Prediabetes, Type 2 Diabetes
Conditions
Brief summary
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
DRUGMetformin
Titrated to 1000 mg BID
DRUGLiraglutide
Titrated to 1.8 mg/day
DRUGGlargine
Titrated to target fasting glucose \<90 mg/dl
DRUGPlacebo
Matching to metformin 1000 mg BI
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
RISE Study Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ß-cell Response Measured by Hyperglycemic Clamp | 3-months after medication washout (Month 15) | Clamp measures of ß-cell response, co-primary outcomes |
| Insulin Sensitivity, M/I | 3-months after a medication washout | Clamp measure of insulin sensitivity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ACPRg | 3-months after a medication washout | First phase response from the hyperglycemic clamp |
| ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Secondary analysis was on all participants with a Month 12 visit. | Participants had 12-months of active therapy. Secondary results at the end of active intervention. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
Metformin: Titrated to 1000 mg BID | 65 |
| 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.
Metformin: Titrated to 1000 mg BID
Glargine: Titrated to target fasting glucose \<90 mg/dl | 67 |
| Placebo Placebo - 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 | 67 |
| 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).
Metformin: Titrated to 1000 mg BID
Liraglutide: Titrated to 1.8 mg/day | 68 |
| Total | 267 |
Baseline characteristics
| Characteristic | Metformin Alone | Total | Liraglutide + Metformin | Placebo | Glargine Followed by Metformin |
|---|---|---|---|---|---|
| 2-hour OGTT glucose | 10.1 mmol/L STANDARD_DEVIATION 2.4 | 10.1 mmol/L STANDARD_DEVIATION 2.3 | 9.9 mmol/L STANDARD_DEVIATION 2.2 | 10.1 mmol/L STANDARD_DEVIATION 2.3 | 10.3 mmol/L STANDARD_DEVIATION 2.4 |
| Age, Continuous | 55.2 years STANDARD_DEVIATION 8.2 | 53.9 years STANDARD_DEVIATION 8.9 | 54.0 years STANDARD_DEVIATION 8.1 | 52.8 years STANDARD_DEVIATION 10 | 53.5 years STANDARD_DEVIATION 9.3 |
| Body mass index (BMI) | 35.0 kg/m^2 STANDARD_DEVIATION 5.1 | 35.0 kg/m^2 STANDARD_DEVIATION 5.7 | 35.6 kg/m^2 STANDARD_DEVIATION 5.8 | 34.4 kg/m^2 STANDARD_DEVIATION 5.9 | 35.0 kg/m^2 STANDARD_DEVIATION 5.9 |
| Fasting glucose | 6.21 mmol/L STANDARD_DEVIATION 0.67 | 6.15 mmol/L STANDARD_DEVIATION 0.63 | 6.11 mmol/L STANDARD_DEVIATION 0.5 | 6.08 mmol/L STANDARD_DEVIATION 0.58 | 6.22 mmol/L STANDARD_DEVIATION 0.74 |
| HbA1c | 5.77 % of glycosylated hemoglobin STANDARD_DEVIATION 0.4 | 5.75 % of glycosylated hemoglobin STANDARD_DEVIATION 0.39 | 5.69 % of glycosylated hemoglobin STANDARD_DEVIATION 0.39 | 5.73 % of glycosylated hemoglobin STANDARD_DEVIATION 0.43 | 5.80 % of glycosylated hemoglobin STANDARD_DEVIATION 0.33 |
| Race/Ethnicity, Customized Race/Ethnicity All other | 6 Participants | 17 Participants | 2 Participants | 5 Participants | 4 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black | 19 Participants | 81 Participants | 20 Participants | 21 Participants | 21 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 6 Participants | 28 Participants | 6 Participants | 11 Participants | 5 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic White | 34 Participants | 141 Participants | 40 Participants | 30 Participants | 37 Participants |
| Sex: Female, Male Female | 37 Participants | 114 Participants | 29 Participants | 25 Participants | 23 Participants |
| Sex: Female, Male Male | 28 Participants | 153 Participants | 39 Participants | 42 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 67 | 0 / 67 | 0 / 68 |
| other Total, other adverse events | 29 / 65 | 28 / 67 | 23 / 67 | 30 / 68 |
| serious Total, serious adverse events | 5 / 65 | 2 / 67 | 3 / 67 | 7 / 68 |
Outcome results
Primary
Insulin Sensitivity, M/I
