Abstract

Type 2 diabetes mellitus (T2DM) is often linked to metabolic dysfunction-associated steatotic liver disease (MASLD), a metabolic liver condition defined by excessive lipid deposition within hepatocytes and is frequently accompanied by increased circulating liver enzyme levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as linagliptin, may exert pleiotropic effects on hepatic metabolism; however, their effects on liver enzyme profiles remain uncertain. This systematic review and meta-analysis aimed to evaluate the impact of linagliptin on liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT),alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), in patients with Type 2 diabetes mellitus (T2DM). A systematic literature search was performed across five electronic databases up to 11 May 2026 following the PRISMA 2020 guidelines. Randomized controlled trials and cohort studies were included, and pooled mean differences (MDs) were calculated using random-effects models. Eight studies involving 1262 participants were analyzed. Linagliptin was associated with a modest reduction in aspartate aminotransferase AST (MD −1.58 U/L, 95% CI −2.85 to −0.31) with low heterogeneity, whereas the change in alanineaminotransferase (ALT) was not statistically significant (MD −1.86 U/L, 95% CI −4.14 to 0.42), and substantial heterogeneity was observed. No significant effects were observed for gamma-glutamyl transferase (GGT), while evidence for alkaline phosphatase (ALP) was limited to a single study and was insufficient to determine the effect of linagliptin. Overall, linagliptin demonstrated limited and inconsistent effects on liver enzyme profiles.

Abstract

Introduction: 

Sodium-glucose cotransporter-2 (SGLT2) inhibitors haveemerged as an important therapy in heart failure (HF). However, their safety and efficacy in elderly patients remain underexplored, as this group is often underrepresentedin clinical trials.

Aim: 

This study aimed to evaluate safety outcomes and describe changes in clinical parameters following initiation of Sodium-glucose cotransporter 2 (SGLT2) inhibitors in elderly Malaysian patients with heart failure.

Methods: 

A multicentre, single-arm, retrospective cohort study was conducted from January to December 2023 at two Malaysian hospitals. Patients aged ≥65 years initiated on empagliflozin or dapagliflozin were included. Safety outcomes assessed were acute kidney injury (AKI), orthostatic hypotension, genitourinary infections, hypoglycemia, volume depletion, and diabetic ketoacidosis (DKA). Efficacy outcomes included changes in left ventricular ejection fraction (LVEF), glycatedhaemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), and New York Heart Association (NYHA) class. Descriptive statistics and chi-square tests were applied.

Results: 

Among 126 patients (median age 70 years), acute kidney injury (AKI) was the most frequent adverse event (12.1%), followed by orthostatic hypotension (3.0%) and urinary tract infection (1.5%). More than half (51.4%) showed left ventricular ejection fraction (LVEF) improvement, while 38.2% of diabetic patients achieved better HbA1c control. Renal functionimproved or was preserved in 40.7%, and 21.4% demonstrated New York Heart Association (NYHA) class improvement. Significant associations were observed between chronickidney disease (CKD) and acute kidney injury (AKI) (p = 0.003), and between systolic blood pressure (BP) ≤140 mmHg and both eGFR improvement (p = 0.034) and New York Heart Association (NYHA) class improvement (p = 0.029).

Conclusion: 

In this retrospective cohort, Sodium-glucose cotransporter 2 (SGLT2) inhibitor use was associated with observed improvements in selected cardiometabolic and functional parameters, with acute kidney injury being the most frequently recorded adverse event. However, given the single-arm retrospective design and the absence of a comparator group, these observed changes cannot be definitively attributed to Sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy alone and should therefore be interpreted as associations rather than evidence of a causal treatment effect. Careful clinical monitoring remains essential, particularly in patients with underlying renal impairment.

Abstract

Background: 

Sodium-glucose cotransporter 2 inhibitors (SGLT2i),as key therapeutic agents for type 2 diabetes, have in recent years been recognized as potentially exerting europrotective effects on the central nervous system. However, systematic comparative evidence remains lacking regarding whether different Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exhibit differential effects on dementia risk. By conducting a network meta-analysis to compare the association between different Sodium-glucose cotransporter 2 inhibitors (SGLT2i)and the risk of dementia onset, the relative efficacy of each drug in reducing dementia risk is determined.

