A Phase 4 interventional study of Long-acting bedtime insulin detemir (Levemir) and Insulin detemir and pre-meal insulin aspart. in Type 2 Diabetes, sponsored by University of Florida. Completed at 1 site in United States. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2016-09-28.
Sponsored by University of Florida · Phase 4, Interventional, and Treatment
The optimal insulin therapy in T2DM is controversial and its impact on nonalcoholic fatty liver disease (NAFLD) has not been systematically studied before, and in particular, never when using the new insulin formulations detemir (Levemir®) or aspart (Novolog®). This study is to determine the effect on hepatic steatosis and insulin secretion/action of lowering the fasting plasma glucose (FPG) to target with once daily basal insulin detemir alone or combining insulin detemir with premeal insulin aspart in patients with uncontrolled type 2 diabetes mellitus (T2DM).
In the first 3 months the investigators will optimize metabolic control in all patients with intensive basal (bedtime) detemir insulin aiming at a normal fasting plasma glucose. After this treatment period, patients will be randomized in the second 3 months in a 2:1 ratio to insulin detemir or detemir plus aspart. The investigators propose that insulin will improve day-long glycemic control and A1c, reduce hepatic steatosis (NAFLD) (primary endpoint) and insulin secretion/sensitivity being well tolerated while causing minimal weight gain and hypoglycemia (secondary endpoints). The study will allow to assess if there is an additional benefit of adding pre-meal rapid-acting insulin aspart to basal insulin to these endpoints.
The control of hyperglycemia in T2DM ameliorates the metabolic abnormalities of T2DM but whether this improves hepatic steatosis has not been examined carefully with the use of improved insulin formulations (long-acting insulins detemir or glargine, alone or combined with pre-meal short-acting insulins). Most research studies have focused on glycemic control without a careful examination to the underlying mechanisms, with some of these studies reporting on improved hepatic and muscle insulin sensitivity. The investigators have found in the laboratory that intensified insulin therapy in T2DM is associated with enhanced glycogen synthase fractional velocity and non-oxidative glucose disposal, but with no improvement at the level of insulin-stimulated insulin receptor tyrosine phosphorylation, hexokinase II mRNA or enzyme function, phosphatidylinositol 3-kinase (PI 3-kinase) associated with IRS-1, or Akt phosphorylation. Our work did not examine hepatic steatosis or insulin secretion/action, nor was designed to distinguish between the relative contribution of reduced glucotoxicity on insulin sensitivity vs. beta-cell function from pre-meal regular vs. NPH insulin. It is possible that the beneficial effects of insulin therapy of reduced plasma glucose and FFA concentrations may be offset by excessive hyperinsulinemia and weight gain from the use of insulins with suboptimal pharmacokinetics compared to the newer insulin formulations.
Insulin detemir is an insulin analogue approved in 2005 by the FDA. It is a long-acting insulin analogue that has shown to be more predictable in achieving therapeutic plasma insulin levels compared to NPH insulin. This is associated with several clinical benefits, such as better glycemic control, less hypoglycemia, modest weight gain and better quality of life for patients with type 2 diabetes. If gluco-lipotoxicity likely play an important role in the development of hepatic steatosis (NAFLD) in T2DM the investigators speculate that if reversed by a strategy of basal long-acting insulin (insulin detemir) alone, or combined with a rapid-acting analog (pre-meal insulin aspart) may be a good strategy for the treatment of T2DM.
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To participate patients must:
All participants must have the following laboratory values:
Exclusion Criteria:
Patients will be excluded if any of the following criteria are present:
Patients with uncontrolled T2DM are treated with insulin detemir for 6 months. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl. This group will receive Long-acting bedtime insulin detemir (Levemir).
Drug: Long-acting bedtime insulin detemir (Levemir)
After baseline evaluations, insulin detemir will be given at bedtime and titrated to achieve a fasting plasma glucose between 80-100 mg/dl. After 3 months patients will be admitted to assess the metabolic effects of intervention. After this, insulin aspart (insulin detemir plus aspart) will be added before breakfast, lunch and dinner titrated to normalize the postprandial plasma glucose. After another 3 months patients are readmitted and all study procedures repeated. This group will receive Insulin detemir and pre-meal insulin aspart.
Drug: Insulin detemir and pre-meal insulin aspart.
This group will receive Insulin detemir. Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.
Also known as: Levemir insulin (trademark insulin by Novo Nordisk)
This group will receive Insulin detemir plus aspart. The group will start with Insulin detemir at bedtime. Then in three months they will Insulin aspart before breakfast, lunch and dinner.
Also known as: Insulin detemir = Levemir (Novo Nordisk), Insulin aspart = Novolog (Novo Nordisk)
Hepatic Steatosis
Hepatic steatosis measured by proton magnetic resonance spectroscopy (1H-MRS).
Time frame: 3 and 6 months
Metabolic Control as Measured by the A1c
Time frame: 3 and 6 months
Change in Insulin Secretion
Derived from the hyperglycemic clamp (Plasma C-peptide change vs. pretreatment in first and second phase).
Time frame: 3 and 6 months.
Intramyocellular (IMCL) by Magnetic Resonance Imaging and Spectroscopy (MRS).
Percent intramyocellular (IMCL) by magnetic resonance imaging and spectroscopy (MRS).
Time frame: 3 and 6 months.
Plasma Lipid Concentration.
Fasting plasma lipid concentration on day of admission at 3 and 6 months.
Time frame: 3 and 6 months.
Change in Anthropometric Measure (Body Weight).
Change in anthropometric measure (body weight) done on day of admission at 3 and 6 months.
Time frame: 3 and 6 months.
Number of Hypoglycemic Events
Defined as hypoglycemia \<40 mg/dl and/or requiring medical assistance during the trial.
