Aims Circadian heart rate (HR) fluctuations are associated with cardiovascular health. We examined their relationship with microvascular disease and long-term survival in patients with diabetes. Methods and results In this secondary analysis from the CHAMP1ON cohort of 497 adults with metabolic disease, 349 participants who had type 1 or type 2 diabetes, baseline 24-h ambulatory blood pressure and HR monitoring (ABPM), and survival data over a 21-year observational follow-up were included. Clinical features, microvascular complications, and mortality rates were examined in participants with low circadian HR fluctuations [24-h HR standard deviation (SD) below the median of 30.4] and blunted nocturnal HR dip (<10%). Low 24-h HR SD and blunted nocturnal HR dip were associated with an adverse cardiometabolic risk profile and 12-23% higher prevalence of cardiac autonomic neuropathy and nephropathy. After 6251 person-year follow-up [21.0 (14.0-21.0) years], a total of 136 (39%) deaths occurred, of which 100 (68%) of cardiovascular cause. The low 24-h HR SD group had a higher risk for both cardiovascular [adjusted hazard ratio (aHR) 2.00, 95% confidence interval (CI) 1.30-3.08, P = 0.002] and all-cause mortality (aHR 1.61, 95% CI 1.13-2.29, P = 0.009), compared with high 24-h HR SD. Similarly, patients with blunted nocturnal HR dip had a higher risk for cardiovascular (aHR 1.63, 95% CI 1.08-2.46, P = 0.019) and all-cause mortality (aHR 1.69, 95% CI 1.20-2.38, P = 0.003), compared with those with preserved nocturnal HR dip. Conclusion Impaired circadian HR fluctuations are associated with microvascular disease and long-term cardiovascular and all-cause mortality in diabetes. The ABPM-derived HR measures may provide a widely available and inexpensive risk stratification tool in this high-risk population.

AIMS:Nephrinuria and podocinuria have been proposed as early markers of podocytopathy. We explored whether nephrin and podocin are expressed in subcutaneous (SAT) and visceral adipose tissue (VAT), and report their determinants. METHODS:Forty-one subjects with obesity (OS, age: 51 [41-57] yrs, M/F: 6/34) and twenty-nine lean controls (HC, age: 43 [35-51] yrs, M/F: 9/20) were studied. During metabolic bariatric surgery (MBS) VAT and SAT samples were collected. Only SAT samples were collected from HC. VAT samples from lean surgical patients served as an additional comparison group. Nephrin and podocin mRNA and protein expression were assessed in VAT/SAT, and nephrin and podocin levels were measured in plasma and urine. RESULTS:Podocin was not expressed in SAT or VAT. Nephrin mRNA was detected in VAT but not SAT, and nephrin protein expression was higher in OS. In plasma, low levels of nephrin were detected, which were directly associated with insulin sensitivity. Urinary nephrin exhibited an inverse association with insulin sensitivity, which persisted two years after MBS. CONCLUSIONS:Nephrin is ectopically produced in VAT. Circulating and urinary nephrin show opposite associations with insulin sensitivity, compatible with early nephrin loss into the urine and compensatory regulation of VAT derived nephrin. These findings warrant further investigation.

Evidence supporting the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) in individuals aged ≥ 80 years remains limited, particularly regarding treatment persistence and real-world outcomes. In this retrospective real-world study, 292 individuals with type 2 diabetes (T2D) aged ≥ 80 years who started SGLT2i (n = 155) or GLP1-RA (n = 137) after the age of 75 were stratified by age at treatment initiation (75–80 vs. > 80). Primary outcomes were all-cause mortality and treatment persistence; longitudinal renal function was also assessed. Survival analyses were performed using Cox models adjusted for confounders. Over a median follow-up of 40 (37–43) months, 47 deaths (16.1

