Standard CV Risk Factors Don't Explain the Doubling of Vascular Disease Risk in Diabetes

July 01, 2010

July 1, 2010 (Orlando, Florida) — Diabetes is a risk factor not only for ischemic vascular diseases such as MI and ischemic stroke, it also seems to pose a significant risk across the spectrum of different forms of vascular disease, including hemorrhagic stroke, suggests a meta-analysis encompassing almost 700 000 patients [1]. Moreover, it showed that the elevated risks were largely independent of conventional cardiovascular risk factors, suggesting that diabetes must be raising vascular risk through less familiar mechanisms.

The study, according to Dr Nadeem Sarwar (University of Cambridge, UK), suggests that, contrary to expectations, "very little of the excess cardiovascular risk associated with diabetes is explained by obesity, blood pressure, lipids, inflammatory markers, or renal function." Controlling for those factors, he told heartwire , had little effect on the approximately twofold increase in vascular risk associated with diabetes.

"That means there are yet-to-be discovered pathways that better explain why people with diabetes are at increased [cardiovascular] risk," he said. And that risk accounts for a substantial amount of all cardiovascular disease. Sarwar and his colleagues estimate that, assuming 10% prevalence of diabetes across the adult population, diabetes on its own accounts for 11% of deaths due to vascular disease.

Fasting blood glucose (FBG) levels also predicted cardiovascular risk, but only when they were themselves elevated; normal FBG levels showed no significant relation with the different vascular disease end points.

Sarwar presented the meta-analysis of patient-level data from 102 prospective trials, encompassing 698 782 patients initially without known vascular disease, here at the American Diabetes Association 2010 Scientific Sessions. The analysis of diabetes-related risk was based on 97 of the studies; 54 of them contributed to the separate analysis of risk associated with FBG. The study, conducted by the Cambridge-based Emerging Risk Factors Collaboration, was also published June 26, 2010 in the Lancet.

"One of the key findings of our study is, surprisingly, a remarkably consistent association [between diabetes and vascular risk] across all the studies that contributed to the analysis," Sarwar said. Collectively, they provided 8.5 million person-years of follow-up, with a median time to a first vascular event, fatal or nonfatal, of 10.8 years. The patients had not been selected for their respective studies on the basis of previous vascular disease, and all had been followed for at least a year. Women made up 43% of the cohort, and 96% were in Europe, North America, and Australasia.

One of the more striking findings in the analysis, Sarwar observed, was the >50% increase in hemorrhagic stroke risk associated with diabetes, a relation that is less intuitive than the well-recognized effect of diabetes on risk of ischemic events, such as MI and ischemic stroke. That, he said, underscores the message that "diabetes isn't just related to ischemic vascular disease, it may be relevant to all vascular disease."

Hazard Ratios for Individual Vascular Disease Events Associated With Diabetes

Vascular event HR (95% CI)*
Coronary heart disease 2.00 (1.83-2.19)
Ischemic stroke 2.27 (1.95-2.65)
Hemorrhagic stroke 1.56 (1.19-2.05)
Unclassified stroke 1.84 (1.59-2.13)
Other vascular deaths 1.73 (1.51-1.98)

*Adjusted for age, smoking status, body-mass index, and systolic blood pressure. "Hazard ratios did not change appreciably after further adjustment for lipid, inflammatory, or renal markers," according to the authors.

Elevated FBG concentrations were also associated with increased vascular risk, but not as strongly, and untoward risk wasn't observed at levels considered normal (<5.6 mmol/L). But levels of at least 7.0 mmol/L were associated with a >70% elevation in risk of vascular events.

In an accompanying editorial [2], Dr Hertzel C Gerstein (McMaster University, Hamilton, ON) writes that the demonstration of a "basement" to the graded relation between FBG and cardiovascular risk, as well as "the fact that this basement comprises normal glucose concentrations, is a unique and important contribution. Indeed, the observation that normal glucose is not associated with cardiovascular risk is likely due to the essential requirement for glucose to sustain metabolic activity and life. This finding distinguishes glucose concentrations from blood pressure and lipid levels, for which a cardiovascular-risk basement has not yet been identified."

Hazard Ratio for Coronary Heart Disease by Fasting Blood Glucose (FBG) Concentrations in Nondiabetics

FBG concentrations (mmol/L) HR (95% CI)*
<3.90 1.07 (0.97–1.18)
3.90 to <5.60 (reference range) 1.00 (0.95–1.06)
5.60 to 6.09 1.11 (1.04–1.18)
6.10 to 6.99 1.17 (1.08–1.26)
>7.00 1.78 (1.56-2.03)

*Adjusted for age, smoking status, body-mass index, and systolic blood pressure

"In complete contrast to conventional risk factors like cholesterol or blood pressure, which have very strong and linear associations across their regular values, fasting glucose is not linearly related," Sarwar explained, pointing out that the >5.60 mmol/L levels that predicted elevated risk account for only about a third of adults. "About two-thirds of the population falls into the part of the distribution that is not related to risk."

"The generalizability of our findings to populations in developed countries is supported by broadly consistent results across 102 cohorts in 25 countries," Sarwar and his colleagues write. "Because our data derive mostly from high-income countries, however, we could not estimate vascular disease burden attributable to diabetes for low-income and middle-income countries.

The following members of study's writing committee report relevant financial disclosures; "all other members of the writing committee declare that they have no conflicts of interest." Dr John Danesh (University of Cambridge) has received research funding from the British Heart Foundation, BUPA Foundation, Denka, diaDexus, the European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Medical Research Council, Merck Sharp and Dohme, the National Heart, Lung and Blood Institute; the National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Wellcome Trust, and UK Biobank; and has served on advisory boards for Merck and Novartis. Dr Alexander Thompson (University of Cambridge) reports receiving honoraria and reimbursement of speaker's expenses from GlaxoSmithKline. The Emerging Risk Factors Collaboration coordinating center is partly funded by Pfizer. Gerstein reports that he has consulted for Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Medtronic, Merck, Bayer, Bioavail, and Jansen Ortho; has been an investigator in clinical trials sponsored by Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Merck, and Roche; has "been on research committees or given presentations for or made a video for" Sanofi-Aventis, GlaxoSmithKline, Servier, Bayer, Eli Lilly, and Novo Nordisk.

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