Clinical Briefs
By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is an advisor for Endo, Kowa, Pricara, and Takeda.
Attenuated CV Benefits of Clopidogrel in Diabetes
Source: Andersson C, et al. Association of clopidogrel treatment with risk of mortality and cardiovascular events following myocardial infarction in patients with and without diabetes. JAMA 2012;308:882-889.
There is no controversy over whether antiplatelet therapy (e.g., aspirin, clopidogrel, prasugrel) reduces cardiovascular (CV) events when used for secondary prevention (i.e., post-acute coronary syndrome, post-myocardial infarction [MI], post-stroke). It is equally apparent that risk reduction through antiplatelet therapy is not equal among all risk groups. For instance, although aspirin (ASA) consistently shows CV risk reduction in mixed populations post-MI, two clinical trials of ASA comprised solely of diabetics failed to show benefit. Diabetics are known to have greater platelet reactivity, and their platelets are relatively resistant to antiplatelet effects as measured by medication-induced platelet aggregation inhibition testing.
Comparative benefits of clopidogrel in diabetics vs non-diabetics have not been described well enough. To assess whether diabetics fare as well with clopidogrel post-MI as non-diabetics, Andersson et al reviewed data from the Danish nationwide administrative registries of patients discharged from the hospital post-MI (n = 58,851), of which 12% had diabetes.
One-year follow-up compared outcomes among all persons treated with clopidogrel. Although all groups did have CV risk reduction from clopidogrel treatment, there was a significant difference between diabetics and non-diabetics, favoring non-diabetics. For instance, the hazard ratio (HR) for all-cause mortality was more than twice as favorable for non-diabetics (HR = 0.75, a 25% reduction) than diabetics (HR = 0.89, an 11% reduction).
The obstacle of clopidogrel-resistant platelets can be overcome by dose intensification (i.e., more clopidogrel), combination therapy (i.e., clopidogrel + ASA), or consideration of another P2y12 agent (i.e., prasugrel). Unfortunately, however, each of these methods has been associated with an increased risk for bleeding. Optimization of antiplatelet therapy in diabetics remains somewhat elusive.
Is A1c Always the Best Game in Town to Monitor Type 2 Diabetes?
Source: Wright LAC, Hirsch IB. The challenge of the use of glycemic biomarkers in diabetes: Reflecting on hemoglobin A1C, 1,5-anhydroglucitol, and the glycated proteins fructosamine and glycated albumin. Diabetes Spectrum 2012;25:141-148.
Even as time-honored a metric as A1c has limitations. There are, for instance, situations in which A1c can markedly mis-estimate actual sustained glucose concentrations. Since A1c measurement requires hemoglobin to be exposed to excess glucose for the entire life of a red cell (90-120 days), anything that shortens red cell life (e.g., thalassemia, Hgb C, HbS, hemolysis) will underestimate actual sustained glucose levels (since red cells don't live long enough to become fully glycosylated). Hemoglobin F, which is persistent in a small percentage of adults, glycosylates so rapidly that even very modest elevations of glucose can induce marked elevations of A1c (A1c 12%-17% or greater), grossly overestimating sustained glucose levels.
Fructosamine is a composite measure of relatively short-lived serum proteins that have become converted into irreversible ketoamines, of which glycated albumin is the primary component (approximately 90%). Since this process occurs over a few weeks, red cell life span shortened or not has no impact. Similarly, however, the measurement of fructosamine only provides an observation window of the sustained glucose levels in the preceding 2-3 weeks. Any condition that alters serum protein turnover (e.g., thyroid dysfunction, hypopoproteinemia, nephrotic syndrome) can invalidate fructosamine measurement.
Glycated albumin, the primary protein constituent of fructosamine, has been compared with A1c and fructosamine in patients with advanced chronic kidney disease, and found to be the most accurate marker in this population, although it is subject to the same perturbations as fructosamine mentioned above.
One other serum marker not used commonly in the United States, but widely used in Japan, is 1,5 anhydroglucitol (1,5-AG), which reflects sustained glucose over a 2-14 day period. Normally, 1,5-AG is reabsorbed by renal tubules; when plasma and urine glucose are high, they compete with 1,5-AG for reabsorption, resulting in loss of 1,5-AG in the urine, with a corresponding diminution in plasma 1,5-AG. This metric has been found to be particularly useful in measurement of postprandial glucose excesses.
For the time being, A1c will remain the metric of choice for most patients. When A1c and individual glucose measurements are discordant, consideration of another metric is appropriate.
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