Effect of Different Treatment Durations of Sodium-Glucose Cotransporter 2 Inhibitor on Cardiovascular Outcomes in Patients with Type 2 Diabetes: A Target Trial Emulation Study

Authors: Kyungyeon Jung, et al.

This nationwide South Korean study evaluated whether longer treatment duration with sodium-glucose cotransporter 2 inhibitors (SGLT2is) is associated with greater cardiovascular benefits in patients with type 2 diabetes. Using healthcare data from 2012 to 2023, researchers identified 1,174,088 patients with type 2 diabetes who initiated SGLT2i therapy. Participants were categorized according to treatment duration: less than 1 year, 1–2 years, 2–3 years, and 3 years or longer. The primary outcomes were major adverse cardiovascular events (MACE) and hospitalization for heart failure (HHF) over a 5-year follow-up period. The study population had a mean age of 57.3 years, and 40.5% were female. Compared with patients treated for less than 1 year, longer treatment durations were associated with progressively lower cardiovascular risk. For MACE, the risk ratios (RRs) were 0.93 (95% confidence interval [CI], 0.90–0.96) for 1–2 years of treatment, 0.82 (95% CI, 0.78–0.85) for 2–3 years, and 0.69 (95% CI, 0.67–0.72) for 3 years or longer. Similarly, the risk of HHF decreased with longer treatment duration, with RRs of 0.93 (95% CI, 0.90–0.97), 0.91 (95% CI, 0.80–0.99), and 0.74 (95% CI, 0.67–0.79), respectively.

Overall, longer persistence with SGLT2i therapy was associated with progressively greater reductions in the risk of major adverse cardiovascular events and hospitalization for heart failure, supporting the cardiovascular benefits of sustained treatment.

National Patterns of SGLT2i and GLP-1RA Use in U.S. Cancer Survivors with Diabetes

Authors: Elle Billman, et al.

This study evaluated the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) among U.S. adults with diabetes, comparing cancer survivors (DM+c) with individuals without a history of cancer (DM−c). Using National Health and Nutrition Examination Survey (NHANES) data from 2015–2020, researchers analyzed an estimated 16 million adults with diabetes, including 2 million cancer survivors and 14 million individuals without cancer. Adults with DM+c were older than those with DM−c (68 vs. 59 years) and were more likely to have comorbidity-based indications for these therapies (49.9% vs. 33.8%). Between 2015 and 2020, use of SGLT2is and GLP-1RAs was low overall and particularly low among cancer survivors. Among adults with DM+c, 0.6% used SGLT2is and 2.6% used GLP-1RAs, compared with 5.4% and 3.3%, respectively, among those without cancer (both p<0.01). Over time, SGLT2i use increased substantially among individuals without cancer, rising from 2.8% in 2015–2016 to 9.7% in 2017–2020. In contrast, SGLT2i use among cancer survivors declined from 2.2% to 0.3%. GLP-1RA use decreased modestly in both groups, from 5.4% to 3.4% among individuals without cancer and from 5.3% to 3.5% among cancer survivors. After adjustment for sociodemographic and clinical factors, a history of cancer was not a significant predictor of SGLT2i or GLP-1RA use. The only significant predictor was longer diabetes duration (odds ratio 1.05 per year; 95% confidence interval [CI], 1.01–1.10).

Overall, cardioprotective diabetes therapies were underused in adults with diabetes who are cancer survivors, despite their higher cardiovascular risk.

Harmony: A Head-to-Head Phase 3 Study of HTD1801 vs. Dapagliflozin

Authors: Linong Ji, et al.

The Phase 3 HARMONY study compared the efficacy and safety of Berberine Ursodeoxycholate, HTD1801, an anti-inflammatory metabolic modulator, with dapagliflozin (Dapa) in patients with type 2 diabetes (T2D) receiving stable metformin therapy. A total of 367 patients were randomized to receive either HTD1801 1000 mg twice daily (n=186) or dapagliflozin 10 mg once daily (n=181) for 24 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline. At Week 24, HTD1801 reduced HbA1c by 1.12% compared with a 0.93% reduction with dapagliflozin. The least-squares mean difference between treatments was −0.20% (95% confidence interval: −0.37% to −0.03%; p<0.001), demonstrating non-inferiority of HTD1801. A greater proportion of patients receiving HTD1801 achieved an HbA1c level below 7% compared with dapagliflozin. Beyond glycemic control, HTD1801 showed greater improvements in key lipid parameters. Estimated glomerular filtration rate (eGFR) increased in patients treated with HTD1801, whereas no change was observed with dapagliflozin. Treatment-emergent adverse events were reported in 73.1% of patients receiving HTD1801 and 64.1% of those receiving dapagliflozin.

