Gender disparities in time-to-initiation of cardioprotective glucose-lowering drugs in patients with type 2 diabetes and cardiovascular disease: a Danish nationwide cohort study.

BACKGROUND: We aimed to examine the impact of gender and specific type of cardiovascular disease (CVD) diagnosis (ischemic heart disease [IHD], heart failure, peripheral artery disease [PAD] or stroke) on time-to-initiation of either a sodium glucose cotransporter 2 inhibitor or glucagon-like peptide 1 analogue (collectively termed cardioprotective GLD) after a dual diagnosis of type 2 diabetes (T2DM) and CVD. METHODS: In a nationwide cohort study, we identified patients with a new dual diagnosis of T2DM and CVD (January 1, 2012 and December 31, 2018). Cumulative user proportion (CUP) were assessed. Poisson models were used to estimate the initiation rate of cardioprotective GLDs. The final analyses were adjusted for potential confounders. RESULTS: In total, we included 70,538 patients with new-onset T2DM and CVD (38% female, mean age 70 ± 12 years at inclusion). During 183,256 person-years, 6,276 patients redeemed a prescription of a cardioprotective GLD. One-year CUPs of cardioprotective GLDs were lower in women than men. Initiation rates of GLDs were lower in women (female-to-male initiation-rate-ratio crude: 0.76, 95% CI 0.72-0.81); adjusted 0.92, 95% CI 0.87-0.97). In CVD-stratified analysis, the adjusted initiation rate ratio was lower in female patients with IHD and heart failure (IHD: 0.91 [95% CI 0.85-0.98], heart failure: 0.85 [95% CI 0.73-1.00], PAD: 0.92 [95% CI 0.78-1.09], and stroke: 1.06 [95% CI 0.93-1.20]). CONCLUSIONS: Among patients with a new dual diagnosis of T2DM and CVD, female gender is associated with lower initiation rates of cardioprotective GLDs, especially if the patient has IHD or heart failure.

Low physical activity is associated with impaired endothelial function in patients with type 2 diabetes and controls after 5 years of follow-up.

BACKGROUND: The long-term association between physical activity and endothelial function has not previously been investigated in patients with type 2 diabetes. Therefore, we aimed to evaluate the relationship between physical activity and endothelial function, assessed by peripheral arterial tonometry, in patients with type 2 diabetes and non-diabetic controls after 5 years of follow-up. METHODS: We included 51 patients with newly diagnosed type 2 diabetes and 53 sex- and age matched controls. Participants underwent baseline clinical characterization including objective measurement of physical activity level using accelerometery. After 5 years of follow-up, participants were re-examined, and endothelial function was assessed as natural logarithm of reactive hyperemia index (lnRHI). RESULTS: Physical activity at baseline was associated with lnRHI after 5 years of follow-up in both patients with type 2 diabetes and controls. An increase of 1 standard deviation (SD) in daytime physical activity corresponded to a 6.7 % increase in RHI (95 % confidence interval: 1.1;12.5 %, p = 0.02). We found no difference in lnRHI between patients with diabetes and controls (0.67 ± 0.29 vs. 0.73 ± 0.31, p = 0.28). CONCLUSIONS: Daytime physical activity is associated with endothelial function after 5 years of follow-up in patients with type 2 diabetes and controls.

Effects of semaglutide and empagliflozin on oxygenation, vascular autoregulation, and central thickness of the retina in people with type 2 diabetes: A prespecified secondary analysis of a randomised clinical trial.

