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.
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).
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.