Human Biomonitoring (HBM) is a key tool for assessing human exposure to environmental contaminants and identifying early biological changes potentially associated with adverse health effects. However, as contaminated sites are characterized by multiple pollutants, exposure pathways and biological targets, a structured decision-support process is required to guide exposure assessment, biomarker selection, and early health-risk evaluation. This manuscript does not report biomonitoring results but describes the methodological process used to design the INSINERGIA_RT HBM study in two contaminated areas of Tuscany, Italy. The study design integrated environmental evidence, toxicological knowledge, epidemiological priorities, biomarker relevance, analytical feasibility, logistical considerations, and public health needs. Instead of proposing a universally applicable framework, the manuscript presents a structured approach that may support the design of HBM studies in similarly complex settings. Biomarkers are organized within a hierarchical model reflecting successive stages of the biological response to environmental exposure. A central feature is a mechanistic, multi-level approach encompassing upstream pathways (oxidative stress and inflammation), early markers of adverse effects and subclinical organ damage, including cardiovascular, renal, and respiratory alterations, and integrative indicators of cumulative biological responses, such as telomere length, epigenetic changes, and metabolomic profiles. Applicability is illustrated through an ongoing HBM study in Livorno and Piombino (Tuscany).

BACKGROUND AND AIMS:The burden of type 2 diabetes (T2D)-related complications (DRCs) shows marked interindividual variability. We aimed to develop a method to estimate the burden and rate of accumulation of complications in relation to disease duration using standard clinical assessments. METHODS AND RESULTS:We analyzed the clinical records of 1302 subjects from four diabetes clinics who underwent comprehensive screening for macrovascular and microvascular complications. Overt and subclinical complications were defined using standardized criteria and assigned 3 and 1 point, respectively. Microvascular and macrovascular complications tended to cluster (chi2 p < 0.0001). The global DRC score increased with diabetes duration (r = 0.34, p = 1∗10-21), and regression analysis indicated a theoretical score of zero approximately 13 years before diagnosis. Assuming -13 years as intercept, we calculated the individual rate of complication accrual and classified patients into tertiles corresponding to low (LB), moderate (MB), and high burden (HB) groups. The mean accrual rates were 0.14 [95%CI:0.13-0.16], 0.88 [95%CI:0.85-0.91], and 2.31 [95%CI: 2.24-2.39] points per 10 years, respectively. According to these models, the first subclinical complication was expected to occur approximately 65 years after diagnosis in the lowest tertile and 2 and 9 years before diagnosis in the moderate and highest tertiles, respectively. The three groups showed only marginal differences in age, diabetes duration, and HbA1c. CONCLUSION:Using real-world data, we identified thresholds that allow classification of patients with T2D according to the rate of accrual of complications relative to disease duration. This framework may facilitate research aimed at identifying biological determinants of variability in complication development. TRIAL REGISTRATION:NCT07250607, registered on 23/11/2025.

Introduction and Objective: Albuminuria incompletely predicts diabetic kidney disease (DKD) progression. Urinary post-translationally modified Fetuin-A (uPTM-FetA) reflects kidney stress-related pathophysiology. We evaluated whether uPTM-FetA predicts renal outcomes independent of albuminuria and eGFR in CREDENCE participants with type 2 diabetes and CKD. Methods: Baseline urine from 1,466 participants was analyzed for uPTM-FetA. Associations with UACR and eGFR were assessed using Spearman correlation. Cox models evaluated risk of the renal composite (≥40% eGFR decline, ESKD, or renal death). Multivariable models adjusted for UACR and eGFR. Results: Over median 2.68 years, 112 renal events occurred. uPTM-FetA correlated with UACR (ρ=0.46) and inversely with eGFR (ρ=−0.22). Higher uPTM-FetA predicted renal outcomes (HR per log unit 2.02 [1.70-2.40], p=2.1×10−15) and remained significant after adjustment (HR 1.25 [1.02-1.54], p=0.035). Risk increased across tertiles (HR T2 vs T1 2.36; HR T3 vs T1 5.80). Conclusion: uPTM-FetA predicts renal disease progression independent of albuminuria and eGFR in type 2 diabetes with CKD. Increasing levels identify progressively higher renal risk, supporting uPTM-FetA as a biomarker for improved DKD risk stratification. Disclosure T.K. Tseng: Board Member; Current; Bio Preventive Medicine Corp. E. Button: None. C. Rossi: None. F. Raggi: None. A. Solini: None. C. Huang: Employee; Current; Bio Preventive Medicine Corp. E. Ferrannini: Research Support; Current; Precsion Diabetes, Inc. Consultant; Ended; 23andMe, Inc.

