Personalized Diabetes Medication Adjustment for Type 2 Diabetes

(CHANGE Trial)

Overseen By Lawrence S Phillips, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Foundation for Atlanta Veterans Education and Research, Inc.

Must not be taking: Systemic glucocorticoids

Disqualifiers: CVD, Heart failure, Pregnancy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 2.5 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new methods for adjusting diabetes medications in people with Type 2 diabetes. It aims to determine if maintaining normal blood sugar levels can protect insulin-producing cells and prevent complications like eye and kidney issues. Participants will be divided into groups, with medication adjustments guided either by regular blood sugar checks or by the HbA1c blood test, which shows average blood sugar over several months. This process is known as the intensification of diabetes medication. Suitable candidates for this trial have had Type 2 diabetes for some time, with blood sugar levels slightly above normal. As an unphased trial, this study offers a unique opportunity to contribute to innovative diabetes care strategies.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research shows that the treatments in this study are generally safe for people. Some studies have found that adjusting diabetes medication based on blood sugar levels effectively lowers blood sugar. The medications used include metformin, pioglitazone, semaglutide, and empagliflozin, all commonly used and considered safe for most patients.

Metformin is often the first choice and is usually easy for people to handle. Some might experience mild side effects like an upset stomach, but these often subside over time. Pioglitazone and semaglutide are also generally well-tolerated, though they can cause side effects like weight gain or nausea. Empagliflozin is another safe option, but it may lead to increased urination.

The other treatment method, based on HbA1c levels, uses the same medications. These drugs are part of standard diabetes care, so they are considered safe for most people.

Overall, while each medication can have side effects, they are widely used and generally well-tolerated. It's important to consult a doctor about any concerns, especially when considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a more personalized approach to managing Type 2 diabetes. Unlike standard treatments, which often rely on a one-size-fits-all medication regimen, this trial tests two innovative methods: one intensifies diabetes medication based on self-monitored blood glucose levels, and the other uses HbA1c levels as a guide. This personalized approach aims to optimize medication adjustments, potentially leading to better blood sugar control and fewer side effects. By tailoring treatment to individual needs, researchers hope to improve outcomes and quality of life for people with Type 2 diabetes.

What evidence suggests that this trial's treatments could be effective for Type 2 Diabetes?

This trial will compare two methods for adjusting diabetes medications. One method adjusts medications based on self-monitored blood glucose (SMBG) levels, while the other uses HbA1c levels as a guide. Research has shown that adjusting medications based on blood sugar levels can help control blood sugar and reduce high spikes. Studies have found that increasing treatment can lower average daily blood sugar without causing frequent low blood sugar episodes. Additionally, adding medications like SGLT-2 inhibitors to the treatment plan can further lower blood sugar levels. This approach may slow the progression of type 2 diabetes by reducing the strain on insulin-producing cells. Overall, these personalized adjustments offer a promising way to manage diabetes and potentially reduce complications. ^{1 2 3 6 7}

Who Is on the Research Team?

Mary K Rhee, MD, MSCR

Principal Investigator

Emory University School of Medicine, Atlanta VA Medical Center

Lawrence S Phillips, MD

Principal Investigator

Emory University School of Medicine, Atlanta VA Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 40-74 with Type 2 Diabetes, having specific glucose levels and HbA1c between 6.0-7.4%. It's not for those who've had bariatric surgery, severe kidney issues, dementia, recent heart problems or pancreatitis, are pregnant or extremely overweight.

Inclusion Criteria

Your blood sugar level after drinking a sugary drink is higher than 155 mg/dl.

I am between 40 and 74 years old.

You have been diagnosed with diabetes through an oral glucose tolerance test (OGTT).

Exclusion Criteria

I have pancreatitis.

I have a family or personal history of MEN2A.

