BACKGROUND Functional vitamin B12 deficiency, also known as metformin-associated cobalamin deficiency, can occur in patients receiving metformin due to impaired gastrointestinal absorption of vitamin B12. This condition can coexist with diabetic neuropathy and may result in impaired myelin formation in the spinal cord and peripheral nerves, leading to subacute combined degeneration of the spinal cord. This report describes a patient with diabetes mellitus and metformin-associated functional vitamin B12 deficiency who presented with subacute combined degeneration of the spinal cord and gastrointestinal symptoms. CASE REPORT A 57-year-old man with a 1-year history of metformin therapy for type 2 diabetes mellitus presented with anorexia, vomiting, weight loss, and gait ataxia. Neurological examination revealed impaired superficial sensation at the T10 to L1 level and bilaterally diminished patellar reflexes. Despite a normal serum vitamin B12 level, further metabolic evaluation revealed a substantially elevated homocysteine level. Electromyography demonstrated peripheral neuropathy in the right upper limb, involving both motor and sensory axons. Spinal magnetic resonance imaging showed characteristic T2 hyperintensity of the dorsal columns. Based on these findings, a definitive diagnosis of subacute combined degeneration was made. The patient was promptly treated with high-dose intramuscular vitamin B12 supplementation and supportive care, resulting in clinically significant improvement in subsequent weeks. CONCLUSIONS This case of metformin-associated cobalamin deficiency with subacute combined degeneration of the spinal cord highlights the importance of monitoring vitamin B12 status and neurological symptoms in patients with metformin-treated diabetes.

BACKGROUND: Continuous glucose monitoring (CGM) provides real-time glucose data, aiding diabetes management. Identifying glucose patterns is difficult for patients due to data overload, hindering self-management. This study aimed to systematically identify glucose patterns using Accu-Chek SmartGuide and quantify their impact on glucose management. METHODS: This retrospective, observational analysis included real-world CGM data from 3379 individuals with type 1 diabetes (T1D; N = 2198) or type 2 diabetes (T2D; N = 1181), encompassing 23 486 valid user-weeks. An algorithm identified 29 predefined glucose patterns weekly. Pattern prevalence, demographic influence, persistence, their attribution to time above range/time below range (TAR/TBR) as well as their potential impact on time in range (TIR) in case of pattern resolution were analyzed. RESULTS: Resolving glucose patterns, defined as repeatedly occurring glucose events, showed varying potential for glycemic improvement. Cumulatively, actionable patterns contributed significantly to total TAR (T1D: 66.2 ± 14.7%, T2D: 58.0 ± 14.3%) and TBR (T1D: 56.3 ± 2.6%, T2D: 42.2 ± 1.4%). For instance, resolving the day-time hyperglycemia pattern could improve TIR by up to +10.72% (4.26, 16.9) in T1D and +5.16% (0.0, 12.92) in T2D, addressing an average of 9.33 (8.0, 10.75) events per week in T1D and 9.29 (8.0, 10.67) in T2D. CONCLUSION: The majority of glucose excursions in T1D and T2D can be explained by recurring glucose patterns. Detecting these actionable patterns provides an opportunity to improve TIR. Targeting therapy and behavior change toward resolving these patterns is a critical step toward more personalized diabetes management.

BACKGROUND: Several reports have indicated an association between insulin resistance and hyperferritinemia, and a recent consensus statement has suggested the term metabolic hyperferritinemia (MHF) for patients with metabolic syndrome and increased serum ferritin. The objective of this study was to examine the association between serum ferritin levels and insulin resistance in an unselected Norwegian population. METHODS: Two thousand people were randomly selected from the public registry in one municipality in Nord-Trøndelag County, Norway. Of the respondents, 1115 completed a screening glucose tolerance test to determine the prevalence of impaired glucose tolerance (IGT)/type 2 diabetes mellitus (T2DM), and these individuals were then selected for further examination. A control group comprising 100 age- and gender-matched individuals with normal glucose tolerance and CRP less than 5 was retrospectively generated from the same cohort. RESULTS: One hundred and seventy-six people were diagnosed with impaired glucose tolerance or diabetes mellitus type 2 (IGT/T2DM), and 17 (10%) of these patients had elevated ferritin levels according to the MHF definition. In the control group with normal glucose tolerance, 11% also had hyperferritinemia based on the same ferritin cut-off. Multiple regression revealed a significant association between serum ferritin, male sex, 2-hour glucose value after the glucose load and waist circumference among the patients with IGT/T2DM, while there was no association with age or transferrin saturation. CONCLUSIONS: This study demonstrated a prevalence of metabolic hyperferritinemia in one out of ten people with IGT/T2DM; however, a comparable level of serum ferritin was also detected in the matched control group. Only one person in the IGT/T2DM group had ferritin levels higher than 550 mmol/L. Thus, hyperferritinemia is prevalent in this unselected Norwegian cohort. A relationship between s-ferritin and metabolic syndrome parameters was found in patients with IGT/T2DM, but hyperferritinemia is likely not related to iron overload.

