Posted Apr 19 , 2019 09:14 AM

The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study).

Laiteerapong N, et al. Diabetes Care 2019;42:416-426

Institute Summary (excerpted from the Abstract):

To examine for a legacy effect of early glycemic control on diabetic complications and death. In individuals with type 2 diabetes. This cohort study of managed care patients with newly diagnosed type 2 diabetes and 10 years of survival (1997–2013, average follow-up 13.0 years, N = 34,737) examined associations between HbA1c <6.5% (<48 mmol/mol), 6.5% to <7.0% (48 to <53 mmol/mol), 7.0% to <8.0% (53 to <64 mmol/mol), 8.0% to <9.0% (64 to <75 mmol/mol), or > 9.0% (> 75 mmol/mol) for various periods of early exposure (0–1, 0–2, 0–3, 0–4, 0–5, 0–6, and 0–7 years) and incident future microvascular (end-stage renal disease, advanced eye disease, amputation) and macrovascular (stroke, heart disease/failure, vascular disease) events and death, adjusting for demographics, risk factors, comorbidities, and later HbA1c. Compared with HbA1c <6.5% (<48 mmol/mol) for the 0-to-1-year early exposure period, HbA1c levels > 6.5% (> 48 mmol/mol) were associated with increased microvascular and macrovascular events (e.g., HbA1c 6.5% to <7.0% [48 to <53 mmol/mol] microvascular: hazard ratio 1.204), and HbA1c levels > 7.0% (> 53 mmol/mol) were associated with increased mortality (e.g., HbA1c 7.0% to <8.0% [53 to <64 mmol/mol]: 1.290). Longer periods of exposure to HbA1c levels > 8.0% (> 64 mmol/mol) were associated with increasing microvascular event and mortality risk.

Why is this important?

The so called ‘legacy effect’ also called ‘metabolic memory’ of early glucose control has been shown in several studies of type 1 diabetes, and appears to occur in type 2 diabetes as well (see: Legacy benefits of blood glucose, blood pressure and lipid control in individuals with diabetes and cardiovascular disease: Time to overcome multifactorial therapeutic inertia? Khunti K, et al Diabetes Obesity and Metabolism 2018;20:1337-1341) and the hypothesis is that extended periods of exposure to high glucose levels persistently dysregulate fibrotic and inflammatory genes in endothelial and vascular smooth muscle cells. Furthermore, epigenetic processes may contribute to metabolic memory as these changes may persist after exposure to high glucose levels is terminated. In the very large analysis above, among patients with newly diagnosed diabetes and 10 years of survival, HbA1c levels > 6.5% (> 48 mmol/mol) for the 1st year after diagnosis were associated with worse outcomes as were higher and higher levels for longer periods of time. If you get a copy of the article by clicking on the link below, Figures 2A,B &C are quite striking in showing this effect. Immediate, intensive treatment for newly diagnosed patients may be necessary to avoid irremediable long-term risk for diabetic complications and mortality.

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