Combination Therapies for Type 2 Diabetes

Recruiting at 1 trial location

Overseen By Muhammad Abdul-Ghani, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: The University of Texas Health Science Center at San Antonio

Must be taking: Metformin

Disqualifiers: Pregnancy, CHF, Cancer, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to evaluate the efficacy, durability, and mechanism of HbA1c reduction produced by the combination of pioglitazone plus tirzepatide compared to metformin plus sitagliptin in patients with recently diagnosed type 2 diabetes mellitus.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that participants can be drug naïve or on metformin only. If you are taking other medications, you might need to discuss this with the trial coordinators.

What data supports the effectiveness of the drug combination therapies for Type 2 Diabetes?

Research shows that tirzepatide, a part of the combination therapy, is effective in controlling blood sugar and reducing weight in people with type 2 diabetes. Additionally, sitagliptin, when combined with metformin and pioglitazone, has been shown to improve blood sugar control in patients who were not adequately managed with other treatments. ^{1 2 3 4 5}

Is the combination therapy for type 2 diabetes safe for humans?

Research shows that tirzepatide, a part of the combination therapy, has been evaluated for safety in treating type 2 diabetes. Studies have reviewed its safety profile, indicating it is generally safe for human use in this context. ^{2 3 6 7 8}

What makes the combination drug for Type 2 Diabetes unique?

This combination drug for Type 2 Diabetes is unique because it combines multiple medications, including Metformin HCI XR, Pioglitazone, Sitagliptin, and Tirzepatide, which work together to improve blood sugar control through different mechanisms, offering a comprehensive approach to managing the condition. ^{9 10 11 12 13}

Research Team

Muhammad Abdul-Ghani, MD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Eligibility Criteria

This trial is for people who have been recently diagnosed with type 2 diabetes. Participants should not have taken any long-term medications for diabetes before joining the study.

Inclusion Criteria

Stable body weight over the preceding 3 months

Agreement to adhere to Lifestyle Considerations throughout study duration

Ability of subject to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Presence of hematuria in the urine analysis

I have had cancer within the last 5 years.

I have had pancreatitis before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either pioglitazone plus tirzepatide or metformin plus sitagliptin. Sub-groups have specific titration schedules.

6 months

Monthly visits for dose titration and monitoring

Sub-study

A subgroup of patients participates in a sub-study exploring metabolic/molecular mechanisms.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on long-term HbA1c reduction.

54 months

Treatment Details

Interventions

• Metformin HCI XR (Biguanide)
• Pioglitazone (Thiazolidinedione)
• Sitagliptin (DPP-4 Inhibitor)
• Tirzepatide (GLP-1 Receptor Agonist)

Trial Overview The trial tests two different combinations of diabetes medications: one group will take pioglitazone and tirzepatide, while another group will take metformin and sitagliptin. The goal is to compare how well each combination helps control blood sugar levels over time.

Participant Groups

Group I: Group IC Experimental Treatment 2 Interventions

Tirzepatide starting at 2.5mg weekly titrated to 15mg weekly (2.5 month 1, 5mg month 2, 10mg month 3 and 15mg at month 4) with Pioglitazone beginning at 15mg daily and ending at 45mg daily (15mg month 1, 30mg month 2 and 45mg at month 3 onwards).

Group II: Group II Active Control 2 Interventions

Metformin starting at 1000mg XR daily and Sitagliptin 100mg daily at week 4, Metformin will be increased to 200mg.

Group III: Group 1B Active Control 2 Interventions

Pioglitazone will be started at 15mg and increased to 45 mg by month 3. At month 6, tirzepatide 2.5mg will be started and increased weekly as tolerated.

Group IV: Group IA Active Control 2 Interventions

Tirzepatide will be started at 2.5mg and increased to 15mg by month 4. At month 6, Pioglitazone will be added to the Tirzepatide, 15 mg daily.

Who Is Running the Clinical Trial?

