Weight change and sulfonylurea therapy are related to 3 year change in microvascular function in people with type 2 diabetes

AIMS/HYPOTHESIS: Although cardiovascular disease is the biggest cause of death in people with diabetes, microvascular complications have a significant impact on quality of life and financial burden of the disease. Little is known about the progression of microvascular dysfunction in the early stages of type 2 diabetes before the occurrence of clinically apparent complications. We aimed to explore the determinants of endothelial-dependent and -independent microvascular function progression over a 3 year period, in people with and without both diabetes and few clinical microvascular complications. METHODS: Demographics were collected in 154 participants with type 2 diabetes and in a further 99 participants without type 2 diabetes. Skin microvascular endothelium-dependent response to iontophoresis of acetylcholine and endothelium-independent responses to sodium nitroprusside were measured using laser Doppler fluximetry. All assessments were repeated 3 years later. RESULTS: People with type 2 diabetes had impaired endothelial-dependent microvascular response compared with those without (AUC 93.9 [95% CI 88.1, 99.4] vs 111.9 [102.3, 121.4] arbitrary units [AU] × min, p < 0.001, for those with vs without diabetes, respectively). Similarly, endothelial-independent responses were attenuated in those with diabetes (63.2 [59.2, 67.2] vs 75.1 [67.8, 82.4] AU × min, respectively, p = 0.002). Mean microvascular function declined over 3 years in both groups to a similar degree (p(interaction) 0.74 for response to acetylcholine and 0.69 for response to sodium nitroprusside). In those with diabetes, use of sulfonylurea was associated with greater decline (p = 0.022 after adjustment for co-prescriptions, change in HbA(1c) and weight), whereas improving glycaemic control was associated with less decline of endothelial-dependent microvascular function (p = 0.03). Otherwise, the determinants of microvascular decline were similar in those with and without diabetes. The principal determinant of change in microvascular function in the whole population was weight change over 3 years, such that those that lost ≥5% weight had very little decline in either endothelial-dependent or -independent function compared with those that were weight stable, whereas those who gained weight had a greater decline in function (change in endothelial-dependent function was 1.2 [95% CI −13.2, 15.7] AU × min in those who lost weight; −15.8 [−10.5, −21.0] AU × min in those with stable weight; and −37.8 [−19.4, −56.2] AU × min in those with weight gain; p(trend) < 0.001). This association of weight change with change in endothelial function was driven by people with diabetes; in people without diabetes, the relationship was nonsignificant. CONCLUSIONS/INTERPRETATION: Over 3 years, physiological change in weight was the greatest predictor of change in microvascular function. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00125-020-05125-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.