BACKGROUND: The predicted skeletal muscle mass index (pSMI), derived from the serum creatinine-to-cystatin C ratio (CCR), has emerged as a novel biomarker for predicting the onset of type 2 diabetes mellitus. However, its application remains primarily limited to East Asian populations, and the relationship between pSMI and mortality in general populations remains unclear. Therefore, this study aimed to investigate the association between pSMI and all-cause mortality in a nationally representative US adult population. METHODS: We analyzed data from three cycles (1999-2004) of the National Health and Nutrition Examination Survey (NHANES). pSMI levels were analyzed both as a continuous variable and categorized into tertiles. To assess the association between pSMI and all-cause mortality, we performed multivariable Cox regression, restricted cubic spline (RCS) analysis, and Kaplan-Meier survival analysis. RESULTS: During a median follow-up of 193.2 months (2217 deaths), multivariable-adjusted analyses revealed that higher pSMI levels were significantly associated with reduced all-cause mortality (HR 0.76, 95% CI 0.72-0.80; p < 0.001). Compared to the lowest tertile (T1:4.98-7.83), T2 (7.84-9.18) and T3 (9.19-19.24) showed progressively lower mortality risks (T2: HR 0.79, 95% CI 0.67-0.94, p = 0.009; T3: HR 0.66, 95% CI 0.50-0.88, p = 0.004). Restricted cubic spline analysis demonstrated an L-shaped association (p for non-linear = 0.003) with an inflection point at 10.0 (HR 0.632, 95% CI 0.543-0.721; p < 0.001). Sex-stratified analyses revealed inflection points at 10.5 (males) and 7.6 (females). Kaplan-Meier analysis confirmed significantly improved survival with higher pSMI levels (all p < 0.001 for total population, males and females). CONCLUSIONS: This study identifies pSMI as an independent predictor of lower all-cause mortality, revealing a nonlinear L-shaped association with a distinct threshold effect. The protective relationship remains consistent across both sexes, though with differing inflection points. These findings highlight the clinical importance of assessing skeletal muscle mass for mortality risk stratification.

The decade from 2016 to 2026 has witnessed an extraordinary transformation in cardiometabolic medicine, propelled by the maturation of cardiovascular outcome trials (CVOTs). What began as regulatory requirements to establish cardiovascular safety for novel glucose-lowering agents has evolved into a robust body of evidence demonstrating profound cardiorenal protective effects-often extending beyond diabetes itself. Landmark trials such as EMPA-REG OUTCOME, LEADER, SELECT, SURPASS-CVOT, and VESALIUS-CV have not only redefined therapeutic priorities but have also catalyzed a conceptual shift from glucocentric management to an integrated cardiorenal metabolic (CRM) framework. This narrative review traces the epidemiological imperatives driving this evolution, chronicles the historical trajectory of CVOTs, synthesizes key findings across major pharmacological classes, and reflects on emerging therapies and risk markers that are shaping the precision-medicine paradigm of 2026.

OBJECTIVE: To evaluate the predictive utility of the initial lactate-to-albumin ratio (LAR) measured within 24 h of admission for in-hospital all-cause mortality in critically ill patients with congestive heart failure (CHF) and diabetes mellitus (DM). METHODS: A retrospective cohort study was performed using the Medical Information Mart for Intensive Care IV (MIMIC-IV; n = 960) and the eICU Collaborative Research Database (eICU-CRD; n = 1,850). Kaplan-Meier curves, Cox regression, restricted cubic splines (RCS), subgroup analyses, and five machine learning models were applied, with predictive performance assessed via receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA). RESULTS: The highest LAR quartile (Q4) was associated with higher in-hospital mortality (MIMIC-IV: 50.83%; eICU-CRD: 29.71%) than lower quartiles (all P < 0.001). LAR was identified as an independent predictor of in-hospital mortality (MIMIC-IV: HR = 1.878, P = 0.009; eICU-CRD: HR = 3.141, P < 0.001). A nonlinear positive association between LAR and in-hospital mortality was demonstrated by RCS (P < 0.001), with inflection points at 2.73 in MIMIC-IV and 2.50 in eICU-CRD. For both outcomes, higher discriminative performance was observed for LAR than for lactate alone in both cohorts. Model performance was further improved when incorporating into machine learning models. CONCLUSION: Initial LAR is a reliable predictor of in-hospital mortality in critically ill CHF-DM patients.