AIMS:A reduced compliance, due to urogenital minor infections, frequently compromises the clinical efficacy of SGLT2 inhibitors in subjects with type 2 diabetes (T2D). The combined use of SGLT2 inhibitors and dipeptidyl-peptidase four inhibitors seems to reduce the incidence of such side effects. We evaluated how these drugs, alone or in combination, might influence resident urinary microbiota. MATERIALS AND METHODS:An open label, randomised clinical study was conducted on 30 T2D individuals for 12 weeks to compare the impact of Empagliflozin and Empagliflozin/Linagliptin on clinical parameters and urinary microbiota. Fifteen healthy individuals served as baseline controls. The composition of urinary bacterial populations was evaluated by Real-Time quantitative PCR and 16S rRNA gene sequencing. RESULTS:BMI was reduced by both treatments, while fasting glucose and HbA1c significantly improved only with the combination. At baseline, T2D showed a higher total bacterial load and abundance of Bacillota than controls. The prevalence and proportion of bacterial species profoundly differed between the groups, revealing a urinary dysbiosis in T2D. A different effect of Empagliflozin alone or combined with Linagliptin on microbial populations was observed: Empagliflozin increased the total bacterial load of Bacillota and Aerococcus, while the combination therapy restored a microbial community similar to that of controls, further reducing the prevalence of potential urinary pathogens. CONCLUSIONS:In T2D subjects, the combination of Empagliflozin and Ligandliptin might help in restoring a normal composition of the urinary microbiota, likely improving compliance and persistence in therapy with SGLT2 inhibitors.

Semaglutide exerts metabolic effects and cardiovascular protection in type 2 diabetes (T2D), also acting on hepatic steatosis and inflammation. No data are, so far, available on the effect of semaglutide on oxidative stress, neither a comparison of injective (InjS) and oral (OrS) formulations has been performed in subjects with T2D and liver steatosis. In a real-life, open label, prospective study we compared standard doses of InjS and OrS in targeting liver inflammation and fibrosis and systemic markers of inflammation and oxidative stress by consecutively prescribing InjS or OrS formulation in a 2:1 ratio to sixty T2D + MASLD subjects (T0), observing them for 6 months (T1). Anthropometry, biochemistry and transient elastography (TE) data were collected; hormones, inflammatory cytokines and peroxidation products were measured. At baseline, InjS and OrS subjects were similar, except for waist circumference, liver enzymes and Controlled Attenuation Parameter (CAP), a measure of liver steatosis (InjS > OrS, all p < 0.05). Differences emerged in T0-T1 variation between the formulations in HbA1c, lipid profile, blood pressure. CAP significantly decreased only in InjS. GLP-1 quite similarly increased; insulin, glucagon and GIP did not vary. InjS and OrS did not modify TNFα, IL-10 (an anti-inflammatory cytokine) and MCP-1, while IL-18 was reduced only by InjS. When exploring oxidative stress, AGEs were unaffected, Thiobarbituric acid reactive substances decreased in InjS, 4-Hydroxynonenal was reduced in OrS. In T2D + MASLD subjects, InjS, better than OrS, improves metabolic control; a significant reduction of IL-18 by InjS, and a mild anti-oxidative effect of both formulations are reported for the first time.

