Dysglycaemia and cardiovascular disease. Aspects on screening, management, and prognosis

Background: Dysglycaemia, in this thesis defined as impaired glucose tolerance (IGT) or type 2 diabetes (T2DM), is a major risk factor for cardiovascular disease (CVD). International guidelines recommend screening for dysglycaemia and target-driven lifestyle and pharmacological management in people with high cardiovascular (CV) risk or established CVD for both men and women. New glucose-lowering drugs with proven CV benefit are now available.

Aims: The overall aim of this doctoral thesis was to investigate the screening and management of patients with CVD or at high CV risk including gender differences and implementation of new cardioprotective glucose-lowering drugs by studying: - the prevalence of dysglycaemia according to different screening tools in patients without known diabetes (Study I) and by gender (Study II); - the value of new screening methods for dysglycaemia in these patients (Study III and IV); - the management of such patients as regards lifestyle habits, use of cardioprotective drugs, and treatment target attainment (Study I) including possible gender disparities (Study II); - gender differences in prognosis (Study II); - whether cardioprotection of the glucagon-like peptide-1 receptor agonist dulaglutide is dependent on metformin (Study V).

Methods: Studies I, II, III and IV were based on the population from the EUROASPIRE V cross-sectional survey; Study II included data from EUROASPIRE IV and V. Both surveys included patients with established coronary artery disease recruited across Europe at least six months prior to the investigation. Data on clinical history, life-style advice and pharmacological treatment was based on validated questionnaires and standardised blood tests at a study visit. Study V is based on patients with T2DM at high CV risk from the randomised controlled trial REWIND.

Results: Prevalence and screening for dysglycaemia: In Study I, 29% of the study population had dysglycaemia detected by screening, with 70% of them being identified by a two-hour postload glucose value (2hPG) during an oral glucose tolerance test (OGTT). Study II found that more women than men had IGT and more men had T2DM. Study III validated a diagnostic algorithm for T2DM based on the assessment of a one-hour postload glucose value (1hPG) during the OGTT, shortening the time needed for glycaemic classification in 79% of them. In Study IV, the diagnostic performance of different insulin resistance indexes was unsatisfactory compared with the yield of an OGTT. Management: Study I showed that multifactorial management after the coronary event was unsatisfactory, with poor adherence to recommended treatment targets for blood pressure, lipids and glycaemic control and a high prevalence of obesity, persistent smoking and limited physical activity. Study II highlighted how this management was particularly inadequate in women, possibly contributing to a worse prognosis compared with men in those with known T2DM. Study V found that CV protection with dulaglutide seems to be present irrespective of metformin treatment at baseline.

Conclusions: There is a compelling need for implementation of screening for dysglycaemia in patients with CAD, and the OGTT should be the preferred method because it identifies more patients with dysglycaemia, which otherwise would be missed. Time might be mature to introduce an algorithm based on the 1hPG value to identify T2DM. Its prognostic implications should however be further investigated. Multifactorial management of these patients is in demand of a substantial improvement, especially in women, where deficient care may be associated with worse prognosis. The use of new glucose-lowering agents with cardiovascular efficacy should be prioritised regardless of background glucose-lowering therapy.

List of scientific papers

I. Ferrannini G, de Bacquer D, De Backer G, Kotseva K, Mellbin L, Wood D, Rydén L. On behalf of the EUROASPIRE V collaborators. Screening for glucose perturbations and risk factor management in dysglycaemic patients with coronary artery disease - a persistent challenge in need of substantial improvement. A report from EUROASPIRE V. Diabetes Care. 2020 Apr; 43(4):726-733.
https://doi.org/10.2337/dc19-2165

II. Ferrannini G, De Bacquer D, Vynckier P, De Backer G, Gyberg V, Kotseva K, Mellbin L, Norhammar A, Tuomilehto J, Wood D, Rydén L; EUROASPIRE IV & V Investigators. Gender differences in screening for glucose perturbations, cardiovascular risk factor management and prognosis in patients with dysglycaemia and coronary artery disease: results from the ESC‑EORP EUROASPIRE surveys. Cardiovascular Diabetology. 2021 Feb; 20(1):38.
https://doi.org/10.1186/s12933-021-01233-6

III. Ferrannini G, De Bacquer D, Gyberg V, De Backer G, Kotseva K, Mellbin LG, Risebrink R, Tuomilehto J, Wood D, Rydén L. Saving time by replacing the standardised two-hour oral glucose tolerance test with a one-hour test. Validation of a new screening algorithm in patients with coronary artery disease from the ESC-EORP EUROASPIRE V registry. Diabetes Research and Clinical Practice. 2022 Jan; 183:109156.
https://doi.org/10.1016/j.diabres.2021.109156

IV. Ferrannini G, De Bacquer D, Erlund I, Gyberg V, Kotseva K, Mellbin L, Norhammar A, Schnell O, Tuomilehto J, Vihervaara T, Wood D, Rydén L. Measures of insulin resistance as a screening tool for dysglycaemia in patients with coronary artery disease. A report from EUROASPIRE V. Diabetes Care. 2022; 45: 2111-2117.
https://doi.org/10.2337/dc22-0272

V. Ferrannini G, Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Dyal L, Lakshmanan M, Mellbin L, Probstfield J, Riddle MC, Shaw JE, Avezum A, Basile JN, Cushman WC, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Pais P, Pīrāgs V, Pogosova N, Raubenheimer PJ, Sheu WH-H, Rydén L. Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin. A subgroup analysis of the REWIND Trial. European Heart Journal. 2021; 42: 2565-2573.
https://doi.org/10.1093/eurheartj/ehaa777