Type 2 diabetes mellitus (T2DM) and prostate cancer are closely linked, affecting overlapping age groups of predominantly male populations. Flutamide (FLU) is metabolized in the liver to hydroxyflutamide (OHF), exerting anti-androgenic effects and is mainly used for prostate cancer treatment. During its use, occasional adverse reactions such as elevated blood glucose and worsening conditions in T2DM patients have been observed, but the cause remains unknown. This study aims to investigate the effects and mechanisms of FLU on hepatic insulin resistance under T2DM conditions. In vitro, a primary mouse hepatocyte model of insulin sensitivity impairment induced by high glucose (HG) was established to observe the effects of FLU/OHF on cellular lipid accumulation, reactive oxygen species (ROS) production, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) signaling, and insulin signaling. NLRP3 inhibitors, ROS scavengers, and hepatocytes from Nlrp3-knockout mice were used to explore the mechanisms of FLU. In vivo, a high-fat diet (HFD)/streptozotocin (STZ) induced-T2DM mouse model was established to observe the effects of FLU gavage on glucose and lipid metabolism, insulin sensitivity, and histopathology. The results showed that FLU exposure exacerbated lipid accumulation, ROS production, over-activation of NLRP3 signaling, and impaired insulin signaling in HG-treated hepatocytes. Inhibition of NLRP3, scavenging of ROS, or knockout of Nlrp3 eliminated the above effects of FLU/OHF. FLU exacerbated glucose and lipid metabolism disorders in HFD/STZ induced-T2DM mice, increased hepatic insulin resistance, and activated the hepatic NLRP3 signaling pathway. The results of this study suggest that FLU treatment is associated with exacerbated hepatic insulin resistance in mice with T2DM, an effect that may be mediated through ROS overproduction and activation of NLRP3 signaling.

BACKGROUND: The systematic review aimed to assess the effects of GLP-1 receptor agonists (GLP-1 RA) and dual GLP-1/GIP agonists on weight loss and body composition in individuals with overweight or obesity, with or without type 2 diabetes mellitus. METHODS: The study protocol was registered in PROSPERO (CRD420251002447). A systematic search of PubMed, Scopus, and Web of Science was conducted up to December 2024 according to PRISMA guidelines. Following the predefined inclusion and exclusion criteria, 36 studies were included in this systematic review and underwent qualitative analysis. In addition, 24 studies met the criteria for quantitative synthesis (meta-analysis). Data were pooled using random-effects models with subgroup analyses by drug type and treatment duration (3, 6, and 12 months). RESULTS: GLP-1 RA treatment consistently reduced body weight, BMI, and waist circumference across all time points. At 3 months, mean body weight decreased by approximately 9%, accompanied by marked reductions in fat mass and visceral adipose tissue. At 6 months, weight reduction averaged 5%, with semaglutide, liraglutide, and exenatide showing comparable effects, while lean mass remained largely preserved. At 12 months, weight loss persisted at around 4%, with variability between agents, most notably liraglutide. Across studies, fat mass decline predominated, whereas reductions in lean body mass were modest. CONCLUSION: GLP-1 RAs provide clinically meaningful weight loss primarily through selective fat mass reduction, with relative preservation of lean tissue, supporting their role in achieving "quality" weight loss. Differences between agents highlight the importance of individualized treatment strategies, complemented by nutritional and exercise interventions to optimize long-term outcomes.

