People with type 2 diabetes (T2D) have achieved remission if their glycated hemoglobin (HbA1c) level is less than 6.5% (48 mmol/mol) at least 3 months after the cessation of glucose-lowering pharmacotherapy, according to a consensus statement from an international expert group convened by the American Diabetes Association (ADA).

The statement was published jointly in the Journal of Clinical Endocrinology & Metabolism on behalf of the Endocrine Society, in Diabetologia on behalf of the European Association for the Study of Diabetes, in Diabetic Medicine on behalf of Diabetes UK, and in Diabetes Care, published by the ADA. ADA.

The group of researchers recommended terminology, objective measures, and principles for data collection and analysis regarding improvement of patients’ glucose levels into the normal range. The group also made suggestions for actively observing patients in remission.


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The consensus group proposed the following:

1. The term used to describe a sustained metabolic improvement in T2D to nearly normal levels should be remission of diabetes.

2. “Remission” should be defined as a return of HbA1c to less than 6.5% (<48 mmol/mol) that occurs spontaneously or following an intervention and that persists for at least 3 months in the absence of usual glucose-lowering pharmacotherapy.

3. When HbA1c is determined to be an unreliable marker of chronic glycemic control, fasting plasma glucose (FPG) less than 126 mg/dL (<7.0 mmol/L) or estimated HbA1c (eA1C) less than 6.5% calculated from continuous glucose monitoring (CGM) values can be used as alternate criteria.

4. Testing of HbA1c to document a remission should be performed just before an intervention and no sooner than 3 months after initiation of the intervention and withdrawal of any glucose-lowering pharmacotherapy.

5. Subsequent testing to determine long-term maintenance of a remission should be done at least yearly thereafter, together with the testing routinely recommended for potential complications of diabetes.

6. Research based on the terminology and definitions outlined in [the new consensus statement] is needed to determine the frequency, duration, and effects on short- and long-term medical outcomes of remissions of type 2 diabetes using available interventions.

For the main defining measurement, the consensus group chose HbA1c below the level currently used for an initial diagnosis of diabetes, 6.5% (48 mmol/mol), and remaining at that level for at least 3 months without continuation of the usual antihyperglycemic agents.

Multiple factors can affect HbA1c measurements, including a variant hemoglobin, differing rates of glycation, or changes in erythrocyte survival that can occur in a variety of disease states, it was noted.

“In cases where the accuracy of HbA1c values is uncertain, CGM can be used to assess the correlation between mean glucose and HbA1c and identify patterns outside the usual range of normal,” the consensus group wrote.

In addition, according to the consensus group, “a diagnosis of remission can only be made after all glucose-lowering agents have been withheld for an interval that is sufficient both to allow waning of the drug’s effects and to assess the effect of the absence of drugs on HbA1c values.”

The direct effects of pharmacotherapy do not continue after remission is established with use of glucose-lowering drugs. However, when a persistent change in lifestyle is associated with remission, changes in food intake, physical activity, and management of stress and environmental factors can favorably affect insulin secretion and activity for an extended period. For metabolic surgery, the effects are stronger and typically more sustained.

For pharmacotherapy, at least 3 months after cessation of any glucose-lowering drugs is needed before testing of HbA1c can reliably assess the response, and subsequent measurements of HbA1c regarding remission should be done every 3 months—but not more often—and at least annually. For surgery, at least 3 months after the procedure and 3 months after cessation of any pharmacotherapy are needed before testing of HbA1c can reliably evaluate the response. For lifestyle, at least 6 months after beginning this intervention and 3 months after cessation of any pharmacotherapy are needed before testing of HbA1c can reliably assess the response.

Less frequent testing of HbA1c may be possible, as routine measurements at 6 months and 12 months may identify remission and risk of relapse in the short term, noted the research group. After remission is reached, use of metformin or other drugs not used for glycemic indications may delay the recurrence of hyperglycemia and protect against progression of other metabolic disturbances.

Maintaining a healthy lifestyle is an important part of ongoing management of patients in remission from type 2 diabetes. Weight gain, stress from illness, and continuing decline of β-cell function can all lead to recurrence of disease.

Patients in remission should still have regular retinal screening, testing for renal function, foot evaluation, and measurement of blood pressure and weight in addition to ongoing monitoring of HbA1c, recommended the consensus group. Clinicians are also advised to monitor for worsening microvascular disease following a rapid reduction of glucose levels after a long period of hyperglycemia.

“In particular, when poor glycemic control is present together with retinopathy beyond the presence of microaneurysms, rapid reduction of glucose levels should be avoided and retinal screening repeated if a rapid decline in blood glucose is observed,” the group stated.

The researchers also noted that the term “cure” should be avoided regarding type 2 diabetes.

The new consensus statement is an update to a 2009 consensus statement that suggested categorizing diabetes remission into partial, complete, and prolonged subcategories. However, according to the new consensus group, this distinction could introduce ambiguity affecting policy decisions regarding insurance premiums, reimbursements, and coding of medical encounters.

“This report is not intended to establish treatment guidelines or to favor specific interventions,” stated the consensus group. “Instead, based on consensus reached by the authors, it proposes suitable definitions of terms and ways to assess glycemic measurements, to facilitate collection and analysis of data that may lead to future clinical guidance.”

Disclosure: Several of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Riddle MC, Cefalu WT, Evans PH, et al. Consensus report: definition and interpretation of remission in type 2 diabetes. J Clin Endocrinol Metab. Published online August 30, 2021. doi:10.1210/clinem/dgab585