I am currently taking steroid medications.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

1 visit (in-person)

Run-in

Establish tolerance to metformin and adherence to self-monitoring of blood glucose

2 weeks

1 visit (in-person)

Treatment

Participants receive lifestyle intervention and randomized to intensive or control treatment arms with regular monitoring

2.5 years

Quarterly visits (in-person) for HbA1c and glucose monitoring

Washout

A 3-month period to assess the sustainability of β-cell function post-treatment

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Intensification of diabetes medication based largely on HbA1c levels
• Intensification of diabetes medication based on glucose levels

Trial Overview The study tests if adjusting diabetes medication to maintain normal glucose levels can preserve insulin-producing cell function better than usual care based on HbA1c levels alone. This could slow disease progression and prevent complications.

How Is the Trial Designed?

Group I: USE OF DIABETES Rx GUIDED BY SELF-MONITORED BLOOD GLUCOSE (SMBG) Experimental Treatment 1 Intervention

1. Guidance by SMBG: 2. Glucose goals: We will aim for \<100 mg/dl premeal (2), \<130 postmeal. 3. Monitoring will include pre-breakfast 2x/wk, and a 5-point profile 1x/wk (before and 1.5-2.5 hr after breakfast, before lunch, before supper, and bedtime). 4. Added Rx will be used if SMBG is \>goal ≥3x in 2 consecutive weeks after ≥4 weeks of MOVE! and/or the previous Rx \[e.g., any 3 of the 7 goals (\<100 mg/dl premeal, \<130 post)\]. Metformin ER will be given first (if not already on it), and increased to 2000 mg/day if there are no side effects. (If metformin is not tolerated, it will be stopped and the second Rx will become the "first Rx" and given instead. If other Rx are not tolerated, the next Rx will be used. The second Rx will be the TZD pioglitazone, followed by the GLP-1 RA semaglutide, then the SGLT-2 inhibitor empagliflozin. If still above goal, glargine insulin will be added, titrated to keep fasting glucose \<100 mg/dl.

Group II: USE OF DIABETES Rx GUIDED LARGELY BY HbA1c LEVELS Active Control 1 Intervention

Extended-release \[ER\] metformin will be added if HbA1c is ≥7.0% after 3 months; if already used and maximized, pioglitazone will be begun. Other Rx will be added each time HbA1c reaches ≥7.5%. The sequence of Rx will be the same as in intensive Rx subjects; those using insulin will also do prebreakfast SMBG, aiming for glucose \<100 mg/dl.

Intensification of diabetes medication based largely on HbA1c levels is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Metformin for:

• Type 2 diabetes mellitus

Approved in United States as Dapagliflozin for:

• Type 2 diabetes mellitus
• Heart failure
• Chronic kidney disease

Approved in United States as Semaglutide for:

• Type 2 diabetes mellitus
• Weight management

Approved in European Union as Saxagliptin for:

• Type 2 diabetes mellitus

Approved in Canada as Empagliflozin for:

• Type 2 diabetes mellitus
• Heart failure

Approved in Japan as Linagliptin for:

• Type 2 diabetes mellitus

Approved in China as Canagliflozin for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Foundation for Atlanta Veterans Education and Research, Inc.

Lead Sponsor

Trials

7

Recruited

930+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Emory University

Collaborator

Trials

1,735

Recruited

2,605,000+

Abbott Diabetes Care

Industry Sponsor

Trials

67

Recruited

25,600+

Robert B. Ford

Abbott Diabetes Care

Chief Executive Officer since 2020

Bachelor's degree from Boston College, MBA from UC Berkeley, Haas School of Business

Dr. Mahmood Kazemi

Abbott Diabetes Care

Chief Medical Officer

Bachelor's and Master's degrees from Stanford University, MD from the University of California, San Francisco

Published Research Related to This Trial

In a study of 8,034 patients with type 2 diabetes, adding a GLP-1 receptor agonist (RA) to basal insulin resulted in better A1C reductions compared to simply increasing basal insulin doses, while also lowering the frequency of hypoglycemia.