PFAS are a group of persistent organic pollutants, that bioaccumulate and are associated with negative health effects. Reviews have suggested that the most critical effects of PFAS are on the immune system, but little is known of effects on development of autoimmunity. Our objective was to map and summarize available evidence concerning exposure to any PFAS and development/presence of autoimmunity, in humans and animals. We assessed studies reporting potential associations between PFAS exposure and autoimmune disease and/or autoantibodies. We searched MEDLINE, Embase, CENTRAL, Scopus, and Web of Science (02.15.2024) and conducted complimentary searches. Results were presented descriptively and we categorized autoimmune diseases and autoantibodies into relevant outcome groups. 51 studies were included, distributed in the following groups: Autoimmune thyroid disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, celiac disease, other diseases and autoantibodies. Cross-sectional studies were most common, limiting opportunities for causal inference. 33 studies showed associations between higher PFAS and increased risk of autoimmunity, while nine studies found lower PFAS associated with increased autoimmunity risk. The results suggest that PFAS have negative health impacts with strongest evidence for celiac and inflammatory bowel disease, weaker evidence for rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes mellitus. No clear indications of association with autoimmune thyroid disease. The majority of the studies showed an association between PFAS and autoimmunity. There is a need for more longitudinal and dose-response studies, to improve our understanding of individual autoimmunity outcomes in the future.Protocol registration: OSF.io ( https://doi.org/10.17605/OSF.IO/3FEVQ ).

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure (HF), yet comparative effectiveness between individual agents in heart failure with mildly reduced ejection fraction (HFmrEF) remains limited.We conducted a retrospective cohort study using the TriNetX Global Collaborative Network electronic health record database. Adults (≥18 years) with HF and left ventricular ejection fraction (LVEF) 41-49% initiating empagliflozin or dapagliflozin between September 1, 2021 and September 1, 2022 were included. Propensity score matching (1:1) balanced demographics, comorbidities, medications, and laboratory values, yielding 1,386 patients per group. Outcomes were assessed over 1 year after treatment initiation and included all-cause mortality, hospitalization, HF exacerbation, and urinary tract infection (UTI). Risk analyses and Kaplan-Meier survival analyses with hazard ratios (HRs) were performed.In the matched cohort, empagliflozin was associated with significantly lower hazards of hospitalization (HR 0.54, 95% CI 0.49-0.60), HF exacerbation (HR 0.63, 95% CI 0.55-0.71) and UTI (HR 0.70, 95% CI 0.55-0.90) compared with dapagliflozin. All-cause mortality was numerically lower with empagliflozin but did not reach statistical significance (HR 0.86, 95% CI 0.67-1.10). In conclusion, in this large real-world HFmrEF population, empagliflozin was associated with lower hazards of hospitalization, HF exacerbation, and UTI compared with dapagliflozin, with no significant difference in mortality. These findings suggest potential heterogeneity in clinical effectiveness among SGLT2 inhibitors in HFmrEF and warrant confirmation in prospective comparative studies.

Metabolic syndrome (MetS) symbolises a cluster of interrelated risk factors including central obesity, dyslipidemia, insulin resistance and hypertension, those significantly increase the risk of cardiovascular diseases (CVD). Individuals with a MetS have a two- to fourfold greater risk of coronary artery disease, stroke, myocardial infarction, and heart failure. The pathophysiology of cardiovascular complications in MetS is multifactorial, driven by visceral obesity, insulin resistance, atherogenic dyslipidemia, endothelial dysfunction, oxidative stress, low-grade chronic inflammation, and prothrombotic states. They accelerate the vascular stiffness, atherosclerotic and thrombotic cascades, eventually increasing CVD related morbidity and mortality. Emerging evidences also associates gut microbiota-derived metabolites, mitochondrial dysfunction, and epigenetic alterations as novel contributors. Pharmacotherapy in MetS mainly focuses to control the different components to prevent cardiovascular complications. Antihypertensives, including ACE inhibitors and angiotensin receptor blockers (ARBs) provide vascular protection with beneficial effects on other metabolic conditions. Calcium channel blockers have the protective effects on cardiovascular complications without any adverse action on other metabolic abnormalities. Newer antidiabetic agents such as GLP-1 receptor agonists and SGLT2 inhibitors demonstrate cardioprotective benefits independent of glycemic regulation. Statins, fibrates, ezetimibe, PCSK9 inhibitors, and omega-3 fatty acids are key in managing dyslipidemia. Antiplatelet agents, particularly aspirin and P2Y12 inhibitors, reduce thrombotic risk. Future perspectives highlight anti-inflammatory therapies, endothelin and mineralocorticoid receptor antagonists, dual RAS-neprilysin inhibitors, gut microbiota-targeted interventions, and personalized medicine approaches as promising strategies. Thus, an integrated understanding of pathogenesis and pharmacotherapy is vital to mitigate the growing global burden of MetS-related cardiovascular complications.

