Intraclass Safety and Efficacy Evaluation of SGLT2 Inhibitors in Elderly Patients with Type 2 Diabetes: A Phase IV Multicenter Randomized Controlled Trial

The primary objective of this study is to compare the proportion of patients with **type 2 diabetes mellitus** treated with each SGLT2 inhibitor (SGLT2i) drug who achieve the individualized HbA1c target without experiencing level-3 hypoglycemia by the end of the 24-month study period. This objective is clinically relevant as it aims to evaluate the efficacy and safety of SGLT2i drugs in managing blood glucose levels while minimizing the risk of severe hypoglycemic events in elderly patients.

Secondary objectives include:

• Comparing the proportion of patients treated with each SGLT2i drug who achieve the individualized HbA1c target without level-2 hypoglycemia at any time during the observation period.
• Intra-class comparison of several study endpoints: changes in HbA1c level, body weight, systolic blood pressure, estimated glomerular filtration rate (e-GFR), urinary albumin excretion rate, concomitant medications and their daily dosages, and treatment satisfaction as quantified by the Diabetes Treatment Satisfaction Questionnaire (DTSQ).
• Evaluation of plasma/serum biomarkers of bone metabolism and cardiac function, including BNP, beta-crosslaps, acid phosphatase, alkaline phosphatase, serum calcium, serum phosphorus, and osteocalcin, in a subset of patients.

The clinical trial involves participants diagnosed with **Type 2 diabetes mellitus**. The study population includes both men and women aged 70 years and older. Participants are required to have established cardiovascular disease, either symptomatic or asymptomatic, or an estimated glomerular filtration rate (eGFR) below 90 ml/min/1.73 m², yet above the threshold for initiating therapy with SGLT2 inhibitors. Additionally, participants must have an HbA1c level higher than their individualized target value and a clinical indication for starting therapy with SGLT2 inhibitors. The ability to provide written informed consent is also necessary. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the safety and efficacy of SGLT-2 inhibitors in elderly patients with **type 2 diabetes mellitus**. The trial will span a period of 24 months, with an estimated end date of November 1, 2026. Participants will be randomly assigned to receive one of the SGLT-2 inhibitors, including empagliflozin, canagliflozin, or dapagliflozin, administered orally in the form of film-coated tablets. The primary objective is to assess the proportion of patients achieving individualized HbA1c targets without experiencing level-3 hypoglycemia by the end of the study.

The study will include several key visits: an initial screening visit, regular follow-up visits, and a final end-of-study visit. During the **screening** visit, eligibility criteria will be assessed, including age (≥70 years), presence of established cardiovascular disease or specific renal function parameters, and the ability to provide informed consent. Follow-up visits will occur at regular intervals to monitor glucose control, HbA1c levels, body weight, blood pressure, and other safety parameters. The end-of-study visit will evaluate the primary and secondary endpoints, including changes in treatment satisfaction and the occurrence of adverse events such as hospitalization, severe hypoglycemia, and other safety concerns.

Participant involvement is expected to last for the entire 24-month duration of the trial. However, conditions that may lead to early termination from the study include the occurrence of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide comprehensive data on the comparative safety and efficacy of SGLT-2 inhibitors in the specified patient population, contributing valuable insights into the management of type 2 diabetes in elderly patients.

The clinical trial involves the administration of several **experimental medications** in the form of film-coated tablets, each containing specific active substances. The first medication, Jardiance, is available in two dosages: 10 mg and 25 mg film-coated tablets. The active substance in Jardiance is **empagliflozin**, a chemical compound. The tablets are administered orally, with a maximum daily dose of 20 mg for the 10 mg tablets and 50 mg for the 25 mg tablets. The treatment period extends up to 36 months.

Another experimental medication used in the trial is Vokanamet, which combines **metformin hydrochloride** and **canagliflozin**. It is available in two formulations: 150 mg/850 mg and 50 mg/1,000 mg film-coated tablets. Both formulations are administered orally, with a maximum daily dose of 300 mg for the 150 mg/850 mg tablets and 100 mg for the 50 mg/1,000 mg tablets. The treatment duration is up to 36 months.

Invokana, containing **canagliflozin**, is also part of the trial. It is available in 300 mg and 100 mg film-coated tablets. The oral administration of Invokana allows for a maximum daily dose of 600 mg for the 300 mg tablets and 200 mg for the 100 mg tablets, with a treatment period of up to 36 months.

Synjardy, another combination medication, contains **metformin hydrochloride** and **empagliflozin**. It is available in 12.5 mg/1,000 mg, 12.5 mg/850 mg, 5 mg/1,000 mg, and 5 mg/850 mg film-coated tablets. The oral administration of Synjardy allows for a maximum daily dose of 25 mg for the 12.5 mg formulations and 10 mg for the 5 mg formulations, with a treatment period of up to 36 months.

Xigduo, containing **metformin hydrochloride** and **dapagliflozin**, is available in 5 mg/850 mg and 5 mg/1,000 mg film-coated tablets. The oral administration of Xigduo allows for a maximum daily dose of 10 mg, with a treatment period of up to 36 months.

Forxiga, containing **dapagliflozin**, is available in 5 mg and 10 mg film-coated tablets. The oral administration of Forxiga allows for a maximum daily dose of 10 mg for the 5 mg tablets and 25 mg for the 10 mg tablets, with a treatment period of up to 36 months.

All medications are administered orally, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to compare the proportion of patients treated with each SGLT2 inhibitor who achieve the individualized HbA1c target without level-3 hypoglycemia at the end of the study at 24 months.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the proportion of patients achieving individualized HbA1c targets without experiencing level-3 hypoglycemia at the end of the study, which is set at 24 months. Secondary endpoints include glucose control without level-2 hypoglycemia, changes in **HbA1c**, body weight, systolic blood pressure, estimated glomerular filtration rate (eGFR), use and dosage of concomitant medications, and treatment satisfaction. Safety parameters will also be monitored, including hospitalization for any cause, heart failure, cardiovascular causes, all-cause death, cardiovascular death, severe hypoglycemia, genitourinary tract infections, dehydration/hypovolemia events, bone fractures, leg/foot amputations, and diabetic ketoacidosis.

Data collection will occur at specified intervals throughout the trial, with the final assessment at 24 months. The trial will utilize validated scales and laboratory tests to measure these parameters. The analysis will focus on comparing the efficacy of different SGLT-2 inhibitors in achieving the desired glucose control and safety outcomes in elderly patients with type 2 diabetes. The trial is designed as a pragmatic, phase IV, multicenter, open-label, randomized controlled trial, ensuring a comprehensive evaluation of the efficacy and safety of the treatments under investigation.