Background Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D). Materials and Methods Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders. Results Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06–1.72), p = 0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01–1.55), p = 0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02–1.53), p = 0.022), but not osteocalcin. Conclusions In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Background: This is a proof of concept, as a pilot study, with the aim to evaluate continuous glucose monitoring metrics (CGM) in subjects with type 2 diabetes (T2DM), treated with nutritional therapy and metformin, before and after testosterone replacement therapy (TRT). Methods: In this longitudinal observational study, subjects affected by T2DM and starting TRT for documented ED and hypogonadism were enrolled. All subjects mounted a CGM system during the v0 visit, one week before the beginning of the TRT (week−1), during v2, four weeks after the start of TRT (week 4), and v4 (week 12). CGM was worn for about 144 h after each visit. Results: A total of seven patients, referring to our clinic for erectile dysfunction (ED), were studied (aged 63.3 ± 2.3 years). Mean (± standard deviation) total testosterone level was 2.3 ± 0.6 ng/mL at baseline. After TRT, total testosterone level was 4.6 ± 3.04 ng/mL at week 4 and 3.93 ± 4.67 ng/mL at week 12. No significant differences were observed in TIR, TAR, TBR, estimated HbA1c, AUC below, and AUC above limit during the intervention period. Conclusions: This is the first study evaluating the effects of TRT on daily glucose excursions in subjects with T2DM and hypogonadism. Though we did not find any significant difference in key CGM metrics during the 12 weeks of TRT, this study confirms the glycometabolic safety of the TRT even on the most novel standardized glycemic targets.

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce renal and heart failure (HF) events in people with and without diabetes. Although their glycemic efficacy is dependent on kidney function, it remains unclear to what extent baseline kidney function influences the magnitude of SGLT2i cardiorenal effects. Methods We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials testing the effects of SGLT2i on renal and CV outcomes (PROSPERO registration number CRD42022325976). Efficacy outcomes, stratified by five estimated glomerular filtration rate (eGFR) categories, included progression of renal disease (as defined in each trial), a composite HF outcome (defined as CV death or hospitalization/urgent visit for HF), and all-cause mortality. Results Eleven trials testing five SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) in 77,541 participants were included. The majority of participants (39.8%) had eGFR values between 60 and 90 ml/min/1.73m2, with only 1.3% having advanced kidney disease (eGFR between 20 and 30 ml/min/1.73m2). Overall, SGLT2i reduced the risk of renal disease progression by 41% (HR 0.59, 95%CI 0.54–0.65, p<0.001) and the risk of HF outcomes by 22% (HR 0.78, 95%CI 0.73–0.83, p<0.001). Meta-regression analyses showed a significant direct relationship between baseline eGFR and the magnitude of SGLT2i renal protection (p=0.040). The greatest relative risk reduction was in participants with eGFR values ≥90 ml/min/1.73m2 (HR 0.43, 95%CI 0.32–0.58) and the smallest was in those with an eGFR between 30 and 45 ml/min/1.73m2 (HR 0.64, 95%CI 0.55–0.76). Conversely, the HF outcome showed a non-significant trend to greater benefit in participants with lower eGFR categories (p=0.086). The greatest relative risk reduction was in those with an eGFR between 20 and 30 ml/min/1.73m2 (HR 0.68, 95%CI 0.48–0.96, p=0.026) and the smallest was in those with an eGFR ≥90ml/min/1.73m2 (HR 0.87, 95%CI 0.56–1.35, p=0.52). Conclusions SGLT2i reduce risk of renal disease progression and HF outcomes for all eGFR subgroups. However, the opposite trends for the influence of baseline kidney function between renal and HF outcomes suggest different SGLT2i mechanisms for renal and cardiac protection.