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Beyond Hemoglobin A1c-Need for Additional Markers of Risk for Diabetic Microvascular Complications - commentary
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Irl B. Hirsch, MD; Michael Brownlee, MD
JAMA. June 8 2010;303(22):2291-2292.
In 1993, The Diabetes Control and Complications Trial1 demonstrated that intensive therapy lowered time-averaged blood glucose values (measured as hemoglobin A1C [HbA1C]) and significantly reduced development of microvascular complications in type 1 diabetes. For example, intensive therapy reduced the risk of sustained retinopathy progression by 73% compared with standard treatment. Such significant reductions led to the recommendation by professional societies that for microvascular disease prevention, the HbA1C goal for nonpregnant adults should be less than 7% or even less than 6.5% of total hemoglobin.
However, few physicians recognized that only 6.6% of the variation in risk of retinopathy for the entire study cohort was explained by the difference in the treatment groups, although it was widely appreciated that nearly all of this treatment group effect was explained by differences in the mean level of HbA1C over time.2 The trial results also considered the instantaneous risk of retinopathy (ie, whether a patient would develop retinopathy at a particular point in time during the study) rather than eventual risk of retinopathy (whether a patient would develop retinopathy over his or her entire life). However, this latter outcome is not feasible to study because it would require lifetime follow-up of patients.
Similarly, HbA1C and duration of diabetes (glycemic exposure) explained only about 11% of the variation in retinopathy risk for the entire study population, suggesting that the remaining 89% of the variation in risk is presumably explained by other factors independent of HbA1C.2 Given the magnitude of the effect of unmeasured elements in the Diabetes Control and Complications Trial, identification of these elements is critically important for designing more effective therapy for type 1 diabetes.
What factors not captured by HbA1C measurements might explain the remaining 89% of microvascular complications risk? Possible factors unrelated to blood glucose levels include genetics, environmental toxins, and metabolic consequences of abnormal insulinization such as increased free fatty acid levels. Possible factors related to blood glucose levels most likely reflect the fact that since HbA1c represents the time-averaged mean level of glycemia, it provides no information about how closely the fluctuations of blood glucose levels around that mean mimic the normal narrow range of blood glucose excursion. In addition, patients with identical HbA1C values differ significantly in amplitude and duration of glycemic spikes.3
Thus, a potential determinant of microvascular complications not captured by HbA1C could be greater magnitude and frequency of glycemic excursions.4 This hypothesis is provisionally supported by experimental evidence that prior episodes of transient hyperglycemia trigger persistent increases in proinflammatory gene expression during subsequent periods of normal glycemia by inducing stable epigenetic changes in the promoter of NF-{kappa}B p65, which increase p65 expression. This in turn causes persistent increased expression of the proinflammatory proteins monocyte chemotactic protein-1, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interleukin-6, and inducible nitric oxide synthase.5-7 These persistent changes in gene expression are induced by spikes of hyperglycemia that have durations considered too short (6-16 hours followed by 6 days of normal glycemia) to influence HbA1C values.5
During the course of the Diabetes Control and Complications Trial,1 blood glucose was measured 1 day every 3 months at 7 time points throughout that day. However, calculation of within-day standard deviation and standard deviation of mean blood glucose values between these quarterly assessments revealed that neither of these measures of glucose variability was associated with increased risk of microvascular complications.8 This result is not surprising because recent continuous subcutaneous glucose monitoring data from patients with type 1 diabetes (288 data points/24 hours) show enormous variability within a single day and between days.9 Furthermore, many of the formulas previously used to estimate glycemic variability (such as mean amplitude of glycemic excursion) only yield data about relative variability, whereas the absolute magnitude of glycemic spikes may be more relevant to the induction of long-lasting changes in gene expression.5
Realizing that the aspects of glycemia that explain the approximately 89% of microvascular complications are unknown, 2 practical questions arise: (1) how should hyperglycemia be treated in patients with diabetes; and (2) how can the critical aspects of hyperglycemia not captured by HbA1C be identified so that more effective therapies can be designed?