The University of Texas Health Science Center at San Antonio

Lead Sponsor

Trials

486

Recruited

92,500+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Tirzepatide, a dual GIP and GLP-1 receptor agonist, has been shown to significantly improve glycemic control and reduce body weight in adults with type 2 diabetes, based on results from the phase 3 SURPASS clinical trials.

It is currently considered the most effective agent for managing type 2 diabetes, with ongoing studies evaluating its potential cardiovascular benefits, with results expected in 2024.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on tirzepatide for the management of type 2 diabetes: a focus on the phase 3 clinical development program. Frías, JP.[2023]

Tirzepatide demonstrated a dose-dependent ability to lower HbA1c levels in adults with type 2 diabetes, with reductions ranging from -17.71 to -22.35 mmol/mol compared to placebo, and was also more effective in reducing body weight than other treatments.

While tirzepatide did not increase the risk of hypoglycaemia compared to placebo and showed lower rates than basal insulin, it was associated with a higher incidence of gastrointestinal side effects, particularly nausea and vomiting, especially at the 15 mg dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. Karagiannis, T., Avgerinos, I., Liakos, A., et al.[2023]

Tirzepatide, approved in 2022, is a novel treatment for type 2 diabetes that acts on both GLP-1 and GIP pathways, showing significant efficacy in lowering blood sugar levels and promoting weight loss in various patient groups.

Clinical trials, including the SURPASS and SURMOUNT studies, indicate that tirzepatide has a safety profile similar to traditional GLP-1 receptor agonists, with common gastrointestinal side effects, making it a promising option for patients needing better glycemic and weight management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. Krauss, Z., Hintz, A., Fisk, R.[2023]

Tirzepatide (Mounjaro™) is a new treatment for type 2 diabetes that acts on both GIP and GLP-1 receptors, showing strong results in lowering blood glucose and promoting weight loss based on evidence from five SURPASS clinical trials.

The safety profile of tirzepatide is similar to that of existing GLP-1 receptor agonists, making it a promising option for early intervention in managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Drug: Tirzepatide (Mounjaro™). Gettman, L.[2023]

In a 26-week study involving 313 patients with type 2 diabetes, adding sitagliptin to metformin and pioglitazone significantly improved glycemic control, reducing HbA1c by an average of 0.7% compared to placebo.

The safety profile of sitagliptin was comparable to placebo, with low incidences of hypoglycemia, indicating it is a well-tolerated option for enhancing diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. Fonseca, V., Staels, B., Morgan, JD., et al.[2022]

In a study involving 492 patients with type 2 diabetes, sitagliptin combined with metformin (SITA/MET) showed greater improvements in blood sugar control compared to pioglitazone (PIO) over 28 weeks, with a significant reduction in A1C levels (-1.7% vs. -1.4%).

SITA/MET also resulted in weight loss (-1.1 kg) while PIO led to weight gain (3.4 kg), and both treatments had a low incidence of hypoglycemia, indicating that SITA/MET may be a safer and more effective option for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes. Pérez-Monteverde, A., Seck, T., Xu, L., et al.[2022]

In a 26-week study comparing liraglutide to exenatide and sitagliptin in patients with type 2 diabetes and A1C <8.0%, liraglutide was more effective in helping patients achieve A1C targets, especially the stricter target of ≤6.5%.

Liraglutide also demonstrated a higher rate of achieving A1C <7.0% without weight gain or hypoglycemia compared to both exenatide and sitagliptin, indicating it is a safe and effective option for patients who do not achieve desired results with metformin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liraglutide achieves A1C targets more often than sitagliptin or exenatide when added to metformin in patients with type 2 diabetes and a baseline A1C King, AB., Montanya, E., Pratley, RE., et al.[2022]

Tirzepatide, a dual GIP and GLP-1 receptor agonist, showed significant reductions in Hemoglobin A1c levels (up to 3.02%) and weight loss in adults with uncontrolled type 2 diabetes, outperforming both placebo and active comparators like semaglutide.

