Forskare Aidin Rawshani med kollegor har tilldelats en prestigefylld topp-tioplacering av European Heart Journal, för sin studie om komplikationer och riskfaktorer vid typ 2-diabetes, publicerad i tidskriften Circulation. European Heart Journal är officiell tidskrift för Europeiska kardiologisällskapet, och utmärkelsen ger en placering bland de mest framstående vetenskapliga publiceringarna på området under 2023. Aidin Rawshani tillhör Institutionen för medicin och är ST-läkare i kardiologi och internmedicin på Sahlgrenska Universitetssjukhuset Östra.

• Läs mer om utmärkelsen: The year in cardiovascular medicine 2023: the top 10 papers in diabetes and metabolic disorders

• Studien: Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study

As editors for the diabetes and metabolic disorders section of the European Heart Journal, we have picked out 10 papers published in 2023 that capture the major advances and trends in diabetes and cardiovascular disease (CVD).

We have focused on practical papers, i.e. identification and management of patients with, or at risk of developing, diabetes  There likely are many other papers worthy of selection as ‘top’ papers in the field, but we hope this selection can help cardiologists optimize management of these patients.

Management of cardiovascular disease in patients with diabetes

The 2023 European Society of Cardiology guidelines¹for the management of CVD in patients with diabetes have a major focus on two aspects: the evaluation and identification of patients with CVD and type 2 diabetes (T2D) and diabetes and chronic kidney disease. It is now recommended that all patients with CVD are screened for the presence of diabetes using fasting plasma glucose and/or glycated haemoglobin (HbA1c). Vice versa, it is recommended that all patients with diabetes should be evaluated for the presence of atherosclerotic CVD (ASCVD) and heart failure (HF), and in addition that they are regularly screened for the presence of chronic kidney disease measuring estimated glomerular filtration rate and albuminuria (urinary albumin-to-creatinine ratio).

The guidelines introduce a novel score, called SCORE2-Diabetes, to estimate the 10-year risk of fatal and non-fatal myocardial infarction (MI) and stroke in patients with T2D. These guidelines introduce a new concept with a major focus on the use of glucose-lowering agents with proven cardiovascular (CV) benefit or safety and that patients that have an agent without proven benefit or safety are switched to another agent, e.g. sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Detailed recommendations are given for patients with ASCVD and T2D with a Class IA recommendation for SGLT2i and GLP-1 RA independent of glucose control and HbA1c. In all patients with T2D and HF, a Class IA recommendation is given for treatment with an SGLT2i. Moreover, recommendations are given for patients with T2D and chronic kidney disease to reduce both CV and kidney failure risk: the guidelines recommend a statin-based regimen to reduce CV risk, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers to reduce kidney failure risk, and with a Class I recommendation, SGLT2i and finerenone as well as blood pressure lowering to reduce both, CV risk and kidney failure risk.

Cardiometabolic risk factors and cardiovascular disease

An important epidemiological study²based on the nationwide Swedish cohort looked at trends for CV events and risk factors in 679 072 individuals with T2D and 2 643 800 matched controls from 2001 to 2019. Among individuals with T2D, the analysis demonstrated a decrease of the incident rates per 10 000 person-years in 2019 as compared to 2001 for acute MI, cerebrovascular disease, and HF. Interestingly, around 2013, a plateau for the incidence of HF has been observed with a trend that persisted until 2019. Overall, the CVD incidence in patients with T2D was much higher compared to matched controls. In addition, the data suggest that body mass index (BMI) alone potentially explained more than 30% of HF risk in T2D patients. This study demonstrates that the rates for ASCVD and HF are generally decreasing but over the last 10 years the incidence of HF in patients with T2D has plateaued with no such effect in subjects without diabetes.

Diabetes and cardiovascular risk stratification

Patients with T2D exhibit an elevated risk of developing CVD. The SCORE2-Diabetes Working Group and the European Society of Cardiology Cardiovascular Risk Collaboration developed a T2D-specific risk score (SCORE2-Diabetes) to estimate the 10-year risk of fatal and non-fatal CV events (MI and stroke) in Europe.³It integrates information on conventional CVD risk factors (age, smoking status, systolic blood pressure, total cholesterol, and high-density lipoprotein-cholesterol) with diabetes-specific information (age at diabetes diagnosis, HbA1c, and estimated glomerular filtration rate) and is validated for patients aged ≥40–69 years without ASCVD or severe target organ damage. According to the results of SCORE2-Diabetes, patients are categorized in those at low (<5%), moderate (5% to <10%), high (10% to <20%), and very high risk (≥20%). The recent guidelines¹have included the SCORE2-Diabetes and patients aged ≥40 years with T2D without ASCVD or severe target organ damage are recommended to undergo CVD risk stratification using the SCORE2 algorithm.

Social isolation, loneliness, and cardiovascular disease in vulnerable patients

This population-based cohort study addresses the association of loneliness or social isolation with CVD in patients with diabetes and their relative importance compared to traditional risk factors.⁴The study has also investigated the putative interaction between loneliness and degree of risk factor control on CVD risk. Loneliness and social isolation are common in today’s societies. Isolation is a measure that describes the absence of social relationships. However, loneliness refers to the subjective feeling of being alone and it is driven by the discrepancy between desired and perceived levels of social contacts.^5,6Such psychosocial factors are emerging as important independent risk factors in CVD.⁷Loneliness, but not social isolation, was associated with a higher risk of CVD in diabetes. The authors also observed a significant additive interaction between perceived loneliness and degree of risk factor control, suggesting that the negative prognostic effect of loneliness on CV events is even worse when traditional risk factors are present. A better understanding of the mechanisms driving the effect of loneliness on CVD risk in vulnerable population is highly needed. Nonetheless, these findings should prompt physicians to evaluate the role of psychosocial factors as biomarkers of CVD.