INTRODUCTION: The number of kidney biopsies performed in patients with diabetes has increased rapidly over the last two decades. However, the overall value of the biopsy has been questioned because any coexisting non-diabetic kidney disease (NDKD) is not identified in many patients. Here, we quantify the frequency of identifying NDKD and examine clinical indications, demographic factors, and histologic parameters that increase the odds of finding NDKD and the impact on developing end stage kidney disease. METHODS: A retrospective analysis of clinical and pathologic parameters of 49,075 biopsied patients with diabetes with and without diabetic nephropathy (DN) from 2001-2024 was performed. Data from the United States Renal Data Service were examined to determine the impact of a NDKD on disease progression to end stage kidney disease. RESULTS: NDKD was found in 58.8% of patients with diabetes who underwent kidney biopsy, including 35.9% without concurrent DN and 22.9% as a second diagnosis in DN. Acute kidney injury and acute nephritic syndrome had greater odds of a NDKD diagnosis in patients with DN. The youngest (under 30 years) and oldest (60 years and older) patients had a higher prevalence of NDKD. Higher chronicity on biopsy was associated with a lower prevalence of NDKD diagnosis. Patients with NDKD were 2.56-fold less likely to develop end stage kidney disease compared to patients with DN alone. CONCLUSION: This is the largest analysis examining prevalence of a NDKD in patients with diabetes and the impact of biopsy indication on finding a second diagnosis in biopsy-proven DN. The objective is to provide nephrologists with guidance in when to perform a biopsy based on the odds of finding a NDKD related to the patient's clinical indication. Given the high prevalence of NDKD, our study shows that kidney biopsy remains a critical tool in the care of diabetic patients.

Despite similarities in the pathophysiology of type 2 diabetes mellitus in humans and cats, the specific role of the gut microbiota in feline diabetes remains unclear. We determined the ileal microbiota composition of lean, overweight, and diabetic cats, and assessed the association of the ileal gut microbiota with key markers of insulin signaling and glucose regulation in the pancreas and muscle, and liver fat content. Ileal contents were collected from a client-owned population of total 32 (lean, n=13; overweight, n=8; diabetic=11) cats, and DNA extracted for 16S rRNA analyses. Results revealed significant differences in beta diversity between lean and diabetic cats, indicating distinct microbial community compositions. At the phylum level, relative abundance of Bacteroidota decreased in diabetics compared to lean and overweight cats. At the genus level, Alloprevotella was elevated in lean compared to overweight and diabetic cats. Further, Turicibacter was increased in treated diabetics compared to other groups. Partial least squares regression unveiled distinct microbial and tissue markers associated with diabetic status. Lean and overweight cats were associated with higher relative abundances of the genera Sutterella and Oscillibacter, and elevated muscle insulin receptor substrate-1, and pancreas insulin and insulin receptor mRNA levels. Conversely, diabetic cats were associated with higher relative abundances of the genera Peptostreptococcus and Escherichia-Shigella, and a higher liver fat percent. Together, these findings indicate that diabetic and overweight cats have distinct compositional differences in ileal microbiota, and that alterations in enteric microbial diversity and composition are associated with markers of insulin signaling in feline diabetes.

BACKGROUND: Diabetes mellitus (DM) is associated with an elevated risk of cognitive decline, though trajectories are heterogeneous. This study investigated whether a novel, clinically applicable measure of brain network integrity, the Morphometric Inverse Divergence (MIND) network, could differentiate and predict cognitive progression in DM. METHODS: We retrospectively analyzed 101 DM participants (41 cognitively normal, 60 with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative, classifying them into stable (DM_S, n=64) or decline (DM_D, n=37) group based on longitudinal diagnostic conversion. MIND networks were constructed from multiple cortical morphological features derived from T1-weighted MRI and graph theory measurements were further analyzed. Using network-based statistics (NBS) and its extension NBS-predict, we tested whether subject-level connectomes were associated with long-term DM-related cognitive worsening. RESULTS: At baseline, DM_D individuals exhibited significantly lower cognitive scores and a focal subnetwork of disrupted morphometric similarity, primarily involving temporal regions. Longitudinally, DM_D individuals showed a more targeted pattern of network change that significantly altered global efficiency, local efficiency, and path length exclusively, while stable individuals, the brain underwent more widespread changes. Crucially, baseline MIND networks significantly predicted long-term cognitive progression status (accuracy = 63.1%, p = 0.034). The predictive subnetwork was rich in transmodal connections involving the temporoparietal, default mode, and limbic networks. CONCLUSION: These findings indicate that cognitive decline in DM is preceded by specific disruptions in the brain's structural connectome. The MIND method shows promise as a network-based biomarker for identifying at-risk individuals and predicting cognitive trajectory, potentially driving advanced network analyses toward real-world applicability.

