Primary outcomeGeometric mean· 3-months after medication washout (Month 15)
ß-cell Response Measured by Hyperglycemic Clamp
| Group | Value (nmol/L) |
|---|---|
| Metformin Alone | 3.65 |
| Glargine Followed by Metformin | 3.58 |
| Placebo | 3.60 |
| Liraglutide + Metformin | 3.73 |
Trial · Interventional
CompletedPhase 3Results postedRegistry dataRISE Adult Medication Study
Short name RISE Adult
Overview
- Status
- Completed
- Phase
- Phase 3
- Enrollment
- 267 participants (actual)
- Sponsor
- RISE Study Group · Network
- Design
- Randomized · Quadruple masking
- Countries
1 country
United States
- Start
- Apr 2013
- Primary completion
- Feb 2019
- Completion
- Aug 2019
- First posted
- 30 Jan 2013 (estimated)
- Last update posted
- 11 May 2023
- Conditions
- Prediabetes · Type 2 Diabetes
Timeline
1 trial · 1 completed · 1 with posted results
- Completed
- Ongoing
- Not yet recruiting
- Stopped
- Estimated dates (est.)
- Results posted
2014201620182020
- Ph 3
Registry summary
Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.
The RISE Adult Medication Study is a 4-arm, 3-center, clinical trial of adults with prediabetes and early type 2 diabetes to address the hypothesis that aggressive glucose lowering will lead to recovery of beta-cell function that will be sustained after withdrawal of treatment. Adult participants (ages 20-65) will be randomized to one of the following treatment regimens: (1) blinded placebo, (2) blinded metformin alone, (3) early intensive insulin treatment with basal insulin glargine followed by open-label metformin, (4) the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide plus open-label metformin. The primary clinical question RISE will address is: Are improvements in ß-cell function following 12 months of active treatment maintained for 3 months following the withdrawal of therapy? Secondary outcomes will assess durability of glucose tolerance following withdrawal of therapy, and whether biomarkers obtained in the fasting state predict parameters of ß-cell function, insulin sensitivity and glucose tolerance and the response to an intervention.
Interventions
- MetforminDrug
- LiraglutideDrug
- GlargineDrug
- PlaceboDrug
Arms4
Active comparator
Metformin alone
Metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment.
Active comparator
Glargine followed by Metformin
Basal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months.
Placebo comparator
Placebo
Placebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin.
Active comparator
Liraglutide + Metformin
Liraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day).
Primary outcomes2
Outcomes the sponsor listed as primary.
ß-cell Response Measured by Hyperglycemic Clamp
Time frame · 3-months after medication washout (Month 15)
Registry description
Clamp measures of ß-cell response, co-primary outcomes
Insulin Sensitivity, M/I
Time frame · 3-months after a medication washout
Registry description
Clamp measure of insulin sensitivity
Secondary outcomes(2)
ACPRg
Time frame · 3-months after a medication washout
Registry description
First phase response from the hyperglycemic clamp
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
Time frame · Secondary analysis was on all participants with a Month 12 visit.
Registry description
Participants had 12-months of active therapy. Secondary results at the end of active intervention.
Posted results
Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.
Primary outcome results
Primary outcomeGeometric mean· 3-months after a medication washout
Insulin Sensitivity, M/I
| Group | Value (x 10-5 mmol/kg/min per pmol/L) |
|---|---|
| Metformin Alone | 3.53 |
| Glargine Followed by Metformin | 3.38 |
| Placebo | 3.63 |
| Liraglutide + Metformin | 3.49 |
Secondary and other outcome results(2)
Secondary outcomeGeometric mean· 3-months after a medication washout
ACPRg
| Group | Value (nmol/L) |
|---|---|
| Metformin Alone | 1.68 |
| Glargine Followed by Metformin | 1.68 |
| Placebo | 1.68 |
| Liraglutide + Metformin | 1.68 |
Secondary outcomeGeometric mean· Secondary analysis was on all participants with a Month 12 visit.
