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............................................................................................................................................................................. 4.8.1. Key risk factor concepts and newer paradigms Except for glucose management, prevention of ASCVD follows the same principles as for people without type 2 DM. Achieving BP and LDL-C targets is particularly important. More recently, trial evidence has shown that drugs in the sodium-glucose cotransporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 receptor agonist (GLP- 1RA) classes lower ASCVD, HF, and renal risks independently of baseline HbA1c and whether patients are on metformin. Such benefits are most evident in those with existing ASCVD, HF, or CKD, but appear to extend to groups at elevated risk. This has led to newer treatment algorithms.

4.8.1.1 Lifestyle intervention Lifestyle management is a first priority for ASCVD prevention and management of DM. Most persons with DM are obese, so weight control is crucial. Several dietary patterns can be adopted, where the predominance of fruits, vegetables, wholegrain cereals, and low-fat protein sources is more important than the precise proportions of total energy provided by the major macronutrients. Salt intake should be restricted. Specific recommendations include limiting saturated and trans fats and alcohol intake, monitoring carbohydrate consumption, and increasing dietary fibre. A Mediterranean-type diet, where fat sources are derived primarily from monounsaturated oils, is protective against ASCVD. More detail is provided in section 4.3.2. A combination of aerobic and resistance exercise training is effective in preventing the progression of type 2 DM and for the control of glycaemia. Smokers should be offered cessation support (see section 4.5). Lifestyle intervention lowers future microvascular and macrovascular risks as well as mortality in the longer term.603 Intensive lifestyle changes with low-calorie diets and mean weight losses in the region of 10 kg leads to remission of type 2 DM in around 46% of cases at 1 year and 36% by 2 years.585 In those with prediabetes, other ASCVD risk factors should be assessed both before (to incentivize improvements) and after lifestyle changes have taken place.604

4.8.1.2 Glycaemic control The UKPDS587 established the importance of intensive glucose lowering with respect to CVD risk reduction in persons newly diagnosed with DM, with better evidence to support metformin, which correctly remains the first agent of choice for the majority of patients diagnosed with DM. Three trials were conducted to see if CV events could be reduced further with more intensive glycaemia treatment.559,588,593 However, there were unexpected increases in total and ASCVD deaths in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial559 and a similar trend in VADT (Veterans Affairs Diabetes Trial).593 The results prompted concerns about pursuing tight glucose control, particularly in older people with DM and in those with existing ASCVD. Subsequent meta-analyses of relevant trials showed reductions in non-fatal AMI and CAD events, but no effect on stroke or total mortality.605,606 The meta-analyses suggested that CVD benefits for an average HbA1c reduction of 0.9% over 5 years were less than via treatment of cholesterol and BP. HbA1c targets should be personalized to individual characteristics and preferences. Four trials of dipeptidyl peptidase-4 inhibitors607610 in patients with DM and existing ASCVD or at high risk demonstrated noninferiority (i.e. safety) but not superiority with respect to CVD risk.

Glycaemia targets A target HbA1c for the reduction of CVD risk and microvascular complications of DM of <7.0% (53 mmol/mol) is recommended for the majority of adults with either type 1 or type 2 DM.587,588 I A For patients with a long duration of DM and in old or frail adults, a relaxing of the HbA1c targets (i.e. less stringent) should be considered.588 IIa B A target HbA1c of <_6.5% (48 mmol/mol) should be considered at diagnosis or early in the course of type 2 DM in persons who are not frail and do not have ASCVD.587,588 IIa B Treatment of hyperglycaemia and ASCVD/cardiorenal risks Metformin is recommended as first-line therapy, following evaluation of renal function, in the majority of patients without previous ASCVD, CKD, or HF.589 I B In persons with type 2 DM with ASCVD, metformin should be considered, unless contraindications are present.5,590592 IIa B Avoidance of hypoglycaemia and excessive weight gain should be considered.559,588,593 IIa B In persons with type 2 DM and ASCVD, the use of a GLP-1RA or SGLT2 inhibitor with proven outcome benefits is recommended to reduce CV and/or cardiorenal outcomes.590592 I A In patients with type 2 DM and TOD,c the use of an SGLT2 inhibitor or GLP-1RA with proven outcome benefits may be considered to reduce future CV and total mortality.594597 IIb B In patients with type 2 DM and CKD, the use of an SGLT2 inhibitor is recommended to improve ASCVD and/or cardiorenal outcomes.598,599 I A In patients with type 2 DM and HFrEF, use of an SGLT2 inhibitor with proven outcome benefits is recommended to lessen HF hospitalizations and CV death.600,601 I A In patients with type 2 DM but without ASCVD, HF, or CKD, use of an SGLT2 inhibitor or GLP- 1RA should be considered based on estimated future risks (e.g. with the ADVANCE risk score or DIAL model) for adverse CVD or cardiorenal outcomes from risk factor profiles.602 IIa B

ACR = albumin-to-creatinine ratio; ADVANCE = Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; CV = cardiovascular; DIAL = Diabetes lifetime-perspective prediction; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; GLP-1RA = glucagon-like peptide-1 receptor agonist; HbA1c = glycated haemoglobin; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; PA = physical activity; SGLT2 = sodium-glucose cotransporter 2; TOD = target organ damage. aClass of recommendation. bLevel of evidence. cSee Table 4 for details. ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/34/3227/6358713 by guest on 07 October 2026