OBJECTIVE: We aimed to assess the relationship between postnatal left ventricular mass (LVM) z-score and clinical outcomes among infants of diabetic mothers (IDMs). STUDY DESIGN: We performed a retrospective cohort study of infants born to mothers with pregestational diabetes mellitus. The primary predictor was postnatal LVM z-score; the primary outcome was hospital length of stay (LOS). A secondary outcome was maximum glucose infusion rate (GIR) during hospitalization. RESULTS: There were 112 infants who met the inclusion criteria (52% male). After multiple linear regression, there was a weak relationship between LVM z-score and LOS (R = 0.055;  = 0.002); the relationship between LVM z-score and maximum GIR was somewhat stronger (R = 0.205,  < 0.001). CONCLUSION: LVM measured by echocardiography during the first week of life is weakly but independently associated with total LOS and maximum GIR among infants born to mothers with pregestational diabetes mellitus. The impact of left ventricular hypertrophy in IDMs on clinical outcomes should be considered in clinical context. KEY POINTS: · Increased LVM is marginally associated with longer LOS in IDMs.. · Elevated LVM is linked to higher maximum GIR in IDMs.. · Higher LVM may reflect illness severity in IDMs..

AIM: To investigate the appropriateness of lower doses of loxoprofen in patients with type two diabetes (T2D) with bone fractures/surgeries in comparison to common NSAIDs. METHODS: The current study is a prospective cross-sectional study. A total of 174 patients treated for bone fractures/orthopedic surgeries were recruited from orthopedic outpatient clinics in Amman, Madaba, and University of Jordan Hospital. Risk stratifications were performed for cardiovascular (CV), gastrointestinal (GI), renal, and hepatic complications. We created in-depth comparisons of safety and effectiveness of common NSAIDs in alleviating postoperative/ fracture pain. RESULTS: All NSAIDs showed variable reductions in the numerical pain score (NPS) after four weeks. Loxoprofen was the only NSAID prescribed at lower daily doses of 60-120 mg. Loxoprofen resulted in the most reduction in NPS; the fastest onset of action; the least time to reach peak analgesia; decrease in nocturia and the strongest overall pain relief in bone fractures and postoperative pain, p < 0.05. Celecoxib had the highest variability in pain relief among the agents. CONCLUSION: Lower doses of loxoprofen provide an effective strategy to alleviate postoperative and bone fracture pain and increase patient satisfactions among T2D at lower systemic risks compared to other NSAIDs. Such low dosing approach provides a plausible balanced triad of safety, effectiveness and maximum bone healing which lead to maximum patient satisfaction.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underused in clinical practice, one of the reasons may be the fear of adverse events which have been emphasized during the first years of use. This comprehensive review aims to give an update on the safety and tolerability profile of SGLT2is. AREAS COVERED: An extensive literature search identified randomized controlled trials, observational cohort studies and pharmacovigilance reports that investigated the safety of SGLT2is in patients with type 2 diabetes (T2D), with or without comorbidities or presenting at-risk conditions. EXPERT OPINION: Some adverse events pointed out initially have been confirmed, especially a higher risk of genital infections, though not the initial fear of urinary tract infections. A euglycemic diabetic ketoacidosis remains exceptional in patients with T2D. Volume depletion is a rare event that may be anticipated. Of note, several severe adverse events that led to warnings by regulatory agencies have not been confirmed in further studies: bone fractures, lower-limb amputations, severe perineal infections, acute renal injury. The safety profile of SGLT2is appears globally reassuring even in special at-risk populations. However, data remain rather scarce in patients with severe comorbidities and in very old or frail people, so that caution use is classically recommended.