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
| Group | Value (nmol/L) |
|---|---|
| Metformin Alone | 1.93 |
| Glargine Followed by Metformin | 1.88 |
| Placebo | 1.69 |
| Liraglutide + Metformin | 2.68 |
Adverse events, as posted
| Group | Deaths | Serious events | Other events |
|---|---|---|---|
| Metformin AloneMetformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Participants randomized to the metformin-alone arm will be blinded to treatment. Metformin: Titrated to 1000 mg BID | 0 / 65 | 5 / 65 | 29 / 65 |
| Glargine Followed by MetforminBasal insulin glargine for 3 months titrated to achieve a morning fasting blood glucose of 80-90 mg/dl, followed by open-label metformin (titrated up to 2000 mg/day) for 9 months. Metformin: Titrated to 1000 mg BID Glargine: Titrated to target fasting glucose \<90 mg/dl | 0 / 67 | 2 / 67 | 28 / 67 |
| PlaceboPlacebo - masked to metformin-alone. Placebo will be titrated to the maximum number of tablets equivalent to maximum dose of metformin. Placebo: Matching to metformin 1000 mg BI | 0 / 67 | 3 / 67 | 23 / 67 |
| Liraglutide + MetforminLiraglutide + open-label Metformin. Liraglutide will be titrated to the maximum dose tolerated (up to 1.8 mg/day) after which metformin will be titrated to the maximum dose tolerated (up to 2000 mg/day). Metformin: Titrated to 1000 mg BID Liraglutide: Titrated to 1.8 mg/day | 0 / 68 | 7 / 68 | 30 / 68 |
Each cell reads participants affected / participants at risk, as the registry posted them.
Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works
Studies5
Studies that cite this trial.
Studies with results
3 studies on this page
Indexing hint: Randomized controlled trial · 2022
3 results
Weight loss and β-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.
Utzschneider et al. 2022Obesity (Silver Spring, Md.)
PMID 35894078PMC10849844DOI 10.1002/oby.23475PUB-35894078
Rights unknown3 results
Indexing hint: Randomized controlled trial · 2021
1 result
Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.
Sam et al. 2021Diabetes carecited by 40
PMID 34131048PMC8740917DOI 10.2337/dc21-0027PUB-34131048
Rights unknown1 result
Indexing hint: Randomized controlled trial · 2021
6 results
Effect of Medical and Surgical Interventions on α-Cell Function in Dysglycemic Youth and Adults in the RISE Study.
Kahn et al. 2021Diabetes carecited by 4
PMID 34135015PMC8740921DOI 10.2337/dc21-0461PUB-34135015
Rights unknown6 results
Indexing hint: Randomized controlled trial · 2014
Restoring Insulin Secretion (RISE): design of studies of β-cell preservation in prediabetes and early type 2 diabetes across the life span.
Diabetes carecited by 81
PMID 24194506PMC3931376DOI 10.2337/dc13-1879PUB-24194506
Free to read · publisher termsCC BY-NC-ND
More studies
1 study on this page
PubMed tag: none · 2019
Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes.
Diabetes carecited by 60
PMID 31178434PMC6702605DOI 10.2337/dc19-0556PUB-31178434
Rights unknown
Other registry references
References listed at the registry that are not in PepBank. They link to PubMed.