The safety profile of tirzepatide was comparable to semaglutide regarding gastrointestinal adverse effects, and it did not increase the incidence of major cardiovascular events compared to insulin glargine, indicating it may be a valuable addition to diabetes treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tirzepatide, the Newest Medication for Type 2 Diabetes: A Review of the Literature and Implications for Clinical Practice. Bradley, CL., McMillin, SM., Hwang, AY., et al.[2023]

In a study of 154 Type 2 diabetic patients, adding miglitol to their existing treatment of glibenclamide and metformin resulted in a significant reduction in HbA1c levels by 0.55% and postprandial glucose by 2.6 mmol/l compared to placebo, indicating its efficacy in improving blood sugar control.

Miglitol was generally safe to use, with no reported cases of hypoglycemia; however, it did lead to more gastrointestinal side effects like flatulence and diarrhea in some patients, though overall adverse events were only slightly higher than in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics. Standl, E., Schernthaner, G., Rybka, J., et al.[2022]

CGRP antagonists, including second-generation gepants like rimegepant and ubrogepant, have been shown to be effective for both acute and preventive treatment of migraines, with no increased mortality risks associated with their use.

While serious adverse events were reported, they were likely unrelated to the medications, indicating a favorable safety profile; however, ongoing monitoring for long-term side effects, particularly in elderly populations, is recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gepants for Acute and Preventive Migraine Treatment: A Narrative Review. Rissardo, JP., Caprara, ALF.[2022]

Zavegepant, a newly approved intranasal gepant, represents a significant advancement in migraine treatment by antagonizing the CGRP receptor, which is linked to chronic migraine conditions.

Unlike earlier gepants, zavegepant and other recent oral gepants like rimegepant and ubrogepant have been approved without warnings for hepatotoxicity, suggesting a potentially safer profile, although long-term safety and efficacy data are still needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focus on zavegepant: the first intranasal third-generation gepant. Scuteri, D., Tarsitano, A., Tonin, P., et al.[2022]

A new series of heterocycle derivatives were developed as CGRP receptor antagonists, showing high affinity and reduced time-dependent inhibition of the CYP3A4 enzyme, which is important for drug metabolism.

Some of these compounds demonstrated strong in vivo efficacy, achieving up to 87% inhibition of CGRP-induced activity in a marmoset model, although challenges with low oral bioavailability persist.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead. Luo, G., Jiang, XJ., Chen, L., et al.[2021]

Atogepant, a CGRP receptor antagonist, shows significantly increased systemic exposure when taken with strong inhibitors like itraconazole and single-dose rifampin, indicating potential interactions that could enhance its effects.

Conversely, co-administration with multiple-dose rifampin, a strong CYP3A4 inducer, significantly decreases atogepant levels, which could reduce its efficacy; overall, treatment-related side effects were mostly mild to moderate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of CYP3A4 inhibition/induction and OATP inhibition on the pharmacokinetics of atogepant in healthy adults. Boinpally, R., Chen, W., McGeeney, D., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

An update on tirzepatide for the management of type 2 diabetes: a focus on the phase 3 clinical development program. [2023]

2. Germany pubmed.ncbi.nlm.nih.gov

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Tirzepatide: Clinical review of the "twincretin" injectable. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

New Drug: Tirzepatide (Mounjaro&#8482;). [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. [2022]

6. India pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sitagliptin and the fixed-dose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Liraglutide achieves A1C targets more often than sitagliptin or exenatide when added to metformin in patients with type 2 diabetes and a baseline A1C [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Tirzepatide, the Newest Medication for Type 2 Diabetes: A Review of the Literature and Implications for Clinical Practice. [2023]

9. Ireland pubmed.ncbi.nlm.nih.gov

Improved glycaemic control with miglitol in inadequately-controlled type 2 diabetics. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Gepants for Acute and Preventive Migraine Treatment: A Narrative Review. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Focus on zavegepant: the first intranasal third-generation gepant. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead. [2021]

13. England pubmed.ncbi.nlm.nih.gov

Effects of CYP3A4 inhibition/induction and OATP inhibition on the pharmacokinetics of atogepant in healthy adults. [2023]