Table 3.

Summary of evidence from intervention studies of established lifestyle and pharmacological interventions for type 2 diabetes on cerebral small vessel disease, retinopathy, stroke, cognitive dysfunction, and depression^‡

Intervention	Cerebral small vessel disease	Retinopathy	Stroke	Cognitive dysfunction†	Depression
Lifestyle interventions (diet and/or exercise)	Look AHEAD found beneficial effects on WMHV and TBV	Systematic review found insufficient evidence for beneficial effect	Systematic review found insufficient evidence for beneficial effect	Systematic review found insufficient evidence for beneficial effect	Meta-analysis of 15 trials found beneficial effect
Intensified vs. standard glucose-lowering treatment	ACCORD MIND found beneficial effect on TBV, but not on WMHV	Meta-analysis with individual participant data of four trials found beneficial effect. Another meta-analysis including 9 trials also found a beneficial effect	Meta-analysis of 13 trials found no beneficial effect	Meta-analysis of 4 trials found no beneficial effect	ACCORD found no beneficial effect
Novel glucose-lowering drugs: DPP4 inhibitors, GLP-1 agonists and SGLT2 inhibitors	No data available	Meta-analysis of 37 trials found no beneficial effect for DDP4i, GLP-1a and SGLT2i	Meta-analysis of 97 trials found no beneficial effect on all strokes for DDP4i, GLP-1a and SGLT2i. However, GLP1a, but not DDP4i and SGLT2i, were associated with reduction in nonfatal strokes	Systematic review on DPP4i and GLP-1a found insufficient evidence for beneficial effect. Recent trial on DDP4i found no beneficial effect. No data on SLGT2 inhibitors	No data available
Antihypertensive drugs	ACCORD- MIND found beneficial effect on WMHV, but not on TBV	Meta-analysis of 7 trials found beneficial effect	Two meta-analyses including 19 trials and 49 trials, respectively, found beneficial effect	ACCORD-MIND and ADVANCE found no beneficial effect	ACCORD found no beneficial effect
Lipid-modifying drugs	ACCORD-MIND found no beneficial effect of fenofibrate on TBV	Meta-analysis of 8 trials, mostly on fenofibrate, showed protective effect on retinopathy progression	A meta-analysis of the Cholesterol Treatment Trialists’ Collaboration of 14 statin trials and another meta-analysis of 12 trials, mostly on statins, found beneficial effect	ACCORD on fenofibrate and substudy of the PROSPER trial on statins found no beneficial effect	No data available

References to the individual studies are given in the online appendix

^‡Evidence based on trials that had MRI features of cerebral small vessel disease retinopathy, stroke, cognitive dysfunction, or depression as a primary or secondary outcome or in which type 2 diabetes status was used in a subgroup analysis. No data available on other measures of cerebral microvascular function or structure

^†Cognitive dysfunction includes cognitive decline, incident mild cognitive impairment and incident dementia

Look AHEAD = Action for Health in Diabetes; ACCORD-MIND = Action to Control Cardiovascular Risk in Diabetes-Memory In Diabetes; DPP4i = dipeptidyl peptidase-4-inhibitors; GLP-1a = glucagon-like-peptide-1 agonists; SGLT2i = sodium-glucose co-transporter 2 inhibitors; WMHV = white matter hyperintensity volume; TBV = total brain volume; PROSPER = Pravastatin in elderly individuals at risk of vascular disease