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............................................................................................................................ There was, however, an increase in the rate of hospitalization for HF with saxagliptin in the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction) trial.608

4.8.1.3 Newer diabetes mellitus drug classes: cardiovascular disease benefits Recent trials from two classes of drugs (SGLT2 inhibitors and GLP- 1RAs) have shown CVD benefits that appear independent of glycaemic control and, where examined, of baseline metformin use.596,597,611 Their results have recently been systematically metaanalysed (Supplementary Figures 1  4).590,591 For SGLT2 inhibitors, three trials demonstrated the CV benefits of empagliflozin, canagliflozin, and dapagliflozin.611613 Major adverse CV events (MACE) were reduced modestly, by 14%, with no clear effect on stroke and an unclear effect on myocardial infarction.590 However, reductions in incident HF hospitalization/CVD death by 24% and renal endpoints by 44% were seen.590 The MACE benefits were evident only in those with baseline ASCVD, but HF and renal benefits appeared to extend to those with type 2 DM with multiple risk factors. However, a more recent trial in people with type 2 DM and ASCVD showed ertugliflozin to be non-inferior to placebo with respect to MACE outcomes.614 Whether the results represent a class effect is, therefore, not clear. Four further SGLT2 inhibitor trials demonstrated the benefit of canagliflozin598 and dapagliflozin599 in patients with CKD [with DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) showing similar benefits in people without DM], and dapagliflozin600 and empagliflozin601 in patients with HFrEF, with both trials showing similar benefits in those without type 2 DM. The specific pattern of trial results (e.g. early separation of curves for HF hospitalization) suggests that the benefits of SGLT2 inhibitors may relate more to cardiorenal haemodynamic effects than to atherosclerosis.600 Other than genitourinary infections, rates of adverse events (including diabetic ketoacidosis) were generally low. One trial showed an excess of amputations and fractures,612 but none of the other trials noted imbalances. Patients should be advised on the importance of genitourinary hygiene before being prescribed these medications. GLP-1RAs reduce MACE, CV death, and all-cause mortality by around 12%, with around a 9% reduction in myocardial infarction and a 16% reduction in stroke.591 Furthermore, HF is lowered by 9% and a composite renal outcome was lowered by 17%. The results cannot be explained by lowering of glucose levels and, in multiple SGLT2 inhibitor and GLP-1RA trials, subgroup analyses suggested that these benefits could be independent of metformin use.594597 Most trials were conducted in patients with existing ASCVD or, in the REWIND (Researching Cardiovascular Events With a Weekly Incretin in Diabetes) trial, with a significant proportion of patients at high risk for CVD.615 Side-effects of this class mainly include nausea and vomiting, which can lessen with gradual up-titration. Risks of hypoglycaemia can be reduced by lowering doses of sulphonylureas or insulin. The largely positive results of these two classes of drugs (SGLT2 inhibitors and GLP-1RAs) have led to rapid changes in DM algorithms, but with some differences in interpretation.602 Most DM guidelines, including those within the 2020 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus report,592 recommend that metformin should be used as first-line treatment, while the ESC Guidelines5 recommended in 2019 that SGLT2 inhibitors and GLP-1RAs may be used without metformin in people with DM and CVD or at high risk of CVD, as reviewed.602 A subset of the writing groups of the ADA/EASD consensus report and the ESC Guidelines616 was convened as an expert panel. The expert panel emphasized the overall commonalities of approach and the need to ensure that people with type 2 DM, CVD, HF, or CKD are treated appropriately with an SGLT2 inhibitor or GLP-1RA. The panel concluded that this approach should be initiated independent of background therapy, glycaemic control, or individualized treatment goals.616 The view of the ESC is that metformin should be considered, but is not mandatory first-line treatment in patients with ASCVD or evidence of TOD. Certainly, the initiation of metformin in such patients should not forego or delay the initiation of evidence-based SGLT2 inhibitors or GLP-1RAs. A risk score plus cost-effective analyses would be useful to determine which patients free from ASCVD or evidence of TOD may be recommended for these newer drugs. In all the above, there is no evidence of any sex interaction in benefits. Finally, people with type 2 DM should be involved in decision-making after explanation of the potential benefits and side-effects of the drugs.

4.8.2. Type 1 diabetes mellitus The DCCT (Diabetes Control and Complications Trial) established the importance of tight glucose control to lessen the risks of both microvascular and macrovascular disease in both men and women with type 1 DM.617 A 27-year follow-up of this trial showed that 6.5 years of intensive DM therapy was associated with a modestly lower all-cause mortality rate.617 A glycaemic target for HbA1c of 6.57.5% (4858 mmol/mol) appears to be a balanced approach for long-term care. Recently, metformin was shown not to lower progression of carotid IMT in persons with type 1 DM considered to be at elevated CVD risk.618 Its use is not recommended in type 1 DM for this indication. SGLT2 inhibitors improve metabolic control in type 1 DM and may complement insulin therapy in selected patients.

4.9 Antithrombotic therapy

................................................ Recommendations for antithrombotic therapy

Recommendations Classa Levelb

Aspirin 75 - 100 mg daily is recommended for secondary prevention of CVD.619 I A Clopidogrel 75 mg daily is recommended as an alternative to aspirin in secondary prevention in case of aspirin intolerance.620 I B Clopidogrel 75 mg daily may be considered in preference to aspirin in patients with established ASCVD.620,621 IIb A Concomitant use of a proton pump inhibitor is recommended in patients receiving antiplatelet therapy who are at high risk of gastrointestinal bleeding.622,623 I A

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