There is currently considerable interest in the remission of type 2 diabetes, which can be achieved with lifestyle (e.g., low-calorie diet and intensive weight management), pharmacologic (e.g., short-term insulin therapy), or metabolic surgical interventions (13). With each of these interventions, however, the rates of remission reported in the literature have varied considerably between studies (13). One factor potentially underlying this variability is that studies have differed in how they have diagnosed remission, which has been variably defined by achieving A1C, fasting blood glucose (FBG), or oral glucose tolerance test (OGTT) measurements in their respective nondiabetic ranges. In this context, we sought to evaluate the concordance of A1C, FBG, and OGTT criteria for defining remission of diabetes.

The Preserving β-Cell Function in Type 2 Diabetes with Exenatide and Insulin (PREVAIL) trial was a 20-week, open-label, parallel-arm, randomized controlled trial in which adults with type 2 diabetes of <7 years’ duration were treated for 8 weeks with either 1) insulin glargine, 2) glargine plus thrice-daily lispro, or 3) glargine plus twice-daily exenatide, followed by a 12-week washout to assess for remission (4). The study protocol and main findings were recently reported in detail (4). While the three interventions did not differ in their capacity to induce remission at 20 weeks (as defined by A1C <6.5% [<48 mmol/mol] 3 months after stopping therapy) (4), the concomitant performance of a 2-h 75-g OGTT at the washout visit provided the opportunity to assess the concordance of the following criteria for diagnosing remission: 1) A1C <6.5%, 2) FBG <7.0 mmol/L, and 3) OGTT with both FBG <7.0 mmol/L and 2-h glucose <11.1 mmol/L. Furthermore, the OGTT enabled assessment of 1) insulin sensitivity/resistance by Matsuda index and HOMA of insulin resistance (HOMA-IR) and 2) β-cell function by insulin secretion sensitivity index-2 and insulinogenic index/HOMA-IR (4).

In the 88 participants who completed the washout OGTT, the A1C remission criterion displayed only fair to moderate concordance with FBG <7.0 mmol/L (κ statistic 0.48, 95% CI 0.30–0.67) and OGTT criteria (κ 0.29, 95% CI 0.09–0.48). FBG and OGTT criteria similarly exhibited modest agreement (κ 0.38, 95% CI 0.22–0.55), reflecting the fact that only 36% of those with FBG <7.0 mmol/L also had 2-h glucose <11.1 mmol/L (Fig. 1). Of the 46 participants who met at least one of these three definitions of remission, 52% (n = 24) satisfied both A1C and FBG criteria, while 33% (n = 15) met the FBG definition alone and 15% (n = 7) achieved only the A1C criterion (Fig. 1). We next compared these three groups (both A1C/FBG, FBG alone, and A1C alone) to determine if there were clinical or metabolic differences between the individuals that they identify as achieving remission. There were no significant differences between the groups in age, sex, duration of diabetes, BMI, waist circumference, Matsuda index, or HOMA-IR (data not shown). Of note, however, β-cell function progressively decreased from the A1C/FBG group to FBG alone to A1C alone, as evident with both insulin secretion sensitivity index-2 (median 243 [interquartile range 194–331] vs. 196 [155–294] vs. 134 [118–166], P = 0.003) and insulinogenic index/HOMA-IR (median 2.0 [interquartile range 1.3–2.8] vs. 1.8 [0.8–2.9] vs. 0.9 [0.5–1.1], P = 0.045).

Figure 1

Venn diagram showing the distribution of individuals who met at least one of the following three definitions of remission: 1) A1C <6.5%, 2) FBG <7.0 mmol/L, or 3) OGTT with fasting glucose <7.0 mmol/L and 2-h glucose <11.1 mmol/L.

Figure 1

Venn diagram showing the distribution of individuals who met at least one of the following three definitions of remission: 1) A1C <6.5%, 2) FBG <7.0 mmol/L, or 3) OGTT with fasting glucose <7.0 mmol/L and 2-h glucose <11.1 mmol/L.

Close modal

There are three implications that emerge from these findings. First, the modest concordance among the A1C, FBG, and OGTT criteria means that these definitions do not necessarily identify the same individuals as being in remission. Second, the individuals identified by these definitions differ in β-cell function. Indeed, those identified as being in remission by A1C criterion alone (without achieving FBG <7.0 mmol/L) had poorer β-cell function than those meeting only the FBG criterion. Since amelioration of reversible β-cell dysfunction is one of the key determinants of the capacity to achieve remission (whether by lifestyle or by medical or surgical intervention) (3,5), underlying differences in β-cell function are likely to manifest in variability in the durability of the remission in question. Taken together, these two factors (i.e., the identification of distinct groups that then differ in β-cell function) are probable contributors to the heterogeneity of the literature with respect to both the reported capacity to achieve remission and the sustainability thereof.

The third implication is that these findings underscore the need for consensus and uniformity across studies in how remission is to be defined. In this context, it should be noted that the American Diabetes Association recently convened an expert panel that published a consensus report defining remission as A1C <6.5% after at least 3 months without glucose-lowering therapy (3). Going forward, the application of this standardized definition should yield greater consistency across the literature and thereby ultimately provide more robust estimates of the capacity to achieve and maintain remission with lifestyle, medical, and surgical interventions.

Clinical trial reg. no. NCT02194595, clinicaltrials.gov

Funding. This study was supported by the Canadian Institutes of Health Research (MOP 136938) and the University of Toronto Faculty of Medicine, Banting and Best Diabetes Centre, and Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research. R.R. holds the Boehringer Ingelheim Chair in β-Cell Preservation, Function, and Regeneration at Mount Sinai Hospital.

Duality of Interest. R.R. reports grants from Boehringer Ingelheim, grants and personal fees from Novo Nordisk, personal fees from Sanofi, and personal fees from Eli Lilly, all outside the submitted work. C.K.K. reports research support from Boehringer Ingelheim outside the submitted work. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. R.R. and B.Z. designed the study. R.R., A.E., C.K.K., and B.Z. implemented the study and acquired the data. R.R. led study implementation. A.E. oversaw research coordination. J.P. performed the statistical analyses. R.R. wrote the manuscript. R.R. and J.P. verified the data. All authors contributed to interpretation of the data and critical revision of the manuscript. All authors approved the manuscript. R.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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