The major micro- and macrovascular complications in diabetes are related to glycaemia. The diagnostic threshold for diabetes is set at the level at which microvascular complications specific to diabetes appear; they are very rare at HbA
1c <48 mmol/mol (<6.5%), so remission would be expected to reduce the risk of such complications. The very long time course of their development makes it difficult to establish prevention using an experimental RCT design. Instead, robust, long-term observational data are needed, for example from national registries. Single observational studies cannot prove causality, but the existing early evidence all supports the hypothesis that remission reduces or delays clinical complications of type 2 diabetes. In the Da Qing trial of a lifestyle intervention in people with prediabetes (
n=~500), follow-up over 30 years showed persistent prevention of diabetes and suggested some reduction in cardiac complications [
39]. In the Diabetes Prevention Program (DPP) (
n=~3000), an intensive lifestyle intervention decreased CVD risk factors [
40] and there was less microvascular disease in those who did not develop diabetes [
41]. The intensive lifestyle intervention in the Look AHEAD trial, including >5000 participants with a mean type 2 diabetes duration of 6.8 years, resulted in a reduction in nephropathy and retinopathy [
42] and in neuropathic symptoms [
43]. Neither the DPP [
44] nor the Look AHEAD trial [
45] found that a sustained intensive lifestyle intervention, with variable and relatively small weight losses, decreased CVD events overall. However, in the Look AHEAD trial, in which the intensive lifestyle intervention resulted in remission for only 11.5% of participants at 1 year, declining to 7% at 4 years [
46], a post hoc analysis found that cardiovascular events were reduced by 21% among participants who lost >10% of their body weight in the first year, and by 40% in those who achieved remission, an effect that appeared to be modulated by changes in weight, HDL-cholesterol and fitness [
47]. Similarly, the 5-year follow-up of the DiRECT trial also found fewer clinical events after successful intervention.
The magnitude and sustainability of weight loss was also the key for remission and reduction in CVD complications in long-term bariatric surgery studies [
12]. In the Swedish Obese Subjects trial, diabetes remission after bariatric surgery (72.3% at 2 years, 30.4% at 15 years) was associated with fewer macro- and microvascular complications over a median follow-up of 18 years [
13]. Cohort analysis showed 47% fewer microvascular complications in individuals with type 2 diabetes 5 years after surgery (
n=1111) compared with matched control participants who did not undergo surgery (
n=1074) [
48]. Other studies, supporting the trial evidence from Mingrone et al [
29], have shown less progression of retinopathy at 5.9 years in a small cohort of individuals experiencing type 2 diabetes remission after bariatric surgery compared with those not in remission after surgery [
49], and fewer CVD events (mainly cardiac failure) 10 years after surgery than in a well-matched cohort who did not undergo surgery [
50].