AIMS: Semaglutide and empagliflozin have shown cardiovascular protection. In SUSTAIN-6, semaglutide was associated with an increased risk of diabetic retinopathy. We investigated whether changes in retinal oxygenation, retinal vascular autoregulation, and central retinal thickness are altered by semaglutide, empagliflozin or the combination. METHODS: This study was a prespecified, secondary outcome from a randomised, 32 weeks partly placebo-controlled, partly open-label, clinical trial on the effects of semaglutide and empagliflozin on arterial stiffness and kidney oxygenation. A total of 120 participants with type 2 diabetes, established or high risk of cardiovascular disease and age ≥50 years were randomised into four parallel groups (semaglutide, empagliflozin, the combination or tablet placebo, n = 30 for each group). We primarily hypothesized that semaglutide would increase venular oxygenation. RESULTS: We found no changes in retinal arteriolar, venular or venular-arteriolar oxygenation nor in retinal vessel diameter regardless of treatment group. Semaglutide increased central retinal thickness compared to placebo with ~1 % (3.8 µm 95 % CI [0.9;6.7], p = 0.009) with no changes in the empagliflozin or combination group. CONCLUSION: Neither semaglutide, empagliflozin nor the combination alters markers of retinal function. The effect of semaglutide on central retinal thickness was small, but the clinical significance is uncertain.

Volumes of coronary plaque disease in relation to body mass index, waist circumference, truncal fat mass and epicardial adipose tissue in patients with type 2 diabetes mellitus and controls.

OBJECTIVES: Coronary atherosclerosis in patients with type 2 diabetes mellitus may be promoted by regional fat distribution. We investigated the association between anthropometric measures of obesity, truncal fat mass, epicardial adipose tissue and coronary atherosclerosis in asymptomatic patients and matched controls. METHODS: We examined 44 patients and 59 controls [mean (standard deviation) age 64.4 ± 9.9 vs 61.8 ± 9.7, male 50% vs 47%, diabetes duration mean (standard deviation) 7.7 ± 1.5] with coronary computed tomography angiography. Coronary plaques were quantified as total, calcified, non-calcified and low-density non-calcified plaque volumes (mm3). Regional fat distribution was assessed by dual-energy X-ray absorptiometry, body mass index (kg/m2), waist circumference (cm) and epicardial fat volume (mm3). Endothelial function and systemic inflammation were evaluated by peripheral arterial tonometry (log transformed Reactive Hyperemia Index) and C-reactive protein (mg/L). RESULTS: Body mass index and waist circumference (p < 0.02) were associated with coronary plaque volumes. Body mass index was associated with low-density non-calcified plaque volume after adjustment for age, sex and diabetes status (p < 0.01). Truncal fat mass (p > 0.51), waist circumference (p > 0.06) and epicardial adipose tissue (p > 0.17) were not associated with coronary plaque volumes in adjusted analyses. CONCLUSION: Body mass index is associated with coronary plaque volumes in diabetic as well as non-diabetic individuals.

Retinal vessel reactivity is not attenuated in patients with type 2 diabetes compared with matched controls and is associated with peripheral endothelial function in controls.

BACKGROUND AND AIMS: Attenuated retinal vasoreactivity in patients with type 2 diabetes preceding diabetic retinopathy development has been proposed to reflect local endothelial dysfunction. Whether retinal vessel reactivity is associated with peripheral endothelial dysfunction and large artery stiffness in patients with type 2 diabetes remains to be elucidated. METHODS: Twenty patients with type 2 diabetes without retinopathy and 20 sex- and age matched controls (diabetes duration: 9.9 years (range 6.0;12.4), 40% male, age: 66.5 ±â€¯7.3 (diabetes) and 65.2 ±â€¯7.6 years (controls)) were included. Endothelial function was assessed using EndoPAT. Arterial stiffness was assessed by carotid-femoral pulse wave velocity using the SphygmoCor. Retinal blood supply regulation was examined by retinal arteriolar diameter change during 1) isometric exercise (hand-weight lifting), 2) exposure to flickering lights, and 3) a combined stimulus of 1) + 2) using the Dynamic Vessel Analyzer. RESULTS: No significant differences were observed in retinal vessel reactivity in T2DM patients compared to controls. Endothelial function was associated with mean arteriolar diameter change during only the combination intervention, (Beta = 0.033 [0.0013;0.064], p = 0.042) in the overall population of patients and controls. When groups were analyzed separately, the associations was statistically significant only in controls. However, formal test for interaction was not statistically significant, p = 0.40. No association was observed between pulse wave velocity and retinal arteriolar %-diameter change in patients or controls. CONCLUSION: Peripheral endothelial function was associated with retinal arteriolar diameter change in the combined sample. The association seemed to be driven primarily by the controls. Our findings indicate that peripheral endothelial function is reflective of endothelial function in the retina mainly in subjects without T2DM, whereas an association in T2DM without retinopathy was not observed. Further studies are needed in T2DM patients with more advanced retinopathy.

