TRIPLE-AXEL Study Overview

The TRIPLE-AXEL study, a landmark 104-week trial, explored the efficacy and safety of triple combination therapy (TCT) using metformin, dapagliflozin, and saxagliptin in patients with newly diagnosed Type 2 diabetes. The study compared TCT to the conventional stepwise add-on therapy (SAT), which involves the gradual addition of glimepiride and sitagliptin after metformin monotherapy. This direct comparison revealed significant insights into how TCT offers better glycemic control, weight management, and cardiovascular protection.

Mechanisms of Action: Targeting Multiple Pathways for Diabetes Control

Triple combination therapy targets different physiological pathways to manage glucose levels more effectively:

• Metformin decreases liver glucose production, enhances insulin sensitivity, and improves glucose uptake in muscles. This reduces fasting blood glucose levels, making it a cornerstone of diabetes management.
• Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, promotes glucose excretion through urine by blocking glucose reabsorption in the kidneys. This insulin-independent mechanism remains effective even in advanced diabetes stages, and the drug also supports weight loss and cardiovascular health.
• Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, boosts insulin secretion and inhibits glucagon production, improving post-meal glucose control without the risk of hypoglycemia.

By addressing multiple pathways, TCT is a comprehensive approach that enhances glycemic control while also providing added benefits for patients with comorbidities.

Study Findings: Efficacy of Triple Combination Therapy (TCT)

The study included 105 patients with drug-naïve Type 2 diabetes, with HbA1c levels ranging from 8.0% to 11.0%. After screening, 98 participants completed the trial (48 in the TCT group and 50 in the SAT group). The results were significant:

• 39.0% of TCT participants achieved the primary outcome of HbA1c levels below 6.5% without hypoglycemia, weight gain, or drug discontinuation due to adverse events. In contrast, only 17.1% of the SAT group met this outcome.
• Both groups saw significant reductions in HbA1c:
  • The TCT group reduced HbA1c by 2.56%.
  • The SAT group reduced HbA1c by 2.75%.

Although HbA1c reductions were similar, the TCT group experienced fewer cases of hypoglycemia (0% vs. 19%), weight gain, and adverse events, highlighting its superior safety and tolerability.

Additional Benefits: Weight Loss and Cardiovascular Protection

The TCT group demonstrated additional benefits beyond glycemic control, particularly in weight management and cardiovascular health:

• Weight Loss: Participants in the TCT group experienced a mean weight loss of 0.56 kg, while those in the SAT group had a mean weight gain of 3.08 kg (P < 0.001).
• Cardiovascular Protection: Although the systolic blood pressure reduction in the TCT group was not statistically significant, it showed a positive trend compared to the SAT group, which experienced an increase in systolic blood pressure.

These results suggest that TCT may offer broader health benefits, especially for patients managing diabetes along with cardiovascular risk factors.

Fewer Adverse Events and Long-Term Durability

The TCT group reported fewer adverse events overall (38% vs. 57% in the SAT group). Importantly, no cases of hypoglycemia were reported in the TCT group, compared to 19% in the SAT group, which experienced more gastrointestinal side effects likely due to higher doses of metformin.

The study confirmed the long-term durability of TCT, showing that it provides sustained glycemic control over 104 weeks with fewer complications compared to SAT. This makes TCT a promising option for early, intensive management in newly diagnosed Type 2 diabetes patients, especially those with complex conditions like cardiovascular disease or obesity.

Conclusion: A Safer and More Effective Strategy for Type 2 Diabetes

The TRIPLE-AXEL study demonstrated that triple combination therapy with metformin, dapagliflozin, and saxagliptin is a highly effective approach for achieving long-term glycemic control in patients with Type 2 diabetes. It offers:

• Better safety with fewer adverse events.
• Additional benefits like weight loss and cardiovascular protection.
• A comprehensive treatment that addresses multiple pathways involved in glucose regulation.

TCT presents a novel strategy for diabetes management, especially for patients requiring tighter glucose regulation or those not achieving adequate control with dual therapy. Its ability to reduce hypoglycemia risk and promote weight loss adds significant value for long-term diabetes care.

In summary, TCT offers a safer, more effective treatment for newly diagnosed Type 2 diabetes patients, promoting not only glycemic control but also broader health benefits like improved weight management and cardiovascular health.