BACKGROUND AND AIMS:Cardiovascular disease continues to be the leading cause of death worldwide, with atherosclerotic cardiovascular disease (ASCVD) being a major contributor. Elevated low-density lipoprotein cholesterol (LDL-C) levels are an important risk factor, which led to updated guidelines from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) in 2019 recommending lower LDL-C goals for patients at high- and very high-risk. However, many patients do not achieve the recommended LDL-C levels. The SANTORINI study was initiated to evaluate lipid management across Europe. This report presents the results of the 1-year follow-up of the Italian cohort. METHODS AND RESULTS:The study included 2095 patients, with 1993 having 1-year follow-up data. At baseline, 32 % of patients were not receiving lipid-lowering therapy (LLT), decreasing to 2.1 % at follow-up. Monotherapy use increased from 34.2 % to 41.0 %, while combination therapy use increased from 33.8 % to 55.5 %, particularly with high-intensity statin and ezetimibe combinations. LDL-C levels decreased from 2.5 to 1.9 mmol/L overall, with a greater reduction in very high-risk patients. The proportion of patients achieving LDL-C goals increased from 20.8 % to 35.0 %. Cardiovascular events were more frequent in very high-risk patients, with 11 cardiovascular deaths and 80 major adverse cardiovascular events (MACE). CONCLUSION:The Italian cohort of the SANTORINI study demonstrated improved LLT usage and LDL-C management, with a shift towards combination therapy. Despite these improvements, only one-third of patients achieved guideline-recommended LDL-C goals, highlighting the need to further optimise lipid-lowering strategies to reduce cardiovascular risk. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04271280.

BACKGROUND AND AIMS:Bempedoic Acid (Bemp-Ac) is able to reduce LDL cholesterol and cardiovascular events in hypercholesterolemic subjects with a wide risk profile, and is the recommended first line therapy when statins are not tolerated. We explored its efficacy, tolerability, metabolic, systemic and liver anti-inflammatory effects in non-diabetic individuals. METHODS AND RESULTS:Twenty-five statin-intolerant subjects were treated for three months with Bemp-Ac 180 mg/day. Metabolic profile, hormones regulating glucose metabolism and inflammatory markers were measured. Liver status was assessed through Fibroscan. Data were compared with those obtained in twelve subjects treated with Ezetimibe 10 mg/day, following the same protocol. Bemp-Ac reduced total cholesterol by about 25 %. Kidney function did not vary. The relevant anti-inflammatory effect of Bemp-Ac was confirmed by the significant improvement of liver condition (reduced CAP and LS, p = 0.042 and p = 0.008 respectively), persisting after adjustment for confounders; a reduction in white blood cells and cytokines levels was also observed. A detailed evaluation of glucose metabolism unveiled a significant reduction of GLP-1 and insulin, while glucagon and GIP were not influenced by the treatment with Bemp-Ac. CONCLUSION:Beside its hypolipidemic effects, Bemp-Ac reduces liver steatosis and inflammation and modulates glucoregulatory hormones in statin-intolerant, non-diabetic individuals.

