We found slightly lower A1C values in HIV-infected women compared to demographically similar HIV-uninfected women after adjustment for fasting glucose values. After further adjustment, the differences by HIV serostatus of women were largely accounted for by higher MCV values in the HIV-infected group.
A number of conditions are known to alter the relationship between A1C and mean glycemia. Situations that shorten erythrocyte survival or decrease mean erythrocyte age (such as hemolysis or some hemoglobinopathies) are associated with lower A1C values since shortened survival time provides less opportunity for glycation to occur[4
]. Pregnancy, excess Vitamins C and E, hypertriglyceridemia, hyperbilirubinemia, uremia, chronic alcoholism, chronic salicylate ingestion, and opiate addiction may also alter the relationship between A1C and glucose with some assay methods[13
]. It is increasingly well appreciated that factors other than glycemia, such as race[14
] and glycation differences may also influence the A1C[15
]. Indeed, one analysis indicated that only one-half the variance in A1C can be attributed to the glucose profile [15
]. Assay variability due to differences in methodology may be an additional factor.
Our finding that higher MCV values emerged as the single most important factor associated with a lower A1C than predicted by blood glucose is important in this context. One possible explanation is that higher MCV values are a marker of a greater proportion of younger erythrocytes that have had a shorter time to become glycated due to greater red blood cell turnover in the HIV-infected group. This interpretation is consistent with a case series of four HIV-infected subjects who had unexpectedly low A1C values relative to available glucose values; all of these persons were on medications associated with hemolysis [7
]. Furthermore, in a two part study Diop and colleagues first determined that A1C levels underestimated fasting glycemia in HIV-infected subjects and found that the higher the MCV level, the greater the difference between estimated glycemia by A1C and measured fasting glycemia [8
]. The second part of this study documented subclinical hemolysis in a convenience sample of 54 (21.7%) of 249 HIV-infected subjects by low serum haptoglobin levels. Both high MCV and low haptoglobin were associated with nucleoside reverse transcriptase inhibitor (NRTI) use.
Kim and colleagues, however, conducted a prospective study of the relationship between A1C and fasting and non-fasting glucose values in 100 HIV-infected adults with diabetes or impaired fasting glucose and 200 HIV-uninfected controls matched on sex, race, and age [9
]. Using mean glucose calculated from one fasting and one non-fasting sample, they found that A1C underestimated glucose in HIV-infected subjects and that the discordance was associated in multivariate analysis with MCV and NRTI use, specifically abacavir. Haptoglobin, however, was not independently associated with the glucose-A1C discordance, suggesting that hemolysis was not responsible. These findings suggest that the relationship between elevated MCV and glucose-A1C discordance seen in multiple studies, including the present one, may be mediated by (or be a marker of) a mechanism other than hemolysis.
We found that use of diabetic medication was associated with higher log A1C values for any given fasting glucose value among diabetics. One possible explanation for this observation is that certain diabetes medications, such as sulfonylureas, may have greater beneficial effects on fasting glucose than on postprandial glucose [16
]. Since we only measured fasting glucose in this study, we may have overestimated the effect of medical treatment on overall glycemic control by not factoring in potentially higher postprandial glucose levels.
We also found several other notable associations with log A1C values. In this study, after adjusting for log glucose concentration, white and other non-black subjects had lower A1C levels relative to the reference group of blacks. This is consistent with recently published data from the general population indicating that African-Americans have higher A1C at a given glucose concentration relative to whites[14
]. The association between HCV viremia and lower A1C that we observed among HIV-infected diabetic women, however, is novel and unexplained albeit potentially a spurious finding attributable to multiple comparisons. It was, however, not due to ribavirin-induced hemolysis as no diabetic women were treated with ribavirin during the study period.
Our study has several limitations and strengths. We were only able to examine the relationship between fasting blood sugar and A1C; we did not have data on post-prandial glucose values, which may contribute substantially to A1C. We also had no data on hemoglobinopathy, which could affect the relationship between glucose and A1C. Our study population consisted only of women, and our findings may not generalize to HIV-infected men. We were also unable to determine if low grade, subclinical hemolysis may contribute to MCV elevations in the HIV-infected women. While we only included data from visits at which women reported that they were fasting, it is possible that some women may not have been truly fasting at each visit, for example due to ingestion of medications with a caloric beverage. Lastly, for consistency with other analyses from the WIHS cohort [2
], we used a definition of diabetes that included use of diabetic medications as a diagnostic criterion. It is possible that some women were prescribed diabetic medications for indications other than diabetes, such as polycystic ovary disease, impaired glucose tolerance, or abdominal fat accumulation. Strengths of this study include the relatively large sample size and the racial/ethnic diversity of the population.
In summary, we found that A1C modestly underestimated glycemic control, as assessed by concurrent fasting plasma glucose concentration, in HIV-infected women. Fasting blood glucose was therefore a reasonable surrogate for A1C in this population. The small difference in fasting glucose-adjusted A1C observed between HIV-infected and HIV-uninfected women disappeared after adjustment for MCV, which may be increased in HIV-infected women primarily due to concurrent zidovudine use. For individual HIV-infected patients where a discrepancy exists between measured plasma glucose and A1C values, such as in the setting of MCV elevations, clinicians should consider more frequent self-monitoring of blood glucose or using other less well validated measures of glycemia such as fructosamine [17