Original researchA 5-year assessment of the epidemiology and natural history of possible diabetes in remission
Introduction
Under current WHO criteria, type 2 diabetes is considered a “chronic” and “progressive” disease, signifying its known natural history and linked morbidity and mortality. Whilst the benefits of good diabetes control are well established [[1], [2], [3]], the impact of normal or near normal levels of glycaemia, particularly with the use of medication, might be less certain [4] but in such circumstance, the question of whether diabetes “cure” or “remission” might be achieved arises, particularly as there are now a number of studies that demonstrate achievement of near normal or normal glycaemia with non-pharmacological interventions [[5], [6], [7], [8], [9], [10], [11], [12]]. Multiple terminologies for this potential reclassification, such as remission, reversal, or resolution, have often been used interchangeably and the definition of diabetes in remission (DIR) has been variably expressed either in relative terms, such as a reduction in HbA1c or medication use, or in absolute terms with the attainment of glycaemia below diagnostic thresholds for diabetes and pre-diabetes. Current and developing criteria to define DIR are now based on cut offs for fasting blood glucose and/or HbA1C [13]. The American Diabetes Association’s definition of DIR in those previously diagnosed with type 2 diabetes is categorized as follows:
“Partial” – where glycaemic indices are below diagnostic thresholds for diabetes for at least 1 year without use of anti-diabetic drugs, “Complete” – where criteria for normoglycaemia (HBa1c < 5.7% or 39 mmol/mol or fasting glucose <5.5 mmol/L)) are maintained over 1 year and “Prolonged” – if this latter position is sustained over 5 years [14].
In the United Kingdom, a recent position statement from Diabetes UK has considered the challenges in establishing a consensus for DIR, including a void of an epidemiological evidence base, and it outlines relevant clinical factors other than obesity and emphasizes the importance of remission as a concept from the perspectives of the people with diabetes, health care professionals, and healthcare system [15]. Again in the United Kingdom, the Association of British Clinical Diabetologists have also considered DIR, proposing a shorter time frame and a single HbA1c threshold of <6.5% (48 mmol/mol) for its categorization, and have advised the abandonment of other categorizations pertaining to “prolonged” or “complete” and they have called for an international consensus [16].
The implications of defining DIR are manifold. Even using precise diagnostic thresholds, the reported sustainability of DIR is uncertain. Few have considered its potential dis-benefits and risks not least in the interplay of DIR and the long-term complications of diabetes. Studies have suggested that bariatric surgery with attendant significant weight loss and improvement in glycaemic parameters may reduce albumin excretion, CVD risk, progression of retinopathy and protect against new cases of diabetic retinopathy in people with type 2 diabetes, noting that the progression or reversal of established diabetic retinopathy is not guaranteed [[17], [18], [19], [20]]. Therefore, it is recommended that people diagnosed with diabetes continue with retinal screening for life, even if they are considered to have DIR [21,22]. This fundamentally challenges the notion of complete remission. It may lead to confusion in healthcare policies but more importantly, may cause conflict to a person with diabetes in relationship to self-care when allocated such a new diagnostic label.
Obesity plays an important role in development and progression of type 2 diabetes and is a target modifiable risk factor [23]. Studying the effect of weight loss has been a focus in the quest to understand DIR. In a number of studies leading to weight loss, including those of diet & lifestyle [24,25], behavioral changes [25] and bariatric surgery [26,27], the impact on the course of a person’s diabetes can certainly include the normalization of HbA1c and the outcomes from the DIRECT trial [24] have now added low calorie diet based interventions to the list of other known non-surgical interventions [7,24,25]. Thus, amelioration of insulin resistance and the decline in beta cell function with weight loss in type 2 diabetes [28] has shifted the paradigm from “control” to “reversal”. However, there is also evidence that weight loss on its own is not such a strong predictor of “reversibility” of type 2 diabetes [13] as there are multiple other factors such as age at diagnosis, duration of diabetes, waist circumference, lipid profile and absence of complications which are important determinants of diabetes remission [12,28,29].
There are thus several studies adding to the discussions regarding achieving remission or cure in type 2 diabetes. Whatever the finally agreed terminology and classification of DIR, it should preferably be based on firm evidence. Given the increasing awareness and importance of this topic, it is of concern that there is a lack of a systematic characterization of a whole diabetes population to determine the epidemiology of those who may have DIR. Without such systematic characterization, there is a lack clarity of the magnitude of need and the impact of this redefinition of the diabetes condition, over time, for any individual and for a healthcare system. Thus, the aim of our study was a review of our district wide diabetes population to determine the epidemiology and clinical characteristics of those who had a diagnosis of diabetes but did not meet the diagnostic criteria for diabetes at the point of assessment and then to consider their outcomes over a 5-year time frame.
Section snippets
Methods
This was a retrospective cohort study from our centralized diabetes register, which includes all people with diabetes in our local health economy. As previously reported [30], the central Wolverhampton District Diabetes Register goes through a continuous systematic data quality and verification process to maintain its accuracy which includes the verification of the diagnostic criteria for all newly registered diabetes patients. From amongst those alive in 2014 with a confirmed and validated
Results
From a total district population of c 250,000, we identified all 17,308 people with known diabetes, amongst whom were 3407 with a baseline HbA1c < 6.5% (48 mmol/mol) of whom 1110 had type 2 diabetes and were on diet management alone. Over the 5-year period, death occurred in 154 (14%). Altogether, 119 (including 62 who had died) were excluded because they did not have an end point HbA1c estimation. The final cohort was thus 991 people with type 2 diabetes, including 88 who had died but did have
Discussion
As far as we are aware this is the first whole population based assessment of diabetes in remission undertaken in Europe whilst 2 retrospective studies have been conducted in the United States [31,32]. Both these studies excluded bariatric surgery cases, the Kaiser Permanente study [31] did include the whole diabetes population and used various surrogate markers to categorize a diabetes diagnosis (not all on biochemical criteria) before going on to assess onset and durability of remission
Conflicts of interest
None.
Authors contribution
Dr Syed M R Gillani: Researched data, wrote and edited the manuscript.
Prof Baldev Singh: Researched data, wrote and reviewed manuscript.
Dr Rajeev Raghavan: wrote, reviewed/edited manuscript.
Acknowledgements
Dr. Dinesh Nagi, Chair of ABCD, Consultant Diabetologist, Mid Yorkshire NHS Trust, provided us with an overview of current understanding of DIR in the UK.
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