Daily Endocrinology Research Analysis
A network meta-analysis of 99 randomized trials in BMJ found that intermittent fasting strategies achieve weight loss comparable to continuous energy restriction, with small short-term advantages for alternate-day fasting and limited long-term differences. Two large real-world endocrine studies showed that adding SGLT2 inhibitors to insulin therapy reduces cardiovascular and microvascular events versus DPP-4 inhibitors or GLP-1 receptor agonists, while a separate cohort identified higher diabeti
Summary
A network meta-analysis of 99 randomized trials in BMJ found that intermittent fasting strategies achieve weight loss comparable to continuous energy restriction, with small short-term advantages for alternate-day fasting and limited long-term differences. Two large real-world endocrine studies showed that adding SGLT2 inhibitors to insulin therapy reduces cardiovascular and microvascular events versus DPP-4 inhibitors or GLP-1 receptor agonists, while a separate cohort identified higher diabetic ketoacidosis risk with SGLT2 inhibitors among insulin-deficient phenotypes, especially with HbA1c >9% and BMI ≤25 kg/m².
Research Themes
- Intermittent fasting vs continuous energy restriction for weight management
- Real-world effectiveness of SGLT2 inhibitors added to insulin
- Safety and DKA risk stratification with SGLT2 inhibitors in insulin-deficient diabetes
Selected Articles
1. Intermittent fasting strategies and their effects on body weight and other cardiometabolic risk factors: systematic review and network meta-analysis of randomised clinical trials.
Across 99 RCTs, intermittent fasting and continuous energy restriction led to similar weight loss versus ad-libitum diets. Alternate-day fasting conferred a small short-term advantage over continuous restriction (~1.3 kg) and modest lipid improvements over time-restricted eating, but longer-term differences were limited.
Impact: This synthesis provides high-level comparative evidence to guide dietary strategy selection, clarifying modest advantages and limitations of intermittent fasting approaches.
Clinical Implications: Intermittent fasting can be offered as an alternative to continuous energy restriction for weight management, with alternate-day fasting yielding small short-term benefits. Given limited long-term differentials and minimal glycemic differences, individualized choice should prioritize adherence, safety, and patient preference.
Key Findings
- All intermittent fasting and continuous energy restriction strategies reduced body weight versus ad-libitum diets.
- Alternate-day fasting reduced body weight modestly more than continuous energy restriction (mean difference −1.29 kg).
- Alternate-day fasting showed small advantages in lipid profiles over time-restricted eating; long-term (≥24 weeks) advantages were limited.
- No clear differences among strategies for glycemic markers such as HbA1c.
Methodological Strengths
- Network meta-analysis of 99 randomized trials with GRADE assessment.
- Direct and indirect comparisons across multiple fasting modalities and controls.
Limitations
- Heterogeneity in populations, protocols, and durations; few moderate-to-long-term trials.
- Adherence and behavioral co-interventions vary and may confound effects.
Future Directions: Conduct longer-duration head-to-head RCTs comparing intermittent fasting modalities versus continuous restriction with standardized adherence metrics and patient-centered outcomes.