Methods: 

A systematic search was conducted across databases including PubMed, Embase, Web of Science, and the ochraneLibrary, from their inception to the search cutoff date of 1 December 2025. Randomized controlled trials and observational studies comparing Sodium-glucosecotransporter 2 inhibitors (SGLT2i) with other antidiabetic medications or placebo, and reporting dementia outcomes, were included. A network meta-analysis employing arandom-effects model was conducted. Pooled effect sizes were expressed as hazard ratios with 95% confidence intervals. Relative efficacy among different drugs was ranked using the probability of ranking, whilst heterogeneity andconsistency were assessed.

Results: 

Six cohort studies involving 845,433 patients were included in this analysis. The results of the network meta-analysis indicated that canagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98),Dapagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), and Empagliflozin (HR = 0.69, 95% CrI: 0.55, 0.85) significantly reduced the risk of dementia onset. Empagliflozin had the highest probability of being ranked as the most effective treatment (81.2%). However, no statistically significant differences were observed between empagliflozin and dapagliflozin or canagliflozin in the network comparisons. For Alzheimer’s disease, Dapagliflozin (HR = 0.68,95% CrI: 0.48, 0.96) and Empagliflozin (HR = 0.62, 95% CrI: 0.45, 0.87) also demonstrated significant risk reduction, whilst direct comparisons between Empagliflozin and other agents showed no significant differences. For vasculardementia, Empagliflozin (HR = 0.63, 95% CrI: 0.46, 0.87) and Canagliflozin (HR = 0.71, 95% CrI: 0.48, 0.98) also demonstrated favorable outcomes.

Conclusions: 

The findings of this study indicate that dapagliflozin, empagliflozin, and canagliflozin, particularly empagliflozin, demonstrate significant potential in reducing the incidence ofdementia and related cognitive impairments. Compared with Dipeptidyl peptidase-4 (DPP-4) inhibitors, these agents effectively lower the risk of dementia, Alzheimer’sdisease, and vascular dementia, offering an effective therapeutic option for diabetic patients, particularly the elderly.

Abstract

Background

Alterations in serum calcium (Ca2+) and phosphate (Pi)balance have been associated with poor outcomes in heart failure (HF). However, these data are mostly derived from small observational studies. Moreover, the impact of Sodium-glucose cotransporter 2 (SGLT2) inhibitors on calcium (Ca2+)and phosphate (Pi) levels have not been explored in large, randomized HF trials.

Aims

Using EMPEROR-Pooled data we aim to study the prognostic associations of serum calcium (Ca2+) and phosphate (Pi)in patients with heart failure (HF) and study the impact of empagliflozin on calcium (Ca2+) and phosphate (Pi) levels.

Methods

EMPEROR-Pooled (N=9718) was used to create serum calcium (Ca2+) and phosphate (Pi) categories (quintiles, Q). Cox andmixed-effects models were used.

Results

Mean calcium (Ca2+) levels were 2.35 ± 0.12 mmol/L and phosphate (Pi) 1.14±0.18 mmol/L. Compared to patients with higher calcium (Ca2+) levels (Q5, mean 2.5±0.1 mmol/L), those with lower calcium (Ca2+) (Q1, mean 2.2±0.1 mmol/L) presented more peripheral edema and higher NT-proBNP levels (P<0.05). Low calcium (Ca2+) was modestly associated with a higher risk of cardiovascular death or heart failure (HF)hospitalization. The effect of empagliflozin (vs placebo) on cardiovascular death or heart failure (HF) hospitalization was not influenced by serum calcium (Ca2+) levels (interaction-P>0.1), while the mortality reduction appeared more marked among patients with higher serum calcium (Ca2+)(interaction-P=0.08). Serum phosphate levels were not associated with outcomes and did not influence the effect of empagliflozin (interaction-P>0.1). Empagliflozin induced a minor increase in serum calcium (Ca2+) and phosphate(Pi) levels over time: +0.004 (0.001-0.006) mmol/L (P=0.002),and +0.030 (0.026-0.034) mmol/L (P<0.001), respectively.

Conclusion

Low serum calcium (Ca2+) may be associated with poor outcomes but did not influence the effect of empagliflozinin a statistically significant manner.