The addition of GLP-1 RA did not increase overall healthcare costs, despite higher prescription costs, making it a cost-effective strategy for improving glycemic control in patients who struggle with insulin titration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

COMPARING CLINICAL OUTCOMES AND COSTS FOR DIFFERENT TREATMENT INTENSIFICATION APPROACHES IN PATIENTS WITH TYPE 2 DIABETES UNCONTROLLED ON BASAL INSULIN: ADDING GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS VERSUS ADDING RAPID-ACTING INSULIN OR INCREASING BASAL INSULIN DOSE. Levin, P., Fan, T., Song, X., et al.[2022]

The fixed-dose combination of saxagliptin and metformin (SAXA/MET) significantly improves glycemic control in patients with type 2 diabetes who are not adequately managed with metformin alone, demonstrating its efficacy compared to placebo.

SAXA/MET is safe for a wide range of patients, including those with cardiovascular disease and renal impairment, and it has a favorable safety profile with minimal adverse events, making it a patient-friendly option for diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination. Panagoulias, GS., Doupis, J.[2021]

There is significant uncertainty in managing type 2 diabetes due to varying glycemic targets, complex drug therapies, and the lack of evidence comparing all treatment options, which can confuse clinicians.

Personalized medicine approaches could enhance diabetes management by tailoring treatments to individual patient needs, but further research is necessary to establish effective strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does personalized diabetology overcome clinical uncertainty and therapeutic inertia in type 2 diabetes? Esposito, K., Ceriello, A., Giugliano, D.[2022]

The combination therapy of linagliptin (a DPP-4 inhibitor) and empagliflozin (an SGLT2 inhibitor) is effective for patients with inadequately controlled type 2 diabetes, particularly for those with HbA1c levels below 8.5%, providing an additive effect in lowering blood sugar levels.

Both medications have excellent safety profiles, with low risks of hypoglycemia and similar tolerability rates compared to their use as monotherapies, making this combination a safe and effective option for managing type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Empagliflozin and linagliptin combination therapy for treatment of patients with type 2 diabetes mellitus. Triplitt, C., Solis-Herrera, C., Cersosimo, E., et al.[2019]

In a 24-week study involving 286 patients with type 2 diabetes, adding saxagliptin to metformin therapy resulted in a slightly greater reduction in HbA1c levels compared to increasing the metformin dose, although the difference was not statistically significant.

Saxagliptin was associated with fewer gastrointestinal side effects, such as diarrhea, compared to metformin uptitration, suggesting it may be a better-tolerated option for patients struggling with glycemic control on metformin alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study. Hermans, MP., Delibasi, T., Farmer, I., et al.[2013]

In a study of 333 patients with Type 2 diabetes, adding linagliptin to metformin therapy significantly improved glycaemic control, with the 5 mg dose showing the greatest reduction in HbA(1c) levels by 0.73% compared to placebo.

Linagliptin was well tolerated, with no reported hypoglycaemic events, unlike glimepiride, which caused hypoglycaemia in 5% of patients, highlighting linagliptin's safety profile as an add-on therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Forst, T., Uhlig-Laske, B., Ring, A., et al.[2022]

In a study of 9748 adults with type 2 diabetes on metformin, specific patient characteristics such as cholesterol levels and duration of hypertension were found to influence the effectiveness of add-on medications like sulfonylureas (SU), DPP-4 inhibitors, and SGLT-2 inhibitors in reducing HbA1c levels.

Understanding these predictors can help healthcare providers make better decisions about which add-on medication to prescribe, potentially improving treatment outcomes and preventing complications related to diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of HbA1c treatment response to add-on medication following metformin monotherapy: a population-based cohort study. Tan, WY., Hsu, W., Lee, ML., et al.[2023]

In a meta-analysis of long-term studies (up to 4 years) on type 2 diabetes patients who failed metformin, empagliflozin showed better efficacy in glycemic control compared to dapagliflozin and saxagliptin, with 23% of patients maintaining HbA1c levels below 7% after 4 years.

Empagliflozin also outperformed glimepiride, a sulfonylurea, in glycemic control, indicating it may be a more effective second-line treatment option after metformin failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of gliflozins versus gliptins for Type 2 Diabetes after metformin failure: a systematic review and network meta-analysis. Zilli, RW., Rached, CDA., Silva, FPD., et al.[2023]

A Phase III trial showed that the combination of linagliptin and metformin is more effective than either drug alone for managing high blood sugar in patients with type 2 diabetes, especially in those with higher initial HbA1c levels.