Overall, HTD1801 provided glycemic control comparable to dapagliflozin and was associated with additional improvements in lipid parameters and kidney function markers. These findings suggest that HTD1801 may offer a distinctive therapeutic option with broader cardiometabolic benefits for patients with T2DM.

Triple Therapy for Type 1 Diabetes with Insulin, Semaglutide, and Dapagliflozin (TTT1): A Phase 3 Clinical Trial

Authors: Husam A Ghanim et al.

This study evaluated the efficacy and safety of adding semaglutide and dapagliflozin to insulin therapy in overweight adults with type 1 diabetes (T1D) and suboptimal glycemic control. Hypoglycemia and ketosis are known risks of adjunct non-insulin therapies. A total of 78 participants (mean age 45 years, 51% female, mean HbA1c 8.3%, mean body mass index [BMI] 33 kg/m²) were randomized during the first 26 weeks to receive standard insulin therapy alone or insulin plus semaglutide, titrated up to 1.0 mg weekly. During Weeks 26–52, participants receiving semaglutide were further randomized to dapagliflozin 10 mg daily or placebo. During the first 26 weeks, semaglutide significantly improved glycemic control, reducing HbA1c by 0.45% compared with standard care (95% confidence interval [CI]: −0.78 to −0.13; p=0.0072). Semaglutide also produced substantial weight loss, with a mean reduction of 10.2 kg compared with standard care (95% CI: −12.8 to −7.7; p<0.0001). In the second treatment period, adding dapagliflozin to semaglutide resulted in an additional HbA1c reduction of 0.46% compared with placebo (95% CI: −0.78 to −0.14; p=0.003), meeting the primary endpoint. However, no significant additional weight reduction was observed (−1.0 kg; p=0.2219). Over the full 52-week study period, participants receiving both semaglutide and dapagliflozin achieved a greater HbA1c reduction than those receiving standard care alone (−0.36%; 95% CI: −0.67 to −0.05; p=0.0235). Time spent below the target glucose range was not affected by either treatment. However, semaglutide was associated with a higher rate of Level 2 hypoglycemia during the first 26 weeks compared with standard care (17 vs 9 events per patient-year; incidence rate ratio 2.6; 95% CI: 1.4–5.0; p=0.0047). One episode of diabetic ketoacidosis occurred during the study, in a participant receiving placebo during the second treatment period.

Overall, semaglutide improved glycemic control and reduced body weight in overweight adults with T1D, while the addition of dapagliflozin provided further HbA1c reduction without additional significant weight loss.

Efficacy and Safety of DAPA/MET Fixed-Dose Combination (FDC) vs. Co-Administration (Co-ADM) in Chinese Patients with T2DM

Authors: Guang Wang et al.

The EFFICIENT study evaluated the efficacy and safety of a fixed-dose combination (FDC) of dapagliflozin, and metformin (DAPA/MET) compared with co-administration (CO-ADM) of the two drugs in adults with newly diagnosed type 2 diabetes mellitus (T2DM). This 24-week, multicenter, randomized, open-label, non-inferiority study included 590 patients, with 297 receiving DAPA/MET FDC and 293 receiving co-administered dapagliflozin and metformin. Baseline characteristics were comparable between the groups. At Week 24, glycated hemoglobin (HbA1c) decreased by 2.06% in the FDC group and by 2.12% in the co-administration group. The least-squares mean difference was 0.06% (95% confidence interval [CI]: −0.05 to 0.17), meeting the predefined non-inferiority criterion. Both treatment groups also achieved reductions in fasting plasma glucose (FPG) and postprandial glucose (PPG). More than 70% of patients in both groups achieved the HbA1c target of <7%. Continuous glucose monitoring (CGM) metrics also exceeded guideline-recommended targets in both treatment arms. Treatment-related adverse events occurred in 23.7% of patients receiving the fixed-dose combination and 25.4% of those receiving co-administration. Most adverse events were mild in severity.

