Combination Therapies for Type 2 Diabetes

Recruiting at 1 trial location

Overseen By Muhammad Abdul-Ghani, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

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

Must be taking: Metformin

Disqualifiers: Pregnancy, CHF, Cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

256 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of different combinations of diabetes medications for individuals with newly diagnosed type 2 diabetes. It compares a combination of pioglitazone (a thiazolidinedione) and tirzepatide (a new potential drug) against metformin plus sitagliptin to determine which better lowers blood sugar levels over time. Individuals diagnosed with type 2 diabetes within the last five years, currently managing it with metformin alone or not on any medication, might be suitable candidates. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking advancements in diabetes treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tirzepatide is generally safe for people with type 2 diabetes. In the SURPASS-1 trial, it lowered blood sugar and reduced weight. The most common side effects included mild nausea and diarrhea, which were usually temporary and manageable.

Pioglitazone has been used for a while to treat type 2 diabetes and is effective, though some people might gain weight or experience swelling. Both medications have approval for diabetes, indicating their safety.

The combination of tirzepatide and pioglitazone remains under study, but early research suggests they work well together. While this combination is still under investigation, each drug has demonstrated a good safety record in past studies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a fresh approach to managing Type 2 Diabetes by combining medications that work differently from existing options. Tirzepatide, for instance, is a dual-action drug that targets both GLP-1 and GIP receptors, which could enhance glucose control and promote weight loss more effectively than traditional single-action drugs like Metformin. The combination of Tirzepatide with Pioglitazone or Metformin and Sitagliptin aims to optimize these benefits, potentially improving insulin sensitivity and providing a more comprehensive approach to managing blood sugar levels. This multi-pronged strategy could offer patients more effective and personalized treatment options compared to the current standards, which primarily include Metformin, insulin, and sulfonylureas.

What evidence suggests that this trial's treatments could be effective for type 2 diabetes?

In this trial, participants will be assigned to different treatment arms to evaluate the effectiveness of various combinations for managing type 2 diabetes. Research has shown that using pioglitazone and tirzepatide together, as tested in some arms of this trial, can significantly lower HbA1c, a measure of blood sugar levels, and aid in weight loss for people with type 2 diabetes. Tirzepatide alone has controlled blood sugar and reduced weight more effectively than some other diabetes medications. Another arm of this trial will test the combination of metformin and sitagliptin, which has also been proven to lower blood sugar levels. Metformin, a common diabetes drug, when used with sitagliptin, helps improve blood sugar control. Both treatment options have evidence supporting their effectiveness, but pioglitazone and tirzepatide may offer additional benefits for weight management. ^{6 7 8 9 10}

Who Is on the Research Team?

Muhammad Abdul-Ghani, MD

Principal Investigator

The University of Texas Health Science Center at San Antonio

Are You a Good Fit for This Trial?

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

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

HbA1c >6.5% (no limit on upper HbA1c value)

Exclusion Criteria

Presence of hematuria in the urine analysis

I have had cancer within the last 5 years.

I have had pancreatitis before.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Metformin HCI XR
• Pioglitazone
• Sitagliptin
• Tirzepatide

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 (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&#8482;). Gettman, L.[2023]

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]

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]

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]

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]

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]

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Real-World Safety Concerns of Tirzepatide Background: Tirzepatide (Mounjaro or Zepbound), a dual GLP-1/GIP receptor agonist, is approved for type 2 diabetes and weight management.

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Efficacy and safety of GLP-1 agonists in the treatment ... GLP-1RAs improve glycaemic control, with tirzepatide, semaglutide and liraglutide exhibiting the most significant improvements.

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Tirzepatide for Type 2 Diabetes UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data.