Anna Solini

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have become foundational therapies for nephroprotection, transforming the management of chronic kidney disease (CKD) beyond the traditional risk factors. This chapter synthesizes evidence from randomized controlled trials and real-world studies demonstrating that SGLT2i consistently reduce albuminuria, slow estimated glomerular filtration rate (eGFR) decline, and lower the risk of hard renal endpoints, including progression to end-stage kidney disease. Early cardiovascular outcome trials first signalled renal benefit as secondary outcomes, which was subsequently confirmed in dedicated renal trials such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, establishing kidney protection in patients with and without type 2 diabetes and across a broad spectrum of eGFR and albuminuria. Heart failure trials further support renal preservation in high cardiorenal-risk populations. Complementary real-world evidence across multiple health systems corroborates trial findings, extending effectiveness to heterogeneous populations, including older adults and nondiabetic CKD. The chapter also reviews emerging data on combination strategies with GLP-1 receptor agonists or finerenone, long-term treatment considerations, and projections suggesting substantial delays in kidney failure with earlier initiation. Collectively, these data support broad implementation of SGLT2i as core disease-modifying therapy in CKD, while highlighting priority areas for future research in underrepresented populations and optimized combination regimens.

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).

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.

Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools

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/m ² , 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 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.

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/m ² , 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 m ² ; 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 m ² /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.