Overall, the dapagliflozin/metformin fixed-dose combination provided glycemic control and safety comparable to co-administration while offering a simplified treatment approach for patients with newly diagnosed T2DM; providing direct comparative evidence as the first study of its kind.

Metabolic, Hepatic, Renal, and Hemodynamic Effects of DA-2811 vs. Forxiga in Patients with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Study

Authors: Jun Hwa Hong, et al.

This multicenter, randomized, double-blind study compared the efficacy and metabolic effects of DA-2811 (dapagliflozin formate) with dapagliflozin propanediol hydrate in patients with type 2 diabetes mellitus (T2DM) receiving stable metformin monotherapy with HbA1c 7.0-10.0% at screening. A total of 225 patients were included in the efficacy analysis, with 112 receiving DA-2811 and 113 receiving dapagliflozin propanediol hydrate. Baseline characteristics were similar between the groups. The primary endpoint was change in glycated hemoglobin (HbA1c) after 24 weeks of treatment. DA-2811 demonstrated non-inferiority to dapagliflozin propanediol hydrate for HbA1c reduction at Week 24. Improvements in metabolic parameters were also comparable between the two treatments. High-density lipoprotein cholesterol (HDL-C) increased by 3.57±0.75 mg/dL with DA-2811 and 4.15±0.77 mg/dL with dapagliflozin propanediol hydrate, while triglyceride levels decreased by 10.42±4.59 mg/dL and 16.62±4.70 mg/dL, respectively. Both treatments produced similar reductions in hepatic enzyme levels and uric acid. Renal parameters, including estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and N-acetyl-β-D-glucosaminidase (NAG), showed no meaningful changes in either group. Modest reductions in systolic and diastolic blood pressure were observed with both treatments. Body weight and waist circumference also decreased significantly in both groups. No significant differences were found between DA-2811 and dapagliflozin propanediol hydrate for any metabolic, hepatic, renal, or hemodynamic outcome.

Overall, DA-2811 demonstrated efficacy and effects on metabolic, hepatic, renal, and cardiovascular-related parameters comparable to dapagliflozin propanediol hydrate over 24 weeks in patients with T2DM, supporting similar clinical profiles in routine clinical practice.

Effects of Intensification of Canagliflozin from 100 mg to 300 mg Daily on Insulin Initiation in the INTENSIFY Study

Authors: Juan Jose Gorgojo-Martinez, et al.

Insulin therapy is associated with weight gain, low blood glucose levels, increased use of healthcare resources and therapeutic burden. These drawbacks are overcome by SGLT2 inhibitors, which help in delaying insulin initiation This sub-analysis of the real-world INTENSIFY study evaluated the effectiveness and tolerability of increasing canagliflozin from 100 mg/day (CANA100) to 300 mg/day (CANA300) in insulin-naïve patients with type 2 diabetes (T2D) who met criteria for insulin initiation despite treatment with multiple non-insulin glucose-lowering therapies. The analysis included 95 patients with a mean age of 64.2 years, mean glycated hemoglobin (HbA1c) of 7.81%, and mean body mass index (BMI) of 30.0 kg/m². Most patients were receiving triple therapy (71.6%), while 28.4% were on quadruple therapy. Common background medications included metformin (97.9%), dipeptidyl peptidase-4 (DPP-4) inhibitors (53.7%), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (45.3%), and sulfonylureas/glinides (28.4%). After a median follow-up of 15 months, escalation to CANA300 resulted in significant improvements in glycemic control and body weight. Mean HbA1c decreased by 0.64%, and body weight decreased by 3.0 kg (both p<0.0001), resulting in a mean final HbA1c of 7.20%. Importantly, insulin therapy was not initiated in 85.1% of patients during follow-up. Nearly half of the patients (49.4%) achieved HbA1c <7%, while 90.5% achieved HbA1c <8% without requiring insulin treatment. CANA300 was discontinued in 7.4% of patients. Genital fungal infections were reported in 10.5% of patients and urinary tract infections in 4.2%. No cases of volume depletion, amputations, or diabetic ketoacidosis were reported.

Overall, increasing canagliflozin from 100 mg to 300 mg improved glycemic control and reduced body weight, while helping most insulin-eligible patients avoid insulin initiation in routine clinical practice. These findings provide a potential strategy to delay insulin initiation and simplify diabetes management in routine clinical practice.

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