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Insulin resistance in people with type 2 diabetes was predictive of stroke, according to a Swedish nationwide cohort study.

Patients with type 2 diabetes with less insulin resistance as measured by estimated glucose disposal rate (eGDR) saw a significantly lower risk for any kind of first-time stroke over a median 5.6 years of follow-up, reported Alexander Zabala, MD, of the Karolinska Institute in Stockholm.

This association also appeared to be graded, with the less insulin resistance a person had correlating with an even lower risk for stroke in a fully adjusted model, Zabala said in a presentation at the virtual European Association for the Study of Diabetes (EASD) meeting.

For the analysis, insulin resistance was quantified using eGDR, calculated using the variables of waist circumference, presence of hypertension, and HbA1c. Zabala explained, however, that there is another version of this formula for eGDR that swaps out waist circumference for body mass index. And while insulin resistance can also be measured with the hyperinsulinemic-euglycemic clamp method, this method is not suitable for large-scale clinical use due to the high cost and invasiveness, he said. In addition, using eGDR as a proxy for insulin resistance can also be used in a type 1 diabetic population.

Compared with patients who had an eGDR of less than 4 mg/kg/min -- considered the highest grade of insulin resistance -- patients falling into the three categories of less insulin resistance had 23%, 32%, and 40% lower risks for stroke, respectively:

• eGDR 4-5.99 (HR 0.77, 95% CI 0.69-0.87)

• eGDR 6-7.99 (HR 0.68, 95% CI 0.58-0.80)

• eGDR 8+ (HR 0.60, 95% CI 0.48-0.76)

Some factors in the eGDR equation held a higher estimated relative risk for stroke, Zabala reported. Specifically, the presence of hypertension was the factor underlying insulin resistance that most strongly predisposed someone to a stroke. Following that, HbA1c was the second most important clinical factor in this equation, succeeded by waist circumference.

The benefit of less insulin resistance didn't stop at just stroke risk, he noted. The same patterns were also seen with all-cause mortality, with less insulin resistance associated with a significantly lower risk for death:

• eGDR 4-5.99 (HR 0.83, 95% CI 0.76-0.89)

• eGDR 6-7.99 (HR 0.77, 95% CI 0.69-0.77)

• eGDR 8+ (HR 0.72, 95% CI 0.59-0.88)

Nearly an identical pattern was seen when looking only at the risk for cardiovascular-related mortality as well, Zabala said. Compared with type 2 diabetes patients with the highest amount of insulin resistance, those falling into the lesser three categories of insulin resistance saw an 18%, 25%, and 35% lower risk for cardiovascular death, respectively.

The analysis included 104,697 people with type 2 diabetes identified through Sweden's National Diabetes Register. These data were combined with the country's Cause of Death Register, an in-patient registry, along with the longitudinal integrated database for health insurance and labor market studies.

Among this cohort, average age was 63 and about 46% were women. During the median 5.6 years of follow-up, there were a total of 4,201 incidences of stroke, representing 4% of this patient population. This included stroke, ischemic stroke, and hemorrhagic stroke; subarachnoid hemorrhages were not included.

Zabala said the relationship between insulin resistance and stroke risk was largely driven by ischemic stroke, as the risk for hemorrhagic stroke alone was not statistically significant.

The majority of the cohort had a moderate amount of insulin resistance, he noted. Among the total patient population, 24,706 had the highest degree of insulin resistance (eGDR<4); while 40,187 had an eGDR of 4-6; 21,042 had an eGDR of 6-8; and 18,762 had an eGDR of about 8.

Zabala said that not surprisingly, patients with the greatest amount of insulin resistance tended to have a longer duration of diabetes, higher HbA1c levels, higher systolic blood pressure, and were more likely to be treated with a combination of insulin and oral glucose-lowering therapies.

Study limitations, he said, included that the researchers were not able to adjust for specific type of diabetes medications, such as SGLT2 inhibitors, GLP-1 receptor agonists, or DPP-4 inhibitors.

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