In “Understanding Metabolic Memory: A Tale of Two Studies,” Miller and Orchard (1) purportedly disprove “metabolic memory.” However, their analyses do not directly address metabolic memory and their interpretations are flawed.
The Diabetes Control and Complications Trial (DCCT) (2) demonstrated that randomly assigned intensive therapy, with mean HbA1c of ∼7%, dramatically reduced microvascular complications compared with conventional therapy, with mean HbA1c of ∼9%, an effect entirely attributable to the separation in HbA1c levels between the two groups (3). Afterward, all participants were taught intensive therapy and referred to their physicians for care, resulting in similar HbA1c levels of ∼8% in the two original groups. This would have been predicted to narrow the rate of complications between the original groups. However, with further follow-up, the original DCCT conventional group experienced substantially higher risks of further progression of retinopathy, nephropathy, and neuropathy for 4–8 years (4,5). We coined “metabolic memory” to describe the impact of early glycemic separation on complications even after the glycemic differences had disappeared. Metabolic memory appears to last up to 12–15 years, after which waning or “metabolic amnesia” occurs.
Miller and Orchard present analyses based on “A1c months,” the sum of the incremental HbA1c above normal (6.1%) at a visit multiplied by the number of months elapsed from the last HbA1c. Algebraically, the mean HbA1c is proportional to the A1c months and the two are highly correlated. However, Miller and Orchard do not present analyses of the observational Pittsburgh Epidemiology of Diabetes Complications study to explore metabolic memory. Nor do they reanalyze DCCT/EDIC (Epidemiology of Diabetes Interventions and Complications) data to show that the difference in A1c months between groups during the DCCT explains metabolic memory during EDIC.
Nevertheless, Miller and Orchard state: “There is no need to invoke a ‘metabolic memory’ phenomenon to explain the persistence of a lower incidence of complications in the DCCT intensive therapy group compared with conventional therapy group, which can be fully explained by cumulative glycemic exposure.” However, they fail to recognize that cumulative glycemic exposure includes long-term effects, such as metabolic memory.
Miller and Orchard then conclude that the order of glycemic exposure doesn’t matter: “…on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time.”
The association of A1c months, a measure of glycemic exposure, with complications is expected based on the strong association of complications with mean HbA1c in DCCT/EDIC (3). However, the fundamental issue is whether the pattern of glucose exposure makes a difference. Miller and Orchard suggest that 20 years’ duration at an HbA1c of 8% [(8% – 6.1%) × 240 months = 456 A1c months] yields the same risk of outcomes as 10 years at 9.0% followed by 10 years at 7% (also 456 A1c months), or vice versa. DCCT/EDIC results (4,5) clearly demonstrate that this is not the case. No analysis shows that A1c months explains the metabolic memory phenomenon.
Metabolic memory supports a particularly pernicious effect of elevated levels of HbA1c early in the course of type 1 diabetes. We continue to recommend that intensive therapy be initiated as early as possible in the course of type 1 diabetes to minimize the risk of long-term complications.
Funding. Funding support was provided by National Institute of Diabetes and Digestive and Kidney Diseases grant U01-DK094176.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.