Heart failure, peripheral artery disease, and dapagliflozin

A patient-level meta-analysis of DAPA-HF and DELIVER reported the efficacy and safety of the SGLT2i dapagliflozin in high-risk individuals with both HF (left ventricular ejection fraction ≤40% or >40%, respectively) and peripheral artery disease (PAD).⁸In both trials, the primary outcome was the composite of worsening HF or CV death, and amputation was a pre-specified safety outcome. The rate of the primary outcome was higher in PAD patients than in non-PAD patients. The benefit of dapagliflozin on the primary outcome was consistent in both groups. Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo. The analysis confirms the value of dapagliflozin for high-risk HF patients, and highlights the potential for significant benefit amongst the subset with PAD. This is an important finding because early SGLT2i trials generated uncertainty about the balance of benefits and risks of SGLT2i use in patients with PAD. The authors explored efficacy and safety of dapagliflozin use in subgroups with and without PAD, in those with other risks for limb ischaemia such as high-dose diuretic use, T2D, and their combinations. No evidence that dapagliflozin treatment increased the risk of amputation between groups was shown. This analysis and prior studies clearly show that patients with concomitant HF and PAD have elevated rates of morbidity with reduced quality of life and higher premature mortality. The great majority of them are likely to benefit from SGLT2i therapy but current prescription rates remain low. In this context, misconceptions about the balance of benefits and risks largely contribute to prescribing inertia.

Glucagon-like peptide-1 receptor agonist in cardiovascular prevention

A major area of advancement in 2023 was with papers exploring many of the GLP-1 RA.

Semaglutide in patients with heart failure with preserved ejection fraction and obesity

Among the multiple HF with preserved ejection fraction (HFpEF) phenotypes described to date, the obesity phenotype, which is characterized by visceral adiposity/insulin resistance, appears to be the most prevalent. The obesity phenotype of HFpEF is associated with reduced physical function and worse quality of life and represents an unmet treatment need. Therefore, it was postulated that semaglutide—with its benefits on weight, inflammation, and cardiometabolic risk factors—could be an attractive approach to treat obese people with HFpEF. STEP-HFpEF⁹randomized 529 individuals with HFpEF and BMI ≥30 kg/m²to 2.4 mg semaglutide weekly vs. placebo for 52 weeks. Semaglutide significantly improved HF-related symptoms and physical limitation measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score, exercise function measured by 6-minute walking distance, and reduced inflammation and body weight. These findings represent a significant advancement for the management of the obesity phenotype of HFpEF. It is important to underline that STEP-HFpEF was not powered for clinical events and whether semaglutide reduces ‘hard’ outcomes in HF remains largely undefined. Nevertheless, this trial unmasks an important role for semaglutide in the HF treatment arena.

Obesity, glucagon-like peptide-1 receptor agonist, and cardiovascular disease

The SELECT trial studied patients with obesity, but not overt diabetes.¹⁰The trial randomized 17 604 patients who were overweight or had obesity (BMI ≥27 kg/m²and established ASCVD) but without diabetes, to semaglutide 2.4 mg or placebo. The primary endpoint of CV events (cardiovascular death, MI, or stroke) was reduced by semaglutide by 20%, MI alone by 28%, and all-cause mortality by 19% over a mean follow-up period of 3.3 years. The expected gastrointestinal side effects were observed.

The SURMOUNT trials evaluated tirzepatide, i.e. a dual agonist, a glucose-dependent insulinotropic polypeptide and GLP-1 RA. The first trial in patients with obesity found an average 21% weight loss vs. 3% for placebo. The SURMOUNT-2 trial¹¹studied 1514 patients with diabetes and obesity with tirzepatide and found a 15.7% reduction in weight vs. 3.3% for placebo. An additional study, SURMOUNT-4,¹²treated patients with tirzepatide for 36 weeks and then randomized patients to continuing or stopping. Those who continued the agent had up to 25.3% weight loss, but those who stopped had only 9.9% weight loss remaining after a year (P< .001). As such, it suggests that continuation of this class of drugs is needed to maintain full weight loss.

Impact of non-statin lipid-lowering agents on new-onset diabetes

Another aspect of diabetes is that some medications can increase the risk of developing diabetes, and most notably, statins. A dose-related relationship has been seen with statins and the risk of developing new-onset diabetes (NOD), and although this risk is outweighed by a benefit on prevention of CV events, the question of whether other classes of lipid-lowering agents have the same risk is thus important.

The CLEAR OUTCOMES trial¹³was a trial of ∼14 000 patients with statin intolerance that found a benefit of a non-statin agent bempedoic acid on CV outcomes. An analysis by baseline glycemic status showed benefits on CV outcomes across those with diabetes, pre-diabetes, and normoglycemia. Importantly, bempedoic acid did not increase risk of NOD nor did it worsen HbA1c and was associated with modest weight reductions. As such, the efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes.

Similarly, no increase in NOD has recently been seen with ezetimibe,¹⁴as also with PCSK9 inhibitors, so use of any of the non-statin lipid-lowering agents avoids the risk of NOD.

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