today that the lipid modifying, nonstatin drug fenofibrate has been shown in some studies to reduce the risk of retinopathy, and the action was not related to the drug's lipid modifying effects.

It is likely that fenofibrate's impact on microvascular risk is through direct intraocular anti-inflammatory action rather than changes in circulating lipids, he noted. Statins also have anti-inflammatory effects.

"We know that lowering glucose is important, but it can be difficult to achieve good glucose control with some patients," he said. "If we could find another way to reduce microvascular complications -- possibly with a statin or another drug like fenofibrate -- that would be fantastic."

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