Abstract

Objective: 

While glycemic control reduces the progression of diabetic retinopathy (DR), the effects of specific glucose-lowering drugs (GLD) remain incompletely defined. Emerging evidence suggests that sodium-glucose cotransporter‑2 inhibitors (SGLT2i) may confer protective effects on diabetic retinopathy (DR) and diabetic macular edema (DME).

Research design and methods: 

We reviewed human studies comparing sodium-glucosecotransporter‑2 inhibitors (SGLT2i) versus other glucose-lowering drugs (GLD) with primary outcomes of diabetic retinopathy (DR) or diabetic macular edema (DME). Random effects meta-analyses and meta-regression were performed to estimate relative risks (rr) and risk differences (rd) for retinopathy progression.

Results: Of 273 identified studies, 16 met inclusion criteria, comprising 1,785,409 patients. Comparator subclasses included dipeptidyl peptidase-4 inhibitors (DPP-4i), Glucagon Like Peptide 1 -receptor agonists (GLP-1RA), sulfonylureas, and "other" glucose-lowering drugs (GLD). Sodium-glucosecotransporter‑2 inhibitors (SGLT2i) therapy was associated with significantly lower relative risks (rr) of diabetic retinopathy (DR) progression versus all glucose-lowering drugs (GLD) (rr = 0.77;95%CI:0.72,0.82,p < 0.001), and eachof the subclasses. Similar reductions were observed for diabetic macular edema (DME) progression (rr = 0.75;95%CI:0.69,0.82,p < 0.001). Benefits were proportional to baseline rates; for cohorts with a 20% diabetic retinopathy (DR) rate, the absolute risk difference (rd) was approximately 4%. The comparative benefit of Sodium-glucose cotransporter‑2 inhibitors (SGLT2i) was most pronounced versus sulfonylureas than to Glucagon Like Peptide 1 -receptor agonists GLP-1RA and dipeptidyl peptidase-4 inhibitors (DPP-4i).

Conclusions: In patients with established diabetic retinopathy (DR) or diabetic macular edema (DME), Sodium-glucose cotransporter‑2 inhibitors (SGLT2i) may be preferred over dipeptidyl peptidase-4 inhibitors (DPP-4i) and sulfonylureas, whereas choice of Sodium-glucose cotransporter‑2 inhibitors (SGLT2i) versus Glucagon Like Peptide 1 -receptor agonists (GLP-1RA) should be guided by other comorbidities.

Abstract

Aims

Adequate cardiovascular risk control prevents complications. A multifactorial approach for simultaneously managing risk factors is recommended by guidelines. We evaluated cardiovascular risk factors among Dutch diabetes outpatients and described glucose-lowering and cardiovascular prescriptions.

Methods

From the Dutch Pediatric and Adult Registry of Diabetes (DPARD), a cohort of 81,096 patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) was derived from 2017 to 2024.Descriptive statistics reported patient characteristics and the primary outcomes cardiovascular risk targets and medication prescription patterns.

Results

Overall, 3,832 children had type 1 diabetes (T1D),145 children had type 2 diabetes (T2D), 35,934 adults had type 1 diabetes (T1D) and 41,185 adults had type 2 diabetes (T2D). For most cardiovascular risk factors, guideline-recommended targets were met by at least two-thirds of patients, whereas some risk factors had lower attainmentin specific subgroups. HbA1c was the least frequently reached target. The most common medications for type 1 diabetes (T1D) were fast-acting and long-acting insulins. For T2D, these were biguanides, insulins, sulfonylureas, Glucagon Like Peptide 1- agonists (GLP-1 agonists), and Sodium-glucose cotransporter‑2 inhibitors (SGLT2 inhibitors).

ConclusionsThis study shows the extent to which guideline-recommended cardiovascular risk factor targets are met in children and adults with type 1 diabetes (T1D) and type 2 diabetes (T2D), which varies by age group and diabetes type. These findings may refine individually tailored strategies for management of risk factors, particularly HbA1c.

Abstract

Although sodium–glucose co-transporter-2 (SGLT2) inhibitorsprovide cardiorenal benefits, direct comparisons between dapagliflozin and empagliflozin—the two most commonly used and studied agents in this class—remain limited, particularly in patients with advanced chronic kidney disease (CKD). In the current study, we aimed to compare the cardiorenal effectiveness and safety of dapagliflozin versus empagliflozin in adults with type 2 diabetes (T2D) and stage 3B to 5 chronic kidney disease (CKD).

