— Results underscore key role of weight management, Danish researchers say
by Jeff Minerd, Contributing Writer, MedPage Today April 15, 2020

In a large Danish cohort study examining risk factors for type 2 diabetes, obesity overpowered both genetics and lifestyle.

Obese individuals were nearly six times more likely to develop type 2 diabetes compared with people of normal body weight (HR 5.81, 95% CI 5.16-6.55). Individuals with a high genetic risk score, however, were only twice as likely (HR 2.00, 95% CI 1.76-2.27) to develop type 2 diabetes compared with those with low genetic risk, noted Theresia Schnurr, MSc, PhD, of the University of Copenhagen, and colleagues.

As shown in their study online in Diabetologia, for individuals with a low genetic risk score and favorable lifestyle, obesity was associated with a more than eight-fold increase in diabetes risk (HR 8.44, 95% CI 5.43-13.14). Individuals who ranked high for all factors had the greatest risk, a more than 14-fold increase (HR 14.54, 95% CI 8.09-26.13). In contrast, being overweight was associated with a 49% risk increase (HR 1.49, 95% CI 1.34-1.66) and an unfavorable lifestyle with an 18% increase (HR 1.18, 95% CI 1.06-1.30).

“The associations of the genetic risk score and lifestyle score with risk of incident type 2 diabetes are relatively modest compared with the association of obesity with diabetes risk, underscoring the importance of weight management in diabetes prevention,” Schnurr and colleagues wrote. “The results suggest that type 2 diabetes prevention by weight management and healthy lifestyle is critical across all genetic risk groups.”

The study included 4,729 adults with incident type 2 diabetes from the Diet, Cancer and Health Cohort in Denmark; mean age was 56.1 (range 50-65), and 49.6% were women. The study also included a randomly selected cohort of 5,402 individuals, of whom 575 developed incident diabetes. Median follow-up was 14.7 years.

To assess genetic predisposition, the researchers used a risk score that included 192 known type 2 diabetes-associated loci, excluding known body mass index (BMI). The top 20% were defined as high risk, the bottom 20% as low risk, and the rest as intermediate.

Lifestyle was categorized as unfavorable, intermediate, or favorable based on questionnaires that assessed smoking, alcohol consumption, physical activity, and diet. Overall, 40.0% of participants had a favorable lifestyle, 34.6% had an intermediate lifestyle, and 25.4% had an unfavorable lifestyle.

Obesity was defined as a BMI of 30 or higher; overweight as a BMI of 25 or higher; and normal weight as a BMI of less than 25. Overall, 21.8% of participants were obese, 43.0% were overweight, and 35.2% were normal weight. In a sensitivity analysis that excluded 62 individuals who were underweight (BMI less than 18.5), the results were “virtually unchanged,” the study authors said.

Schnurr and colleagues used Prentice-weighted Cox proportional-hazards models to test associations of genetic risk, obesity, and lifestyle with incident type 2 diabetes. The team also examined the interactions of genetic risk with obesity and lifestyle and found no significant interactions between genetic risk score and BMI (P=0.35) or lifestyle (P=0.72) on type 2 diabetes risk.

The researchers noted that the results are different from those of a previous study conducted by the InterAct Consortium, which found that the effect of genetic risk on type 2 diabetes was significantly greater among individuals who were leaner at baseline. However, the genetic risk score in that study was based on only 49 established loci. “It is possible that the present analyses were underpowered to detect an interaction between the genetic risk score and BMI,” Schnurr and co-authors wrote. Alternatively, they added, the inclusion of more than 150 additional recently identified type 2 diabetes risk variants in their study may have improved its accuracy compared with the previous research.

Also, since the current study was conducted entirely in people of European genetic ancestry, the results might not be generalizable to individuals with different genetic backgrounds. “Overall, the results indicate that a favorable lifestyle should be universally recommended in the prevention of type 2 diabetes, regardless of genetic predisposition, thus supporting current public health guidelines,” the investigators suggested.