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Early glimpse at RISC underscores physical activity benefits and suggests insulin sensitivity is not a "sole driver" of risk
Amsterdam, the Netherlands - Baseline characteristics and preliminary results from the Relationship Between Insulin Sensitivity and Cardiovascular Risk (RISC) study suggest that insulin sensitivity is not the "sole driver" of cardiometabolic risk but rather is one of several metabolic factors, including obesity and hyperinsulinemia, that influence cardiovascular risk in this setting, Dr Mark Walker (Newcastle University, UK) reported here at the European Association for the Study of Diabetes (EASD) 2007 Meeting.
Dr Mark WalkerWalker also showed data clearly linking insulin sensitivity to low physical activity levels, irrespective of body weight.
The RISC baseline characteristics and three-year results are an early glimpse at a trial expected to take 10 years to determine whether insulin resistance is directly involved in the development of CVD and whether baseline insulin sensitivity can be used to predict CVD events in healthy, nondiabetic adults. According to Walker, the three-year results being unveiled at the EASD meeting cannot yet answer the question of how insulin resistance is linked to atherosclerosis development—being measured by carotid IMT in this study—but they can still reveal novel insights into a risk factor that for years has been considered to be a core defect leading to the development of cardiometabolic syndrome.
"Supporting evidence for this has been based on proxy measures of insulin resistance such as waist circumference and fasting insulin levels," Walker stated. "But evidence for a direct link between insulin resistance and CVD is lacking."
Walker, who presented the RISC update during an EASD press conference prior to the official presentation, is just one investigator within the European Group for the Study of Insulin Resistance (EGIR) conducting a range of interconnected studies within the RISC cohort.
Patients at RISC
RISC is a prospective, multicenter, observational study that has enrolled 1338 patients at 19 centers across Europe. RISC subjects are for the most part middle-aged and healthy, with no preexisting diabetes, known CVD, or hypertension. For the study, all subjects underwent testing for insulin sensitivity using the euglycemic clamp technique—the "gold standard" for measuring insulin resistance. Subjects also wore an Actigraph movement monitor for five days, for 10 hours per day, to assess activity levels and also filled out the International Physical Activity questionnaire.
One of the first observations from RISC, said Walker, was of the interrelationship of insulin sensitivity, waist circumference, and high insulin levels, these last commonly thought of as proxies for insulin resistance. But measures of all three factors in the RISC cohort show that many people with insulin resistance on clamp testing do not, in fact, have large waist circumferences or high insulin levels. Furthermore, when RISC subjects were assigned a CVD risk score, based on other measurable risk factors, a higher CVD risk score was associated with greater insulin resistance, but researchers saw the same pattern with insulin exposure, waist circumference, and body-mass index (BMI).
"A key question is whether [CVD risk] can all be explained by one factor or are they all contributing," Walker observed. "And in multivariate analyses, we found that each of these traits independently predicted the [cardiovascular risk factor] score: they are all bringing something to the table. So our first conclusion is that insulin resistance is not the sole driver of cardiometabolic risk, but that obesity, particularly central obesity, and also high circulating insulin levels, also contribute."
"Keep moving"
Of the baseline cardiovascular risk factors identified by the EGIR researchers, physical activity emerged as a key moderator of insulin resistance, Walker explained during the press conference. Using the accelerometer data, researchers evaluated total activity, level of moderate and vigorous activity, and "sedentarity," defined as the percentage of time a subject was inactive. For all measures, EGIR researchers found that insulin sensitivity was directly correlated with increasing amounts of total activity and increasing degrees of activity, with insulin sensitivity increasing with more, or more vigorous, activity. Likewise, insulin sensitivity was inversely associated with sedentarity. Strikingly, these associations held up even in patients with higher BMIs, suggesting that even overweight and obese subjects could improve insulin sensitivity by keeping active. Moreover, baseline carotid artery intima-media thickness tests indicated that subjects who were more physically active had less carotid artery stiffness, Walker noted.
Walker offered just a peek at the limited three-year follow-up, stressing that analyses are still ongoing. As of July 2007, 784 subjects had undergone repeat testing, and despite being relatively healthy at baseline, 1% had gone on to develop diabetes, 8% had gone on to develop impaired fasting glucose, 12% had developed impaired glucose tolerance, 13% had developed high blood pressure, and 11% had developed central adiposity. In analyses conducted by Dr Jacqueline Dekker (VU University Medical Center, Amsterdam, the Netherlands) baseline insulin resistance, high waist circumference, and beta cell dysfunction emerged as the major determinants of the progression to impaired glucose tolerance at three years. Investigators have not yet looked at whether physical activity levels at baseline were a predictor of impaired glucose tolerance.
While longitudinal data over the complete planned follow-up period is needed to show whether insulin resistance is an independent predictor of the development of atherosclerosis and CVD, Walker says the preliminary information presented at this year's EASD meeting is still clinically meaningful. The message to physicians and patients is to "keep moving," he said.
"Physical activity is the key determinant of insulin sensitivity. Even if you have an office job, even if you sit around for most of the day, if you go out and increase your physical activity . . . that's good. So long as you get your total activity up, you will have these positive associations with insulin sensitivity."
Commenting on the preliminary RISC results, Dr Stefano Del Prato (University of Pisa, Italy) called the findings "important," in that they extend the accepted notion of cardiometabolic risk to a low-risk patient population.
"We know from other studies that if you take overweight people with impaired glucose tolerance, who are slightly hypertensive, and you put them through a lifestyle/behavior change, they can significantly reduce their risk of developing diabetes," he said. "These results are complementary to that, showing that even the perfectly normal, ideal population, there are still factors that can been moderated to reduce their risk."
Walker disclosed having no conflicts of interest; the RISC trial is sponsored by the European Union and AstraZeneca.