We used the TriNetX network and identified adults with type 2 diabetes and stage 3B to 5 chronic kidney disease (CKD) newly initiating dapagliflozin or empagliflozin. Following a target trial emulation framework, we applied one-to-one (1:1) propensity score matching and Cox proportional hazards models to estimate hazard ratios (HRs) for major adverse kidney events (MAKE), major adverse cardiovascular events (MACE), all-cause mortality, and adverse events.

After matching, 4,361 participants were included per group. The mean age was 67.6–67.9 years and men comprised 45.3–45.9% with a median follow-up duration of 780–790 days. Dapagliflozin users showed comparable hazard ratios (HRs) for major adverse kidney events (MAKE) (1.04; 95% CI: 0.94–1.16), major adverse cardiovascular events (MACE) (1.02; 95% CI: 0.95–1.09), all-cause mortality (0.86; 95% CI: 0.74–1.00),and adverse events (1.03; 95% CI: 0.92–1.14). However, the risk of end-stage kidney disease (ESKD) was higher with dapagliflozin (1.28; 95% CI: 1.11–1.48).

We concluded that in adults with type 2 diabetes (T2D) and advanced chronic kidney disease (CKD), dapagliflozin and empagliflozin demonstrated comparable cardiorenal effectiveness and safety. Dapagliflozin was associated with a modestly higher end-stage kidney disease (ESKD) risk, but this finding warrants cautious interpretation and further study given the observational design and potential residual confounding.

Abstract

The latest Type 2 Diabetes Mellitus (T2DM) management guidelines from the UK National Institute for Health and CareExcellence (NICE; NG28) have raised the profile of sodium-glucose cotransporter-2 inhibitors (SGLT2is) so that they are now the preferred first-line therapy in combination with modified-release metformin (or as monotherapy where metformin is contraindicated or not tolerated) for most individuals.

Previous National Institute for Health and Care Excellence (NICE) recommendations limited use to those with high Cardiovascular Disease (CVD) risk or existing Cardiovascular Disease (CVD) and/or kidney disease for first-line treatment or people with a need for additional glycaemic optimisation at later stages in the pathway. This change brings the guidelines in line with other national and international recommendations regarding sodium-glucose cotransporter-2 inhibitors (SGLT2i) use for the achievement and maintenance of glycaemic targets and lowering of progressive risk for cardiovascular, renal and metabolic (CVRM) complications.

Yet, despite a plethora of evidence supporting the role that sodium-glucose cotransporter-2 inhibitors (SGLT2is) can play in sustaining long-term health outcomes in people with Type 2 Diabetes Mellitus (T2DM), prescribing data from real-world clinical practice show that these therapies are under- prescribed, particularly among those populations most likely to benefit from their use (including individuals with Cardiovascular Disease or high cardiovascular, renal and metabolic risk).

This latest narrative review from the Improving Diabetes Steering Committee examines the place of sodium-glucose cotransporter-2 inhibitors (SGLT2is) within the latest NG28 guidelines and likely reasons for suboptimal sodium-glucosecotransporter-2 inhibitors (SGLT2i) use, providing pragmatic advice on appropriate approaches to initiation and management in daily practice and setting perceived risks intocontext against the potential benefits. Practical tools for healthcare professionals and people with Type 2 Diabetes mellitus are included, and the Committee's previously published sodium-glucose cotransporter-2 inhibitors (SGLT2i) Prescribing Decision Tool for Type 2 Diabetes Mellitus Management has been updated and aligned with the most recent guidelines with the aim of providing a helpful and high-quality quick reference resource.

Abstarct:

Introduction and Objective: Early-onset type 2 diabetes (T2D) is associated with a more adverse cardiometabolic profile and increased cardiovascular (CV) risk. We aimed to characterize cardiovascular risk and subclinical atherosclerosis in young adults with type 2 diabetes (T2D) participating in the YOUNG DIABETES program.

Methods: Observational study including individuals with type 2 diabetes (T2D) diagnosed at ≤50 years and current age ≤55 years enrolled in the YOUNG DIABETES clinical program. Participants underwent clinical and biochemical assessment, cardiovascular (CV) risk estimation (SCORE2-Diabetes), and carotid ultrasound to detect subclinical atherosclerosis.