- DerivedTjaden AH, Edelstein SL, Arslanian S, Barengolts E, Caprio S, Cree-Green M, Lteif A, Mather KJ, Savoye M, Xiang AH, Kahn SE. Reproducibility of Glycemic Measures Among Dysglycemic Youth and Adults in the RISE Study. J Clin Endocrinol Metab. 2023 Sep 18;108(10):e1125-e1133. doi: 10.1210/clinem/dgad135. PMID 36938582
- DerivedUtzschneider KM, Tripputi MT, Kozedub A, Barengolts E, Caprio S, Cree-Green M, Edelstein SL, El Ghormli L, Hannon TS, Mather KJ, Palmer J, Nadeau KJ; RISE Consortium. Differential loss of beta-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study. Diabetes Res Clin Pract. 2021 Aug;178:108948. doi: 10.1016/j.diabres.2021.108948. Epub 2021 Jul 15. PMID 34274407
- DerivedKahn SE, Mather KJ, Arslanian SA, Barengolts E, Buchanan TA, Caprio S, Ehrmann DA, Hannon TS, Marcovina S, Nadeau KJ, Utzschneider KM, Xiang AH, Edelstein SL; RISE Consortium; Rise Consortium Investigators:. Hyperglucagonemia Does Not Explain the beta-Cell Hyperresponsiveness and Insulin Resistance in Dysglycemic Youth Compared With Adults: Lessons From the RISE Study. Diabetes Care. 2021 Sep;44(9):1961-1969. doi: 10.2337/dc21-0460. Epub 2021 Jun 15. PMID 34131047
- DerivedArslanian SA, El Ghormli L, Kim JY, Tjaden AH, Barengolts E, Caprio S, Hannon TS, Mather KJ, Nadeau KJ, Utzschneider KM, Kahn SE; RISE Consortium. OGTT Glucose Response Curves, Insulin Sensitivity, and beta-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve beta-Cell Function. Diabetes Care. 2021 Mar;44(3):817-825. doi: 10.2337/dc20-2134. Epub 2021 Jan 12. PMID 33436401
- DerivedGnesin F, Thuesen ACB, Kahler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2. PMID 32501595
- DerivedRISE Consortium. Obesity and insulin sensitivity effects on cardiovascular risk factors: Comparisons of obese dysglycemic youth and adults. Pediatr Diabetes. 2019 Nov;20(7):849-860. doi: 10.1111/pedi.12883. Epub 2019 Jul 29. PMID 31301210
- DerivedRISE Consortium; RISE Consortium Investigators. Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on beta-Cell Function: Comparison of Responses In Youth And Adults. Diabetes. 2019 Aug;68(8):1670-1680. doi: 10.2337/db19-0299. Epub 2019 Jun 9. PMID 31178433
- DerivedRISE Consortium. Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: II. Observations Using the Oral Glucose Tolerance Test. Diabetes Care. 2018 Aug;41(8):1707-1716. doi: 10.2337/dc18-0243. Epub 2018 Jun 25. PMID 29941498
- DerivedRISE Consortium. Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp. Diabetes Care. 2018 Aug;41(8):1696-1706. doi: 10.2337/dc18-0244. Epub 2018 Jun 25. PMID 29941497
Eligibility
Who could join, as posted.
- Sex
- All
- Age
- from 20 Years up to 65 Years
- Healthy volunteers
- Accepted
Inclusion and exclusion criteria, as posted
Inclusion Criteria:
1. Fasting plasma glucose 95-125 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose on OGTT.
2. Age 20-65 years
3. Body mass index (BMI) ≥25 kg/m2 but ≤50 kg/m2
4. Self-reported diabetes \<1 year in duration
5. Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable glucose lowering agents)
Exclusion Criteria:
1. Underlying disease likely to limit life span and/or increase risk of intervention or an underlying condition that is likely to limit ability to participate in outcomes assessment
2. An underlying disease that affects glucose metabolism other than type 2 diabetes
3. Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
4. Active infections
5. Renal disease (serum creatinine \>1.4 mg/dl for men; \>1.3 mg/dl for women) or serum potassium abnormality (\<3.4 or \>5.5 mmol/l)
6. Anemia (hemoglobin \<11 g/dl in women, \<12 g/dl in men) or known coagulopathy
7. Cardiovascular disease, including uncontrolled hypertension. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.
8. History of conditions that may be precipitated or exacerbated by a study drug:
1. Pancreatitis
2. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
3. Excessive alcohol intake
4. Suboptimally treated thyroid disease
5. Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)
6. Hypertriglyceridemia (\>400 mg/dl despite treatment)
9. Conditions or behaviors likely to affect the conduct of the RISE Study
1. Unable or unwilling to give informed consent
2. Unable to adequately communicate with clinic staff
3. Another household member is a participant or staff member in RISE
4. Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE
5. Weight loss of \>5% in past three months for any reason other than post-partum weight loss. Participants taking weight loss drugs or using preparations taken for intended weight loss are excluded.
6. Likely to move away from participating clinics in next two years
7. Women of childbearing potential who are unwilling to use adequate contraception
8. Current (or anticipated) pregnancy and lactation.
9. Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE
10. Additional conditions may serve as criteria for exclusion at the discretion of the local site.
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