Clamp measure of insulin sensitivity
Time frame: 3-months after a medication washout
Population: All participants with a Month 15 visit
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Metformin Alone | Insulin Sensitivity, M/I | 3.53 x 10-5 mmol/kg/min per pmol/L |
| Glargine Followed by Metformin | Insulin Sensitivity, M/I | 3.38 x 10-5 mmol/kg/min per pmol/L |
| Placebo | Insulin Sensitivity, M/I | 3.63 x 10-5 mmol/kg/min per pmol/L |
| Liraglutide + Metformin | Insulin Sensitivity, M/I | 3.49 x 10-5 mmol/kg/min per pmol/L |
p-value: >0.05Regression, Linear
Primary
ß-cell Response Measured by Hyperglycemic Clamp
Clamp measures of ß-cell response, co-primary outcomes
Time frame: 3-months after medication washout (Month 15)
Population: Primary analysis was on all participants who attended their M15 visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Metformin Alone | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 3.65 nmol/L |
| Metformin Alone | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 4.61 nmol/L |
| Glargine Followed by Metformin | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 4.32 nmol/L |
| Glargine Followed by Metformin | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 3.58 nmol/L |
| Placebo | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 3.60 nmol/L |
| Placebo | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 4.45 nmol/L |
| Liraglutide + Metformin | ß-cell Response Measured by Hyperglycemic Clamp | Steady State C-peptide | 3.73 nmol/L |
| Liraglutide + Metformin | ß-cell Response Measured by Hyperglycemic Clamp | ACPRmax | 4.58 nmol/L |
Comparison: Seemingly unrelated regression was used to compare treatment arms on the combination of insulin sensitivity (M/I as calculated from the hyperglycemic clamp) and insulin secretion (steady-state C-peptide and ACPRmax as co-primary; ACPRg as major secondary,). See statistical analysis plan for further details and R code.p-value: >0.05Regression, Linear
Secondary
ACPRg
First phase response from the hyperglycemic clamp
Time frame: 3-months after a medication washout
Population: Analysis was on all participants able to have a M15 visit.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Metformin Alone | ACPRg | 1.68 nmol/L |
| Glargine Followed by Metformin | ACPRg | 1.68 nmol/L |
| Placebo | ACPRg | 1.68 nmol/L |
| Liraglutide + Metformin | ACPRg | 1.68 nmol/L |
p-value: >0.05Regression, Linear
Secondary
ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12
Participants had 12-months of active therapy. Secondary results at the end of active intervention.
Time frame: Secondary analysis was on all participants with a Month 12 visit.
Population: Secondary analysis was on all participants with a Month 12 visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 11.7 nmol/L |
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPg | 1.93 nmol/L |
| Metformin Alone | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPmax | 13.4 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPg | 1.88 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 11.6 nmol/L |
| Glargine Followed by Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPmax | 14.1 nmol/L |
| Placebo | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 10.8 nmol/L |
| Placebo | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPg | 1.69 nmol/L |
| Placebo | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPmax | 13.6 nmol/L |
| Liraglutide + Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPg | 2.68 nmol/L |
| Liraglutide + Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | ACRPmax | 10.1 nmol/L |
| Liraglutide + Metformin | ß-cell Function Measured by Hyperglycemic Clamp Techniques at M12 | Steady State C-peptide | 21.2 nmol/L |
Comparison: Analyses were completed on a log scale and re-exponentiated for display.p-value: <0.001ANOVA