This combination therapy is weight neutral and well tolerated, with a low risk of hypoglycemia, making it a suitable option for patients who prefer oral medications over insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial combination therapy for patients with type 2 diabetes mellitus: considerations for metformin plus linagliptin. Freeman, JS.[2021]

The combination of saxagliptin and dapagliflozin shows significant improvements in glycemic control, including reductions in glycated hemoglobin and glucose levels, with a low risk of adverse effects such as hypoglycemia.

This combination therapy is well tolerated and may enhance beta-cell function and insulin clearance, making it a promising option for managing type 2 diabetes without the weight gain associated with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with saxagliptin and dapagliflozin for the treatment of type 2 diabetes. Williams, DM., Stephens, JW.[2022]

DPP-4 inhibitors, when used in combination with other oral antidiabetic drugs, provide an effective strategy for early and aggressive management of type 2 diabetes, targeting both postprandial and fasting glucose levels.

These inhibitors have a low risk of causing hypoglycemia and are generally weight neutral, making them suitable for combination therapy with other diabetes medications like metformin and sulfonylureas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing hyperglycemia in patients with type 2 diabetes mellitus: rationale for the use of dipeptidyl peptidase-4 inhibitors in combination with other oral antidiabetic drugs. Freeman, JS.[2010]

Semaglutide, an oral antidiabetic agent approved by the US-FDA, showed the highest efficacy in lowering HbA1c levels in Type 2 Diabetes Mellitus patients, with a significant reduction of 1.6% at a dose of 1.0 mg (p < 0.0001).

The safety profiles of the newer antidiabetic agents were generally similar to placebo, with no fatal adverse events reported; however, gastrointestinal issues and hypoglycemic events were the most common side effects, with alogliptin having the least frequency of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Efficacy and Safety of Newer Antidiabetic Drugs Approved from 2013 to 2017 in Controlling HbA1c in Diabetes Patients. Palanisamy, S., Yien, ELH., Shi, LW., et al.[2020]

Despite rising diagnoses of type 2 diabetes (T2DM), healthcare providers frequently do not intensify insulin regimens as recommended, even when patients' HbA1c levels indicate the need for more aggressive treatment.

The lack of comprehensive studies on insulin intensification patterns highlights a gap in understanding how well patients with T2DM are managed, suggesting a need for better assessment of pharmacologic care quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patterns and trends in insulin intensification among patients with type 2 diabetes: a systematic review. Polinski, JM., Connolly, JG., Curtis, BH., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2359170/

Treatment Intensification and Blood Glucose Control Among ... Antihyperglycemic treatment intensification was strongly associated with decrease in average daily glucose, while hypoglycemia was uncommon.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2200433

Glycemia Reduction in Type 2 Diabetes — Glycemic ... All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, ...

3. diabetesjournals.org diabetesjournals.org/care/article/48/Supplement_1/S181/157569/9-Pharmacologic-Approaches-to-Glycemic-Treatment

9. Pharmacologic Approaches to Glycemic Treatment This guideline provides detailed information on intensification of therapy to meet individualized needs. In addition, the American Diabetes ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3139533/

Insulin initiation and intensification in patients with T2DM ... The goal of insulin intensification within the primary care setting is to minimize patients' exposure to chronic hyperglycemia and weight gain, and reduce ...

5. bmj.com bmj.com/content/385/bmj-2023-077097

Comparative effectiveness of second line oral antidiabetic ... We found that for a broad population of people with type 2 diabetes mellitus, SGLT-2 inhibitors were more effective second line treatments in ...

6. acpjournals.org acpjournals.org/doi/10.7326/M18-1149

Medicines for Treatment Intensification in Type 2 Diabetes ... The World Health Organization developed these guidelines to provide guidance on selection of medicines for treatment intensification in type 2 diabetes.

7. patientcareonline.com patientcareonline.com/view/treatment-intensification-type-2-diabetes-3-cases

Treatment Intensification in Type 2 Diabetes: 3 Cases When intensifying T2DM therapy to reach glycemic goals, newer agents target common comorbidities. Which would you choose in these 3 scenarios?