OBJECTIVE: To assess the effect of intermittent fasting diets, with continuous energy restriction or unrestricted (ad-libitum) diets on intermediate cardiometabolic outcomes from randomised clinical trials. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, and central databases from inception to 14 November 2024. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised clinical trials comparing the association of intermittent fasting diets (alternate day fasting, time restricted eating, and whole day fasting), continuous energy restriction, and ad-libitum diets were included. MAIN OUTCOMES: Outcomes included body weight (primary) and measures of anthropometry, glucose metabolism, lipid profiles, blood pressure, C-reactive protein, and markers of liver disease. DATA SYNTHESIS: A network meta-analysis based on a frequentist framework was performed with data expressed as mean difference with 95% confidence intervals (CIs). The certainty of the evidence was assessed using grading of recommendations assessment, development, and evaluation (GRADE). RESULTS: 99 randomised clinical trials involving 6582 adults of varying health conditions (720 healthy, 5862 existing health conditions) were identified. All intermittent fasting and continuous energy restriction diet strategies reduced body weight when compared with ad-libitum diet. Compared with continuous energy restriction, alternate day fasting was the only form of intermittent fasting diet strategy to show benefit in body weight reduction (mean difference -1.29 kg (95% CI -1.99 to -0.59), moderate certainty of evidence). Additionally, alternate day fasting showed a trivial reduction in body weight compared with both time restricted eating and whole day fasting (mean difference -1.69 kg (-2.49 to -0.88) and -1.05 kg (-1.90 to -0.19), respectively, both with moderate certainty of evidence). Estimates were similar among trials with less than 24 weeks follow-up (n=76); however, moderate-to-long-term trials (≥24 weeks, n=17) only showed benefits in weight reduction in diet strategies compared with ad-libitum. Furthermore, in comparisons between intermittent fasting strategies, alternate day fasting lowered total cholesterol, triglycerides, and non-high density lipoprotein compared with time restricted eating. Compared with whole day fasting, however, time restricted eating resulted in a small increase in total cholesterol, low density lipoprotein cholesterol, and non-high density lipoprotein cholesterol. No differences were noted between intermittent fasting, continuous energy restriction, and ad-libitum diets for HbA CONCLUSIONS: Minor differences were noted between some intermittent fasting diets and continuous energy restriction, with some benefit of weight loss with alternate day fasting in shorter duration trials. The current evidence provides some indication that intermittent fasting diets have similar benefits to continuous energy restriction for weight loss and cardiometabolic risk factors. Longer duration trials are needed to further substantiate these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05309057.
2. Comparative outcomes of adding SGLT2 inhibitors versus incretin-based therapies to insulin in type 2 diabetes.
In insulin-treated T2D, adding SGLT2 inhibitors was associated with lower major adverse cardiovascular events and mortality versus DPP-4 inhibitors, and with fewer major microvascular complications versus both DPP-4 inhibitors and GLP-1 receptor agonists. These findings support preferential selection of SGLT2 inhibitors as add-on therapy to insulin where appropriate.
Impact: Large, well-matched real-world cohorts provide comparative effectiveness data directly relevant to therapeutic choices in advanced T2D on insulin.
Clinical Implications: For insulin-treated T2D, SGLT2 inhibitors may be favored over DPP-4 inhibitors given lower MACE, mortality, and microvascular complications, and over GLP-1 RAs for microvascular outcomes when an injectable is undesirable or contraindicated. Clinicians should balance benefits with risks (e.g., genital infections, volume depletion, and DKA risk in select phenotypes).
Key Findings
- Versus DPP-4 inhibitors, SGLT2 inhibitors lowered major adverse cardiovascular events (aHR 0.57, 95% CI 0.53–0.61).
- All-cause mortality was lower with SGLT2 inhibitors versus DPP-4 inhibitors (aHR 0.42, 95% CI 0.39–0.45).
- Major microvascular complications were reduced with SGLT2 inhibitors versus DPP-4 inhibitors (aHR 0.37) and versus GLP-1 RAs (aHR 0.57).
- Analysis included 20,655 and 10,445 propensity-matched pairs in national claims data, all on concurrent insulin.
Methodological Strengths
- Very large, national, propensity score-matched cohorts enabling head-to-head comparisons.
- Time-to-event analysis with Cox models and adjustment for confounding.
Limitations
- Observational design susceptible to residual confounding and channeling bias.
- Details of microvascular composite definitions and subgroup effects are not fully elaborated.
Future Directions: Head-to-head randomized trials of SGLT2 inhibitors versus GLP-1 RAs added to insulin are needed, with mechanistic endpoints and safety profiling (including DKA and renal outcomes).