 Results: A total of 179 participants were included; 37% were women. Median age was 45 years [37-50] and diabetes duration 4 years [1-10]. Active smoking was present in 18% and 25% were former smokers. Median Body Mass Index (BMI) was 30.1 kg/m² [26.5-34.3], Median Glycated Hemoglobin (HbA1c) 7.2% [6.4-8.6], Median Low-Density Lipoprotein Cholesterol (LDL-C) 101 mg/dL [86-125.3], and calculated cardiovascular (CV) risk by SCORE2-Diabetes 5.2% [3.9-7].Carotid ultrasound was performed in 115 participants and identified subclinical atherosclerosis in 31% (20% had 1-2 plaques and 11% ≥3 plaques). Individuals with atherosclerosis were older (49 vs 42.5 years-old, p=0.0001), had longer diabetes duration (8 vs 2.5 years, p=0.0007), and higher HbA1c levels (7.9 vs 7%, p=0.03), No differences were observed by sex, smoking status, Body Mass Index (BMI), lipid profile, or calculated cardiovascular (CV) risk. In multivariate analysis, diabetes duration (OR 1.09 [1.01-1.17] and smoking exposure (OR 1.04 [1.00-1.07]) were independently associated with greater plaque burden.

 Conclusion: In young adults with type 2 diabetes (T2D), in which SCORE2-Diabetes may underestimate cardiovascular risk, the YOUNG DIABETES program enables comprehensivecardiovascular risk stratification including detection of subclinical atherosclerosis. Carotid plaques were independently associated with longer diabetes duration and smoking exposure, highlighting the importance of early and strict glycemic control and smoking avoidance to reduce cardiovascular risk in young-onset type 2 diabetes (T2D).

Abstarct:

Introduction and Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and Sodium-glucose transporter 2 inhibitors (SGLT2i) are crucial components of type 2 diabetes care, especially for adults with Cardio-vascular disease (CVD) or Diabetic kidney disease (DKD). However, early adoption of Glucagon-like peptide-1 receptor agonists GLP-1RA and SGLT2i remains low. Our aim was to evaluate the association between prescription of of Glucagon-like peptide-1 receptor agonists and Sodium–Glucose Cotransporter 2 Inhibitors medications and presence of indications for the drugs among patients with type 2 diabetes and how prescribing patters have evolved between 2016 and 2023. 

Methods: We analyzed Electronic Health Record (EHR) data from adults with type 2 diabetes with one or more indications for Glucagon-like peptide-1 receptor agonists or Sodium–Glucose Cotransporter 2 Inhibitors - 1) Cardio-vasculardisease (CVD) or Diabetic kidney disease (DKD), 2) obesity, or 3) high Glycated Hemoglobin (HbA1c) level above 8% within a large regional health system. We used cluster-robust linear probability modeling with a primary outcome of receiving a Glucagon-like peptide-1 receptor agonists or Sodium–Glucose Cotransporter 2 Inhibitors prescription and predictor of indication for Glucagon-like peptide-1 receptor agonists or Sodium–Glucose Cotransporter 2 Inhibitors therapy. To examine changes over time, we introduced an interaction term of time period, 2016-2018, 2019-2021, and 2022-2023.

Results: We analyzed data from 7,917 adults and 12,667 patient-time-periods. Cardiovascular disease or Diabetic kidney disease increased probability of prescription of either drug by 6.4%, obesity by 12.6%, and high A1c by 16.3% (p<0.001 for all). Cardiovascular disease or Diabetic kidney disease was not associated with acceleration in prescribing rate over time, while obesity significantly accelerated prescribing in the third time period by 7% (p=0.01 for interaction). For the 2022-2023 period, estimated prescription rates were similar for obesity (50.9%) and high A1c (50.7%) but lower for Cardio-vascular disease or Diabetic kidney disease (46.7%).

Conclusion: Adults with type 2 diabetes and Cardiovasculardisease or Diabetic kidney disease had increased prescribing of Glucagon-like peptide-1 receptor agonists and Sodium–Glucose Cotransporter 2 Inhibitors, continue to receive the Glucagon-like peptide-1 receptor agonists and Sodium–Glucose Cotransporter 2 Inhibitors at lower rates than adults with obesity or high A1c. Targeted clinical interventions, such as clinical decision support tools, are needed to ensure that guideline-based prescribing increases to maximize population benefit in high-risk patients with type 2 diabetes.