Daily Endocrinology Research Analysis
A double-blind multicenter RCT showed that adding dapagliflozin to calorie restriction significantly increased type 2 diabetes remission versus calorie restriction alone. A national target trial emulation found no overall excess thyroid cancer risk with GLP-1RAs vs comparators, but a higher risk of diagnoses in the first year, likely reflecting enhanced detection. A nationwide real-world cohort showed diabetes remission associates with ~30% lower cardiovascular disease risk, even without weight
Summary
A double-blind multicenter RCT showed that adding dapagliflozin to calorie restriction significantly increased type 2 diabetes remission versus calorie restriction alone. A national target trial emulation found no overall excess thyroid cancer risk with GLP-1RAs vs comparators, but a higher risk of diagnoses in the first year, likely reflecting enhanced detection. A nationwide real-world cohort showed diabetes remission associates with ~30% lower cardiovascular disease risk, even without weight loss.
Research Themes
- Type 2 diabetes remission strategies (SGLT2 inhibitor plus diet)
- Medication safety signal evaluation (GLP-1RA and thyroid cancer)
- Cardiometabolic outcomes linked to diabetes remission in real-world care
Selected Articles
1. Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial.
In 328 adults with type 2 diabetes, dapagliflozin plus calorie restriction produced a 44% remission rate at 12 months versus 28% with calorie restriction alone, alongside greater reductions in weight and HOMA-IR and improved metabolic risk factors. Adverse events were similar between groups.
Impact: This high-quality RCT demonstrates a practical, pharmacologically-augmented dietary strategy to achieve diabetes remission, a central goal in modern diabetes care.
Clinical Implications: Consider SGLT2 inhibitor plus structured calorie restriction for remission-oriented care in overweight/obese patients with early T2D, with close monitoring and individualized dosing.
Key Findings
- Diabetes remission at 12 months: 44% with dapagliflozin plus calorie restriction vs 28% with calorie restriction alone (RR 1.56, 95% CI 1.17–2.09).
- Greater reductions in body weight (−1.3 kg vs placebo) and HOMA-IR (difference −0.8) with dapagliflozin.
- Improved body fat, systolic blood pressure, and metabolic risk factors without increased adverse events.
Methodological Strengths
- Multicenter, double-blind, randomized, placebo-controlled design
- Predefined remission endpoint with clinically meaningful composite criteria
Limitations
- Conducted in China; generalizability to other populations requires validation
- 12-month duration limits assessment of durability of remission
Future Directions: Longer-term and multinational trials assessing durability, cost-effectiveness, micro/macrovascular outcomes, and optimal patient selection for remission protocols.
OBJECTIVE: To assess the effect of dapagliflozin plus calorie restriction on remission of type 2 diabetes. DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: 16 centres in mainland China from 12 June 2020 to 31 January 2023. PARTICIPANTS: 328 patients with type 2 diabetes aged 20-70 years, with body mass index >25 and diabetes duration of <6 years. INTERVENTIONS: Calorie restriction with dapagliflozin 10 mg/day or placebo. MAIN OUTCOME MEASURES: Primary outcome: incidence of diabetes remission (defined as glycated haemoglobin <6.5% and fasting plasma glucose <126 mg/dL in the absence of all antidiabetic drugs for at least 2 months); secondary outcomes: changes in body weight, waist circumference, body fat, blood pressure, glucose homoeostasis parameters, and serum lipids over 12 months. RESULTS: Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months, meeting the predefined primary endpoint. Changes in body weight (difference -1.3 (95% CI -1.9 to -0.7) kg) and homoeostasis model assessment of insulin resistance (difference -0.8, -1.1 to -0.4) were significantly greater in the dapagliflozin group than in the placebo group. Likewise, body fat, systolic blood pressure, and metabolic risk factors were significantly more improved in the dapagliflozin group than in the placebo group. In addition, no significant differences were seen between the two groups in the occurrence of adverse events. CONCLUSION: The regimen of dapagliflozin plus regular calorie restriction achieved a much higher rate of remission of diabetes compared with calorie restriction alone in overweight or obese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04004793.
2. GLP-1RA Use and Thyroid Cancer Risk.
In a target trial emulation of 351,913 adults with type 2 diabetes, GLP-1RA initiation was not associated with an overall increased thyroid cancer risk versus SGLT2i, DPP4i, or sulfonylureas, but showed a higher risk within the first year (HR 1.85), likely reflecting detection bias. Absolute risks were low across groups.
Impact: Addresses a timely safety concern amid widespread GLP-1RA use, with large-scale real-world data and causal emulation methods.
Clinical Implications: Clinicians should contextualize the low absolute risk and consider potential early detection effects; routine vigilance and appropriate thyroid evaluation may be reasonable during the first year without over-screening.
Key Findings
- Overall thyroid cancer risk with GLP-1RA vs comparators was not significantly increased (HR 1.24; 95% CI 0.88–1.76).
- Within the first year after initiation, thyroid cancer diagnoses were higher (HR 1.85; 95% CI 1.11–3.08), amplified in as-treated analysis (HR 2.07).
- Absolute incidence was low across all drug classes (0.17%–0.23%).
Methodological Strengths
- Target trial emulation with inverse propensity score weighting and piecewise hazards
- Very large, national, multi-payer claims dataset with mITT and as-treated analyses
Limitations
- Observational design subject to residual confounding and detection bias
- Cancer subtype, nodule workup intensity, and imaging surveillance details limited in claims
Future Directions: Linkage studies with cancer registries and imaging/laboratory data to parse detection vs causation; mechanistic and pharmacoepidemiologic studies by GLP-1RA class and dose.