AIMS: To compare the risks of cardiovascular events and major microvascular complications associated with adding sodium-glucose cotransporter-2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to insulin therapy in patients with type 2 diabetes (T2D). METHODS: Using Taiwan's National Health Insurance Research Database (2008-2021), we identified 20,655 propensity score-matched pairs of SGLT2 inhibitor and DPP-4 inhibitor users, and 10,445 matched pairs of SGLT2 inhibitor and GLP-1 RA users, all receiving concurrent insulin therapy. Cox proportional hazards models were applied to assess outcome risks. RESULTS: SGLT2 inhibitor use was associated with significantly lower risks of major microvascular complications compared to both DPP-4 inhibitors (adjusted hazard ratio [aHR] 0.37, 95% CI: 0.33-0.41) and GLP-1 RAs (aHR 0.57, 95% CI: 0.49-0.66). Compared with DPP-4 inhibitors, SGLT2 inhibitors also conferred a lower risk of major adverse cardiovascular events (aHR 0.57, 95% CI: 0.53-0.61) and all-cause mortality (aHR 0.42, 95% CI: 0.39-0.45). CONCLUSIONS: In patients with T2D on insulin, adding SGLT2 inhibitors was associated with lower risks of cardiovascular events, major microvascular complications, and mortality compared to DPP-4 inhibitors, and lower risk of major microvascular complications compared to GLP-1 RAs.
3. Predictors of diabetic ketoacidosis in patients with insulin-deficient diabetes phenotype initiating SGLT2 inhibitors.
Among insulin-deficient diabetes phenotypes, SGLT2 inhibitor initiation was associated with a higher DKA risk (aHR 1.50) over a median 4.4 years. Poor glycemic control (HbA1c >9%) and lower BMI (≤25 kg/m²) further heightened risk, supporting targeted risk mitigation when prescribing SGLT2 inhibitors.
Impact: The study refines safety profiling for SGLT2 inhibitors by quantifying DKA risk in a high-risk phenotype and identifying practical predictors for clinical triage.
Clinical Implications: In patients with insulin-deficient features, consider enhanced DKA education, ketone monitoring, and avoidance of precipitants (low-carbohydrate intake, dehydration, intercurrent illness). Defer or closely monitor SGLT2 inhibitor use in those with HbA1c >9% or BMI ≤25 kg/m², and establish sick-day rules and rapid cessation protocols.
Key Findings
- SGLT2 inhibitor use increased DKA risk vs non-use in insulin-deficient phenotype (aHR 1.50; 95% CI 1.15–1.95).
- Over median 4.4 years, DKA occurred in 2.22% of SGLT2 users vs 1.54% of non-users (unadjusted HR 1.39).
- Baseline HbA1c >9% increased DKA risk by 53% (aHR 1.53); lower BMI (≤25 kg/m²) was also associated with higher risk.
- Analysis based on 6,572 SGLT2 users and 6,382 matched non-users from an initial cohort of 31,900.
Methodological Strengths
- Large matched cohort with phenotype-based inclusion and time-to-event modeling.
- Clear primary endpoint (first DKA) and multivariable Cox adjustment.
Limitations
- Retrospective design with potential misclassification of phenotype and DKA events.
- Generalizability may be limited to similar healthcare settings; some predictors (e.g., BMI cutoff) were truncated in reporting.
Future Directions: Prospective validation of a DKA risk score integrating HbA1c, BMI, ketone history, and behavioral factors; evaluate mitigation bundles (education, ketone monitoring) alongside SGLT2 initiation.
AIMS: To identify predictors of diabetic ketoacidosis (DKA) in patients with an insulin-deficient phenotype initiating sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy. MATERIALS AND METHODS: This retrospective cohort study analysed data from 31 900 patients with diabetes aged 18-70 identified as having an insulin-deficient phenotype. After applying inclusion and exclusion criteria, patients were matched and divided into SGLT2i users (n = 6572) and non-users (n = 6382). The primary endpoint was the first DKA event in patients with no prior history of DKA. Independent risk factors for DKA were assessed using Cox regression. RESULTS: Over a median follow-up of 4.4 years, 239 patients experienced DKA (143 [2.22%] SGLT2i users vs. 96 [1.54%] non-users; HR [95% confidence interval, CI] 1.39 [1.07-1.79]; p = 0.014). The adjusted model confirmed an increased DKA risk with SGLT2i use (adjusted hazard ratio, aHR [95% CI] 1.50 [1.15-1.95]; p = 0.003). Baseline HbA1c >9% was associated with a 53% higher risk (aHR [95% CI] 1.53 [1.18-1.99]; p = 0.0016), while body mass index (BMI) ≤25 kg/m CONCLUSIONS: SGLT2i use in patients with an insulin-deficient phenotype is associated with increased DKA risk, particularly in those with HbA1c >9% and BMI ≤25 kg/m