AIMS:To investigate the independent association of albuminuria within the normoalbuminuric range with all-cause mortality in normoalbuminuric people with type 2 diabetes with and without chronic kidney disease (CKD). MATERIALS AND METHODS:This observational, prospective, multicentre, cohort study enroled 15,773 individuals with type 2 diabetes in 2006-2008. At baseline, albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR) were assessed together with cardiometabolic risk profile, treatments, complications, and comorbidities. All-cause mortality was verified on 31 October 2015. RESULTS:Of the 15,656 participants (99.3%) with valid information on vital status, 11,460 (71.2%) were normoalbuminuric, 9984 (87.1%) without and 1476 (12.9%) with CKD. Normoalbuminuric individuals were stratified into three (< 5, 5-15, and > 15 mg·day-1) or two (< 10 and 10-29 mg·day-1) AER subcategories. When adjusting for age, sex, eGFR, prior cardiovascular disease, cardiovascular risk factors, and treatments, mortality risk was higher in participants with AER 10-29 versus < 10 mg·day-1 (hazard ratio, 1.120 [95% confidence interval, 1.028-1.221], p = 0.009) and 15-29 versus < 5 mg·day-1 (1.243 [1.099-1.406], p < 0.0001). When stratifying by CKD status, the adjusted risk remained significantly increased only for AER 15-29 versus < 5 mg/24 h in individuals with (1.404 [1.111-1.774], p = 0.005) and, to a lesser extent, without (1.167 [1.009-1.350], p = 0.038) CKD. A non-linear association was observed between AER as Log2 transformed continuous variable and mortality. CONCLUSIONS:For the same level of kidney function, higher AER within the normoalbuminuric range was independently associated with all-cause mortality, thus supporting to the use of albuminuria-lowering drugs in people with type 2 diabetes and mildly elevated albuminuria. TRIAL REGISTRATION:ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Background:Obesity is a leading risk factor for chronic kidney disease, with glomerular hyperfiltration as one of its earliest manifestations. However, absolute glomerular filtration rate (GFR) does not distinguish well between a pressure-driven hyperfiltration and the physiological forms. Insulin resistance and endothelial dysfunction have been proposed as key correlates of maladaptive renal haemodynamics, but their interplay remains unclear. Methods:Cross-sectional pilot study involving 27 adults with severe obesity (mean body mass index of 43.9 kg/m²). Measured GFR (mGFR) was assessed by iohexol plasma clearance and effective renal plasma flow (ERPF) by 123I-ortho-iodohippurate clearance. A hyperfiltration index (P-score) was derived as the standardized difference between filtration fraction and effective renal plasma flow with higher values reflecting a maladaptive phenotype. Endothelial function was assessed by brachial artery flow-mediated dilation and insulin sensitivity by oral glucose insulin sensitivity. Results:Participants were stratified into tertiles of P-score. Across tertiles, mGFR did not differ, but ERPF declined (756 ± 113 vs 505 ± 130 mL/min, P = .001) and of filtration fraction increased (16 ± 3% vs 26 ± 5%, P = .001) from the lowest to the highest tertile. Insulin sensitivity significantly decreased with higher P-score (384 ± 50 vs 308 ± 33, P = .019). Endothelial function was reduced in the highest vs lowest tertile (3.44 ± 1.49 vs 6.21 ± 1.76%, P = .014), while responses to nitroglycerin did not differ. In univariate analyses, P-score was inversely associated with insulin sensitivity (r = -0.36, P = .036) and endothelial dysfunction (r = -0.40, P = .022), whereas measured mGFR showed no associations. In multivariable models, the link between P-score and insulin sensitivity remained significant after adjustment. Conclusion:A maladaptive phenotype characterized by elevated filtration fraction relative to renal plasma flow clustered with insulin resistance and endothelial dysfunction, whereas mGFR alone failed to capture these relationships. Comprehensive haemodynamic profiling may help to refine risk stratification in obesity.

BACKGROUND AND AIMS:Oral semaglutide and empagliflozin are commonly used for the management of type 2 diabetes (T2D), but head-to-head comparisons in real-world settings are limited. We aimed to emulate the PIONEER-2 trial using electronic health records to compare the effectiveness and persistence of oral semaglutide versus empagliflozin. METHODS:This was a retrospective multicentre study using electronic health records from Italian diabetes clinics. New users of oral semaglutide or empagliflozin were matched 1:2 and followed for up to 18 months. The primary outcome was HbA1c change; secondary outcomes included weight change and treatment persistence. Analyses used mixed models for repeated measures under both treatment policy and trial product estimands. RESULTS:After matching, we included new users of oral semaglutide (n = 105) or empagliflozin (n = 207). Mean age was 65 years, diabetes duration 10 years, baseline HbA1c 7.6%, BMI 29 kg/m2, and 94% were on metformin. Only 28.6% of new users of oral semaglutide reached the 14 mg dose and 31.4% of empagliflozin new users reached the 25 mg dose. HbA1c reduction was significantly greater with oral semaglutide than with empagliflozin (mean difference - 0.35%, p <0.001). Weight loss over time was similar, with oral semaglutide showing a modest advantage at 18 months among persistent patients. Persistence was lower for semaglutide (HR for discontinuation 1.47, p = 0.007). CONCLUSIONS:Under routine care, new users of oral semaglutide achieved better glycaemic control compared with empagliflozin new users, with similar weight loss but lower treatment persistence. These findings support the results of PIONEER-2 and its transferability to clinical practice.