Given the lack of studies specifically aimed at reducing glycemic variability to determine the effect of such reductions on clinical end points, new treatment guidelines targeting glycemic variability per se cannot be justified. Since HbA1C, the first long-term marker of glycemic control, did predict the vascular complications of type 1 diabetes,1 despite its low overall contribution to the progression of diabetic retinopathy, it remains the only confirmed predictor. The wider use of clinical monitoring tools such as continuous glucose monitoring and laboratory markers such as 1,5-anhydroglucitol, which indicates the extent to which postprandial hyperglycemia has occurred over the past 2 to 3 weeks,4 will allow a more definitive examination of the effects of glycemic variability on clinical end points. Newer therapeutic tools such as more rapidly acting prandial insulins (now in development), pramlintide, and incretins could allow further reductions in glycemic spikes than traditionally available drugs allow. It is also possible that factors independent of glycemia explain a substantial fraction of the risk.
Recent evidence suggests a role for both blood pressure and lipids in the pathogenesis of diabetic microvascular complications.10 Thus, it seems prudent to integrate earlier use of medications and other approaches to control blood pressure and lipid levels, as well as to include frequent follow-up assessments of retina and renal status into an overall treatment strategy. "Glucometrics" (the complete descriptive analysis of all aspects of glycemia) for assessing variability with continuous glucose monitoring and home blood glucose monitoring are rapidly evolving, along with software programs that can download and analyze these data. Advances in understanding the molecular basis for the variation in diabetes complication risk not explained by HbA1C, combined with development of new tools for measuring glycemic variability now allow prospective studies designed to determine the relationship between glycemic variability and clinical end points.
Increasing understanding about the mechanisms underlying glycemic variability and its potential deleterious consequences and determining how better to reduce the magnitude and frequency of glycemic spikes should become near-term priorities for translational and clinical type 1 diabetes research. Equally important near-term priorities are determining the contribution of abnormalities in metabolism that are independent of glycemia, as well as of genetic differences in individual responses to the metabolic consequences of abnormal insulin action. Physicians will have to realize that much remains to be done in identifying important factors contributing to microvascular complications risk, which are not captured by the HbA1c. The future identification of these factors will have important implications both for devising additional markers for monitoring glycemic control and for designing better treatment methods for achieving it.
AUTHOR INFORMATION
Corresponding Author: Irl B. Hirsch, MD, University of Washington Medical Center-Roosevelt, 4225 Roosevelt Way NE, Ste 101, Seattle, WA 98105 (ihirsch@uw.edu).
Financial Disclosures: Dr Hirsch reports being a consultant for Johnson & Johnson, Roche, and Abbott and receiving grant support from Novo Nordisk and Mannkind Corp. Dr Brownlee reports no disclosures.
Additional Contributions: We thank Ted Gooley, PhD, Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington, Seattle, for his assistance in biostatistical consultation. Dr Gooley received no compensation in association with his contribution to this article.
Author Affiliations: Division of Metabolism, Endocrinology, and Nutrition, School of Medicine, and Diabetes Care Center, University of Washington, Seattle (Dr Hirsch); and Diabetes Research Center and Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York (Dr Brownlee).
REFERENCES
1. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.
2. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN, DCCT/EDIC Research Group. Effect of glycemic exposure on the risk of microvascular complications in the Diabetes Control and Complications Trial-revisIted. Diabetes. 2008;57(4):995-1001.
3. Kovatchev BP, Otto E, Cox D, Gonder-Frederick L, Clarke W. Evaluation of a new measure of blood glucose variability in diabetes. Diabetes Care. 2006;29(11):2433-2438.
4. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA. 2006;295(14):1707-1708.
5. El-Osta A, Brasacchio D, Yao D; et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409-2417
6. Villeneuve LM, Reddy MA, Lanting LL, Wang M, Meng L, Natarajan R. Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc Natl Acad Sci U S A. 2008;105(26):9047-9052.
7. Brasacchio D, Okabe J, Tikellis C; et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009;58(5):1229-1236.
8. Kilpatrick ES, Rigby AS, Atkin SL. The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care. 2006;29(7):1486-1490.
9. Tamborlane WV, Beck RW, Bode BW; et al, Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359(14):1464-1476.
10. Cohen RA, Hennekens CH, Christen WG; et al. Determinants of retinopathy progression in type 1 diabetes. Am J Med. 1999;107(1):45-51.
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