IMPORTANCE: The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) demands a better understanding of their association with thyroid cancer. OBJECTIVE: To estimate the risk of incident thyroid cancer among adults with type 2 diabetes being treated with GLP-1RA vs other common glucose-lowering medications. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a target trial emulation of a comparative effectiveness study using claims data for enrollees in commercial, Medicare Advantage, and Medicare fee-for-service plans across the US. Eligible participants were adults with type 2 diabetes at moderate risk for cardiovascular disease and without history of thyroid cancer who had newly filled prescriptions for GLP-1RA, sodium-glucose cotransporter 2 inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP4i), or sulfonylurea from January 1, 2014, to December 31, 2021. Data were analyzed February 1 to October 31, 2024. MAIN OUTCOMES AND MEASURES: Overall and piecewise (<1, 1-2, and ≥2 years since treatment initiation) hazard ratios (HRs) for thyroid cancer with use of GLP-1RA vs the other 3 drug classes were estimated using inverse propensity score weighted Cox proportional hazards models. Modified intention-to-treat (mITT) (primary) and as-treated (sensitivity) analyses were performed. RESULTS: Of 351 913 patients (mean [SD] age, 65.3 [8.5] years; 173 391 [49.3%] females and 178 522 [50.7%] males), 41 112 started treatment with GLP-1RA; 76 093, with DPP4i; 43 499, with SGLT2i; and 191 209, with sulfonylurea therapy. The numbers of patients diagnosed with thyroid cancer were 69 (0.17%) in the GLP-1RA group, 172 (0.23%) in the DPP4i group, 72 (0.17%) in the SGLT2i group, and 381 (0.20%) in the sulfonylurea group. In the mITT analysis, GLP-1RA initiation was not significantly associated with increased overall risk for thyroid cancer compared to the other 3 diabetes drugs (HR, 1.24; 95% CI, 0.88-1.76). However, the risk for thyroid cancer was significantly higher within the first year after GLP-1RA initiation (HR, 1.85; 95% CI, 1.11-3.08) and was amplified in the overall as-treated analysis that censored patients when therapy was discontinued or another medication was added (HR, 2.07; 95% CI, 1.10-3.95). CONCLUSIONS AND RELEVANCE: This secondary analysis of a target trial emulation of a comparative effectiveness study found that despite the low absolute risk of thyroid cancer among patients receiving GLP-1RA therapy, there was an increased risk of new thyroid cancer diagnoses within the first year of GLP-1RA initiation compared to 3 other diabetes drugs. This finding may have been due to enhanced early detection; therefore, further research is necessary to understand the underlying causes of this association.
3. Impact of diabetes remission or progression on the incidence of cardiovascular disease in Japan: historical cohort study using a nationwide claims database.
In a nationwide Japanese cohort (n=299,967; median follow-up 5 years), diabetes remission was associated with a ~30% lower CVD risk versus continued diabetes (HR 0.71), independent of BMI change. Individuals with diabetes progression had substantially higher CVD rates.
Impact: Provides real-world evidence that achieving diabetes remission translates into reduced cardiovascular events independent of weight loss, reinforcing remission as a meaningful clinical target.
Clinical Implications: Remission-focused care may lower CVD risk even without weight loss; prioritize strategies (e.g., dietary, pharmacologic, combination) to achieve and sustain remission, and intensify CVD risk management in non-remitters and progressors.
Key Findings
- Compared to DM+/no remission, DM+/remission had lower CVD risk (HR 0.71, 95% CI 0.57–0.89).
- CVD incidence rates per 1000 person-years: 7.96 (DM+/no remission), 4.76 (DM+/remission), 1.99 (DM−/no progression), 5.47 (DM−/progression).
- Benefit of remission persisted regardless of BMI change (HR 0.75 with BMI ≤0% change; HR 0.66 with BMI >0% change).
Methodological Strengths
- Very large nationwide cohort with multivariable Cox modeling
- A priori classification of remission/progression using HbA1c and medication changes
Limitations
- Observational design; potential residual confounding and misclassification of remission status
- Claims-based data may lack granularity on lifestyle, imaging, and subclinical disease
Future Directions: Prospective validation assessing durability of remission and cause-specific CVD outcomes; evaluation of remission-inducing interventions and health-economic impact.
BACKGROUND: Previous studies demonstrated that diabetes remission can occur during intensive intervention and in real-world settings. However, the impact of diabetes remission in real-world settings on the incidence of cardiovascular disease (CVD) remains unclear. METHODS: This retrospective cohort study included 299,967 individuals aged 20-72 years who underwent multiple checkups between 2008 and 2020 and completed ≥ 3 years of follow-up. Patients were divided into four groups according to changes in glycated hemoglobin levels and the use of diabetes medications during the 1-year baseline period: diabetes mellitus (DM)+/no remission, DM+/remission, DM-/no progression, and DM-/progression. The risk of CVD was evaluated using multivariable Cox regression analysis. RESULTS: The median follow-up period was 5.0 years. The rates of CVD in the DM+/no remission, DM+/remission, DM-/no progression, and DM-/progression groups were 7.96, 4.76, 1.99, and 5.47 per 1000 person-years, respectively. Compared with DM+/no remission, DM+/remission reduced the risk of CVD [hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.57-0.89]. Meanwhile, the HR for CVD in the DM+/remission group was 0.75 (95% CI = 0.56-0.99) for change in BMI ≤ 0%, versus 0.66 (95% CI = 0.45-0.96) for change in BMI > 0%. CONCLUSIONS: In a real-world setting without intensive intervention, diabetes remission decreased the risk of CVD by approximately 30% regardless of changes in BMI, suggesting that diabetes remission can prevent CVD without weight loss in routine care and emphasizing the importance of achieving remission.