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Statin therapy associated with diabetes progression — US cohort study

Statin use has been associated with increased likelihood of diabetes progression, according to a matched cohort analysis of data from the US Department of Veteran Affairs and the University of Texas researchers, published in JAMA Internal Medicine.

Patients with diabetes who were on statins were more likely to begin taking insulin, become hyperglycaemic, and to develop acute glycaemic complications, and they were also more likely to be prescribed medications from more glucose-lowering drug classes.

Medscape reports that although previous observational and randomised, controlled trials suggested a link between statin use and diabetes progression, they typically relied on measures like insulin resistance, haemoglobin A1c, or fasting blood glucose levels. The new work, however, outlines changes in glycaemic control.

The differences between fasting glucose levels and A1c levels were generally smaller than the differences in insulin sensitivity. But A1c and fasting glucose may underestimate a potential effect of statins, since physicians may escalate anti-diabetes therapy in response to changes.

Insulin sensitivity is also rarely measured in real-world settings. “This study translated findings reported on academic studies of increased insulin resistance associated with statin use in research papers into everyday language of patient care. That is, patients on statins may need to escalate their anti-diabetes therapy and there may have higher occurrences of uncontrolled diabetes events,” said lead author Dr Ishak Mansi.


Mansi, who is staff internist at the VA North Texas Health System and a professor of medicine and data and population science at the University of Texas, both in Dallas, cautioned about over-interpretation of the findings. “This is an observational study; therefore, it can establish association, but not causation.”

No reason to turn down statins

Mansi noted that it's important to distinguish between those being prescribed statins as a primary preventive measurement against cardiovascular disease, and those starting statins with pre-existing cardiovascular disease for secondary prevention. Statins are a key therapeutic class for secondary prevention. “Their benefits are tremendous, and we should emphasise that no patient should stop taking their statins based on our study — rather, they should talk to their doctors,” he said.

The study is one of few to look at statin use and diabetes progression in patients who already have diabetes, and the first with a propensity- matched design, according to Dr Om Ganda, who was asked for comment. The results should not deter physicians from prescribing and patients from accepting statins.

“Statins should not be withheld in people with high risk of cardiovascular disease, even for primary prevention, as the risk of progression of glucose levels is relatively much smaller and manageable, rather than risking cardiovascular events by stopping or not initiating when indicated by current guidelines,” said Ganda, who is the medical director of the Lipid Clinic at the Joslin Diabetes Center and an associate professor of medicine at Harvard Medical School, both in Boston.

It’s possible that statins could increase risk of diabetes progression through promoting insulin resistance, and they may also reduce beta-cell function, which could in turn reduce insulin secretion, according to Ganda.

The study group included 83,022 pairs of statin users and matched controls, of whom 95% were men; 68.2% were white; 22% were black; 2.1% were Native American, Pacific Islander, or Alaska native; and 0.8% were Asian. The mean age was 60 years.

Some 56% of statin users experienced diabetes progression, compared with 48% of control patients (odds ratio, 1.37; P < .001). Progression was defined as intensification of diabetes therapy through new use of insulin or increase in the number of medication classes, new onset chronic hyperglycaemia, or acute complications from hyperglycaemia.

The association was seen in the component measures, including an increased number of glucose-lowering medication classes (OR, 1.41; P < .001), the frequency of new insulin use (OR, 1.16; P < .001), persistent glycaemia (OR, 1.13; P < .001), and a new diagnosis of ketoacidosis or uncontrolled diabetes (OR, 1.24; P < .001).
There was also a dose–response relationship between the intensity of LDL cholesterol-lowering medication and diabetes progression.

More research needed

The findings don’t necessarily have a strong clinical impact, but the researchers hope it pushes toward greater personalisation of statin treatment. The benefits of statins have been well studied, but their potential harms have not received the same attention. Mansi hopes to learn more about which populations stand to gain the most for primary cardiovascular disease prevention, such as older versus younger populations, healthier or sicker patients, and those with well-controlled versus uncontrolled diabetes.

“Answering these questions [would] impact hundreds of millions of patients and cannot be postponed,” said Mansi. He also called for dedicated funding for research into the adverse events of frequently used medications.

Study details
Association of Statin Therapy Initiation With Diabetes Progression
A Retrospective Matched-Cohort Study

Ishak A. Mansi, Matthieu Chansard, Ildiko Lingvay, Song Zhang, Ethan A. Halm, Carlos A. Alvarez.

Published in JAMA Internal Medicine on 4 October 2021

Key Points

Question What is the association of statin treatment initiation and diabetes progression in patients with diabetes?
Findings This large retrospective cohort study included 83 022 propensity-scored matched pairs of statin users and nonusers and found that the diabetes-progression composite outcome was significantly higher among patients with diabetes who used statins than among patients with diabetes who did not use statins. The study examined 12 years of data on patients covered by the Veterans Affairs health system and new-user and active-comparator designs to assess associations between statin initiation and diabetes progression from 2003 to 2015.
Meaning Statin use was associated with diabetes progression in patients with diabetes—statin users had a higher likelihood of insulin treatment initiation, developing significant hyperglycemia, experiencing acute glycemic complications, and being prescribed an increased number of glucose-lowering medication classes.


Statin therapy has been associated with increased insulin resistance; however, its clinical implications for diabetes control among patients with diabetes is unknown.

To assess diabetes progression after initiation of statin use in patients with diabetes.

Design, Setting, and Participants
This was a retrospective matched-cohort study using new-user and active-comparator designs to assess associations between statin initiation and diabetes progression in a national cohort of patients covered by the US Department of Veterans Affairs from fiscal years 2003-2015. Patients included were 30 years or older; had been diagnosed with diabetes during the study period; and were regular users of the Veterans Affairs health system, with records of demographic information, clinical encounters, vital signs, laboratory data, and medication usage.

Treatment initiation with statins (statin users) or with H2-blockers or proton pump inhibitors (active comparators).

Main Outcomes and Measures
Diabetes progression composite outcome comprised the following: new insulin initiation, increase in the number of glucose-lowering medication classes, incidence of 5 or more measurements of blood glucose of 200 mg/dL or greater, or a new diagnosis of ketoacidosis or uncontrolled diabetes.

From the 705 774 eligible patients, we matched 83 022 pairs of statin users and active comparators; the matched cohort had a mean (SD) age of 60.1 (11.6) years; 78 712 (94.9%) were men; 1715 (2.1%) were American Indian/Pacific Islander/Alaska Native, 570 (0.8%) were Asian, 17 890 (21.5%) were Black, and 56 633 (68.2 %) were White individuals. Diabetes progression outcome occurred in 55.9% of statin users vs 48.0% of active comparators (odds ratio, 1.37; 95% CI, 1.35-1.40; P < .001). Each individual component of the composite outcome was significantly higher among statin users. Secondary analysis demonstrated a dose-response relationship with a higher intensity of low-density lipoprotein-cholesterol lowering associated with greater diabetes progression.

Conclusions and Relevance
This retrospective matched-cohort study found that statin use was associated with diabetes progression, including greater likelihood of insulin treatment initiation, significant hyperglycaemia, acute glycemic complications, and an increased number of prescriptions for glucose-lowering medication classes. The risk-benefit ratio of statin use in patients with diabetes should take into consideration its metabolic affects.


Medscape article – Statins Tied to Diabetes Progression (Open access)


JAMA Internal Medicine article – Association of Statin Therapy Initiation With Diabetes ProgressionA Retrospective Matched-Cohort Study (Open access)


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