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Glycosylated Hemoglobin: Finally Ready for Prime Time as a Cardiovascular Risk Factor

Hertzel C. Gerstein, MD, MSc, FRCPC
[+] Article and Author Information

From McMaster University and Hamilton Health Sciences, Hamilton, Ontario L8N 3Z5, Canada.


Potential Financial Conflicts of Interest:Consultancies: Aventis; Honoraria: Aventis; Grants received: Aventis; Patents received: Aventis; Speaker's fees: Aventis, Lilly, Novo Nordisk.

Requests for Single Reprints: Hertzel C. Gerstein, MD, MSc, FRCPC, Department of Medicine, Room 3V38, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.


Ann Intern Med. 2004;141(6):475-476. doi:10.7326/0003-4819-141-6-200409210-00014
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More than 17 million people in the United States currently have diabetes, and this number is rapidly increasing (1). Affected individuals are at high risk for premature death as well as eye, kidney, nerve, cardiovascular, and other chronic diseases. Thus, the annual estimated costs of diabetes exceeded $130 billion in 2002 (2)—an increase of greater than 30% since 1998 (3). This societal burden, and evidence that the diabetes epidemic is being fueled by our current lifestyle (45), means that diabetes is now an urgent public health problem.

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Glycemia Is Not (Yet) an Independent or a Modifiable Risk Factor for Cardiovascular Disease
Posted on October 6, 2004
Mayer B. Davidson
Chares R. Drew University
Conflict of Interest: None Declared

TO THE EDITOR: Although glycemia is certainly associated with cardiovascular disease, correlation does not necessarily bestow causation. Dr. Gerstein states in his editorial, "Glycosylated Hemoglobin: Finally Ready for Prime Time as a Cardiovascular Risk Factor" (1) that the "glycosylated hemoglobin level is an independent progressive risk factor for incident cardiovascular events, independent of diabetes status". That may be, but glycemia is not an independent risk factor when the other risk factors for cardiovascular disease are taken into account (2,3). Furthermore, none of the five prospective studies that have evaluated the effect of lowering glycemia on cardiovascular disease, analyzed either singly (4) or in a meta-analysis (5), have demonstrated a significant beneficial effect. Thus, the evidence to date would suggest that glycemia may be a risk factor, but not independent of other risk factors, and so far, not a modifiable one.

References 1. Gerstein HC. Glycosylated hemoglobin: finally ready for prime time as a cardiovascular risk factor. Ann Intern Med 2004;141:475-76. 2. Stern MP, Fatehi P, Williams K, Haffner SM. Predicting cardiovascular disease: do we need the oral glucose tolerance test? Diabetes Care 2002;25:1851-6. 3. Meigs JB, Nathan DM, D'Agostino RB, Wilson PWF. Fasting and post- challenge glycemia and cardiovascular risk: the Framingham Offspring Study. Diabetes Care 2002;25:1845-50. 4. Wild SH,Ddunn CJ, McKeigue PM, Comte S. Glycemic control and cardiovascular disease in type 2 diabetes: a review. Diabetes Metab Res Rev 1999;15:197-204. 5. Huang ES,Meigs JB, Singer DE. The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes. Am J Med 2001;111:633-42.

Conflict of Interest:

None declared

Glycemia is an Independent Cardiovascular Risk Factor - Modifiability is Being Studied
Posted on November 5, 2004
Hertzel C. Gerstein
McMaster University
Conflict of Interest: None Declared

To the Editors,

In their article, Khaw et al. reported that the glycosylated hemoglobin is clearly associated with cardiovascular disease, and that this relationship is independent of diabetes status (1). However, this prospective study also clearly showed that this relationship is independent of other cardiovascular risk factors including age, BMI, abdominal obesity, systolic blood pressure, cholesterol, smoking and previous cardiovascular disease. At least one other large epidemiologic study also reported a similar independent relationship between markers of dysglycemia (including the glycosylated hemoglobin) and incident cardiovascular events (2). Indeed, after controlling for gender, age, total and HDL cholesterol, systolic and diastolic blood pressure, diabetes and smoking (i.e. factors included in the Framingham Risk Score), the risk of incident cardiovascular disease rose 1.15 fold per 0.71% rise in A1c (95% CI 1.02-1.30; P=0.03). This paper also suggested that post-load glucose levels may independently provide even more information about future cardiovascular risk than the A1c (2).

Therefore, it is clear that glycemia is indeed an independent risk factor for future cardiovascular disease. However, I agree completely with Dr. Davidson that these data provide no information on whether or not it is also a responsive or modifiable risk factor; moreover, none of the clinical trials completed to date were designed to answer that question. Thus we do not yet know with certainty if lowering glycosylated hemoglobin can prevent cardiovascular disease in either people with diabetes or in individuals with lesser degrees of dysglycemia. However, the fact that the epidemiologic data are compelling has led to tremendous interest in addressing this problem. As such, this question is currently being directly answered in several large clinical trials globally that should be completed within the next 5 years.

Reference List

(1) Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141:413-20.

(2) Meigs JB, Nathan DM, D'Agostino RB, Sr., Wilson PW. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care. 2002;25:1845-50.

Conflict of Interest:

None declared

A Comment on Gerstein
Posted on November 12, 2004
Morton Linder
No Affiliation
Conflict of Interest: None Declared

To the Editors:

Regarding the editorial and articles showing positive correlation of HbA1C levels and c.v. mortality in "non-diabetics", the definition of diabetes mellitus as a 2 hr. PPBS of 200 mg/dl or higher is obviously wrong. I have been teaching since 1960, that the 2 hr. PPBS should be 120 mg/dl or less, and that anything higher is abnormal and conducive to organ damage. Whether it is called hidden diabetes, latent diabetes, or just diabetes, the arteries are still damaged by blood glucose levels above that range. The modern HbA1C test and its analysis statistically, only serves to confirm what some of us clinicians have known for more than 40 years.

Respectfully submitted,

Morton Linder, M.D., F.A.C.P. Mount Kisco, NY 10549

Conflict of Interest:

None declared

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