OBJECTIVE:SGLT-2 inhibitors (SGLT-2i) provide good glycaemic control and weight loss, ensuring clinically relevant cardiorenal benefits in subjects with and without type 2 diabetes (T2D); however, their use is related to an enhanced risk of urogenital infections, mainly in female subjects. We performed a prospective observation to assess incidence of urogenital complications in male sex new users of gliflozins. SUBJECTS AND METHODS:In the 2021-2023 years, solely based on clinical indication, we started such therapy in 272 male T2D subjects; follow up visits were performed after about 1 year. RESULTS:At follow up, 90 subjects had discontinued SGLT-2i; 36 of them (40 %) due to onset of urogenital symptoms. We observed 6 cases of phimosis. Subjects who discontinued the treatment due to these side effects had a higher BMI and a better eGFR at baseline and they were less frequently treated with DPP-IV inhibitors. CONCLUSIONS:A proper evaluation of the patient's phenotype might be useful in identifying subjects less prone to develop side effects driving SGLT-2i discontinuation; the combined use of SGLT-2i and DPP-IV inhibitors appears to be associated to a better long-term compliance to therapy in men.

BACKGROUND:Obesity is a critical risk factor for chronic kidney disease and cardiovascular disease. The study aimed to explore the relationship between endothelial function, assessed by flow-mediated dilation (FMD), and kidney function, estimated using cystatin C-based eGFR (eGFRcys), in individuals with severe obesity undergoing bariatric surgery. METHODS:Sixty-five individuals with a BMI >35 kg/m2 scheduled for bariatric surgery were assessed before and 1 year post-surgery. Vascular health was evaluated using FMD, pulse wave velocity and renal resistive index, while kidney function was measured using creatinine-based (eGFRcr) and cystatin C-based (eGFRcys) equations. FMD was calculated using both traditional and allometric scaling methods to account for variations in brachial arterial diameter. RESULTS:Bariatric surgery significantly improved BMI, FMD (p < .001) and eGFRcys (p = .042). Before surgery, eGFRcys was positively correlated with FMD (r = .30, p = .011) and inversely correlated with cf-PWV (r = -.26, p = .020), while eGFRcr showed weaker or non-significant associations with vascular variables. eGFRcys increased post-surgery, correlating positively with improvements in FMD (traditional: r = .26, p = .038; allometric: CI [.19, .82], p = .003). Multivariable mixed models confirmed the robust association between eGFRcys and FMD calculated by allometric scaling, independent of BMI or blood pressure changes. In contrast, eGFRcr showed no significant association with FMD changes. CONCLUSIONS:Bariatric surgery enhances both renal and vascular health in individuals with severe obesity. Cystatin C-based eGFR correlates more strongly with endothelial function improvements than creatinine-based eGFR. These findings highlight the utility of cystatin C as an integrative marker for assessing renal and vascular risk in populations affected by obesity undergoing metabolic surgery.