Detection of biomarkers using a novel proximity extension assay in patients with ST-elevation myocardial infarction.

BACKGROUND: ST-elevation myocardial infarction (STEMI) involves inflammation, activation of platelets, coagulation and changes in fibrinolysis as well as remodelling of myocardial tissue after STEMI. Recently, new proximity extension assays including panels of biomarkers for cardiovascular disease have been developed. This study investigates a wide range of cardiovascular protein biomarkers in the acute phase of STEMI compared with the stable phase three months after STEMI. We hypothesized that major changes in inflammation, haemostasis, tissue remodelling, and proteolysis are prevalent. MATERIALS AND METHODS: This was a prospective, observational study including 48 STEMI patients (mean age 60 ±â€¯12 years, 79% men) treated with primary percutaneous coronary intervention (PPCI). Blood samples were obtained immediately prior to PPCI and again three months later. Levels of 92 biomarkers reflecting inflammation, immune response, cell adhesion, haemostasis, fibrinolysis, tissue remodelling, and proteolysis were assessed using a proximity extension assay (Olink® CARDIOVASCULAR III). RESULTS: When comparing the acute phase of STEMI with the stable phase three months later, a total of 29 biomarkers differed significantly after Bonferroni correction (p < 0.0005). In the acute phase of STEMI, we found an overall increase of biomarkers reflecting immune and inflammatory response, cell adhesion, and haemostasis. Biomarkers reflecting tissue remodelling and proteolysis were increased at three months follow-up compared with the acute phase. Out of the 29 biomarkers, six biomarkers did not confirm our predefined hypotheses. CONCLUSIONS: Using a novel proximity extension assay technique, we detected changes in several biomarkers when comparing the acute phase with three months follow-up in patients with STEMI. These biomarkers may play important roles in the pathogenesis of STEMI.

Antiplatelet effect of aspirin during 24h in patients with type 2 diabetes without cardiovascular disease.

INTRODUCTION: The antiplatelet effect of low-dose aspirin in patients with type 2 diabetes (T2DM) without cardiovascular disease (CVD) has not been thoroughly explored. We investigated if platelet aggregation increased during the standard 24-hour aspirin dosing interval in patients with T2DM compared to non-diabetic controls. Furthermore, we evaluated baseline platelet aggregation, the acute effects of aspirin on platelet aggregation and platelet turnover. MATERIALS AND METHODS: We included 21 patients with T2DM and 21 age and sex-matched controls. Platelet aggregation was measured by impedance aggregometry (Multiplate® Analyzer) and markers of platelet turnover by flow cytometry (Sysmex® XE-5000). Blood samples were obtained at baseline and 1h after administration of 75mg of aspirin. Participants were then treated for 6days with once-daily aspirin, and blood sampling was repeated 1h and 24h after aspirin intake. RESULTS: After 6days of treatment, platelet aggregation levels increased during the 24-hour aspirin dosing interval in both patients and controls (p<0.001) with no difference between patients and controls. At baseline, patients with diabetes had increased platelet aggregation compared to controls (p=0.03). Platelet aggregation was reduced after the first dose of aspirin and significantly further reduced after six days of treatment (p<0.001). Patients with T2DM had numerically higher immature platelet count compared to controls (p=0.09), indicating an increased platelet turnover. CONCLUSION: Patients with T2DM without a history of CVD and controls had increased platelet aggregation at the end of the standard 24-hour dosing interval of aspirin. Further, aspirin-naïve T2DM patients had increased platelet aggregation compared to controls.