AIMS:Chronic kidney disease (CKD) is a prevalent and serious complication of type 2 diabetes (T2D). This study aims to evaluate kidney outcomes in a real-world cohort of patients with T2D and CKD who received SGLT2 inhibitors (SGLT2i) or other glucose-lowering medications (GLM). MATERIALS AND METHODS:This retrospective, multicentre study analysed data from patients aged 18-80 years with T2D and CKD, who initiated an SGLT2i or other GLM between 2015 and 2020. The primary outcome was the change in estimated glomerular filtration rate (eGFR) over time. Secondary outcomes included albuminuria changes and adverse kidney events. Propensity score matching was used to balance baseline characteristics between the two groups. RESULTS:After matching (n = 2020/group), patients (100% T2D with CKD) had a mean age of 63 years, BMI 32 kg/m2, HbA1c 8.2%. New-users of SGLT2i exhibited a slower decline in eGFR compared with new users of comparators (mean difference 1.43 mL/min/1.73 m2; p = 0.048). Albuminuria improved significantly more in the SGLT2i group, with a greater likelihood of category improvement (hazard ratio [HR] 1.17; p = 0.007). SGLT2i initiation was associated with a lower incidence of kidney outcomes, including a ≥40% eGFR reduction (HR 0.63; p = 0.004). When the comparison was restricted to SGLT2i versus GLP-1RA (n = 1266/group), the eGFR slope was significantly better with SGLT2i (mean difference 0.62 mL/min/1.73 m2/year; p = 0.046). CONCLUSIONS:In this large, real-world cohort, initiation of SGLT2i was associated with a significantly slower decline in kidney function and improved albuminuria compared with other diabetes drugs, including GLP-1RA. These findings support SGLT2i as the most effective T2D treatment to slow CKD progression.

Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools for understanding such effects, providing a comprehensive look at how SGLT2 inhibitors might change the metabolic landscape beyond their primary glucose-lowering action. We investigated changes in plasma metabolomic/lipidomic profile and urinary excretion of metabolites that could occur independent of increased diuresis. A two-armed, parallel-design, randomized clinical trial was conducted in subjects with type 2 diabetes and hypertension who received treatment with DAPA 10 mg/day or hydrochlorothiazide 12.5 mg/day for four weeks. Lipidomics and metabolomics were performed by high resolution mass spectrometry in fasting plasma and 24-hour urine samples collected before and after treatment. Compared to hydrochlorothiazide, DAPA significantly increased plasma isoleucine, methionine, citrate, β-hydroxybutyrate and decreased lactate. DAPA induced plasma lipid remodeling towards a significant raise in free fatty acids (FFAs) and some sphingomyelins and lysophosphatidylcholines containing these fatty acids. A significant change was observed in plasma medium- and short-chain acylcarnitines, positively correlated with changes in plasma FFAs and β-hydroxybutyrate. In addition, DAPA, but not hydrochlorothiazide, significantly increased 24-h urinary excretion of several amino-acids, lactate, TCA cycle metabolites, β-hydroxybutyrate and electrolytes, except for a decrease in malate excretion. DAPA treatment has major effects on the plasma lipidomic and the urine metabolomic profiles, with significant increased renal excretion of several metabolites, especially amino-acids, independently of increased diuresis. These data offer insights into the complex metabolic pathways leading to kidney protection by SGLT2 inhibitors. European Union Drug Regulating Authorities Clinical Trials No. 2015-004164-11.

Type 2 diabetes represents a growing challenge for global public health. Its prevalence is increasing worldwide, and, like obesity, it affects progressively younger populations compared to the past, with potentially greater impact on chronic complications. Dual glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists are among the new pharmacological strategies recently developed to address this challenge. Tirzepatide, characterized by its ability to selectively bind and activate receptors for the intestinal hormones GIP and GLP-1, has been tested in numerous clinical studies and is already currently authorized in several countries for the treatment of type 2 diabetes and obesity. In this context, the aim of the present document is to summarize, in the form of a narrative literature review, the currently available data on the main mechanisms of action of GIP/GLP-1 co-agonists and the clinical effects of tirzepatide evaluated in various clinical trials.