Time frame: 3 and 6 months
Metabolic Control as Measured by the Fasting Plasma Glucose Concentration
Time frame: 3 and 6 months
Metabolic Control as Measured by the Postprandial Plasma Glucose During the Day-long Plasma Glucose Profile.
Time frame: 3 and 6 months
Advanced Lipid Testing
Change in lipoprotein particle number was determined using NMR.
Time frame: 3 and 6 months
Change in Anthropometric Measure (Body Mass Index [BMI]).
Change in anthropometric measure (body mass index \[BMI\]) done on day of admission at 3 and 6 months.
Time frame: 3 and 6 months.
Percent Change From Baseline in Vascular Inflammatory Markers
Inflammatory Markers include: Adiponectin, MMP-9, E-selectin, sICAM, and sVCAM
Time frame: 3 and 6 months
Clinical Research Unit
| Milestone | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| Started | 30 | 0 |
| Completed | 30 | 0 |
| Not completed | 0 | 0 |
| Milestone | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| Started | 8 | 22 |
| Completed | 8 | 20 |
| Not completed | 0 | 2 |
| Withdrew: Withdrawal by subject | 0 | 2 |
Hepatic steatosis measured by proton magnetic resonance spectroscopy (1H-MRS).
| percentage of liver fat | Insulin Detemir x 3 Months (All Pts Had Liver MRS) | Insulin Detemir Plus Aspart |
|---|---|---|
| Month 3 | 6.7 ± 4.4 | NA ± NA |
| Month 6 | 8.4 ± 7.2 | 5.9 ± 4.2 |
| percentage of A1c | Insulin Detemir Only (3 and 6 Months) | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month - A1c | 7.4 ± 1.4 | NA ± NA |
| 6-month - A1c | 6.9 ± 0.5 | 6.7 ± 0.7 |
Derived from the hyperglycemic clamp (Plasma C-peptide change vs. pretreatment in first and second phase).
| ng/ml | Insulin Detemir Only (3 and 6 Months) | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month C-peptide level increase in first phase | 0.5 ± 1.3 | NA ± NA |
| 3-month C-peptide level increase in second phase | 1.6 ± 2.5 | NA ± NA |
| 6-month C-peptide level increase in first phase | -0.1 ± 0.9 | 0.2 ± 1.4 |
| 6-month C-peptide level increase in second phase | 0.6 ± 2.0 | 0.2 ± 2.3 |
Percent intramyocellular (IMCL) by magnetic resonance imaging and spectroscopy (MRS).
| % of intramyocellular triglyceride | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month intramyocellular triglycerides | 0.63 ± 0.62 | NA ± NA |
| 6-month intramyocellular triglycerides | 1.05 ± 0.18 | 0.49 ± 0.47 |
Fasting plasma lipid concentration on day of admission at 3 and 6 months.
| mg/dL | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month total cholesterol | 136 ± 36 | NA ± NA |
| 3-month LDL-cholesterol | 76 ± 27 | NA ± NA |
| 3-month triglycerides | 154 ± 76 | NA ± NA |
| 3-month HDL-C | 33 ± 8 | NA ± NA |
| 6-month total cholesterol | 147 ± 31 | 145 ± 37 |
| 6-month LDL-cholesterol | 86 ± 29 | 80 ± 28 |
| 6-month triglycerides | 150 ± 66 | 144 ± 62 |
| 6-month HDL-C | 31 ± 5 | 33 ± 7 |
Change in anthropometric measure (body weight) done on day of admission at 3 and 6 months.
| Change from baseline (Kg) | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month total body weight | -0.8 ± 7.3 | NA ± NA |
| 6-month total body weight | 0.8 ± 1.9 | 0.3 ± 3.5 |
Defined as hypoglycemia \<40 mg/dl and/or requiring medical assistance during the trial.
| Number of events | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month rate of severe hypoglycemia | 0 | NA |
| 6-month rate of severe hypoglycemia | 0 | 0 |
| mg/dL | Insulin Detemir Only (3 and 6 Months) | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month - Fasting plasma glucose | 105 ± 38 | NA ± NA |
| 6-month - Fasting plasma glucose | 89 ± 18 | 116 ± 27 |
| mg/dL | Insulin Detemir Only (3 and 6 Months) | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month - Day-long plasma glucose profile | 168 ± 44 | NA ± NA |
| 6-month - Day-long plasma glucose profile | 153 ± 38 | 170 ± 48 |
Change in lipoprotein particle number was determined using NMR.
| Change in number of particles (nmol/L) | Insulin Detemir Only (3 and 6 Months) | Insulin Detemir Plus Aspart |
|---|---|---|
| VLDL particles (3 months) | -15 ± 39 | NA ± NA |
| VLDL particles (6 months) | -5 ± 38 | -2 ± 31 |
| LDL particles (3 months) | -100 ± 313 | NA ± NA |
| LDL particles (6 months) | 128 ± 206 | 85 ± 209 |
| HDL particles (3 months) | 0 ± 3 | NA ± NA |
| HDL particles (6 months) | 2 ± 4 | 1 ± 4 |
Change in anthropometric measure (body mass index \[BMI\]) done on day of admission at 3 and 6 months.
| Change from baseline (Kg/m2) | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| 3-month body mass index | -0.4 ± 2.7 | NA ± NA |
| 6-month body mass index | 0.3 ± 0.6 | 0.2 ± 1.2 |
Inflammatory Markers include: Adiponectin, MMP-9, E-selectin, sICAM, and sVCAM
| Percentage of change | Insulin Detemir Only | Insulin Detemir Plus Aspart |
|---|---|---|
| Adiponectin (3 months) | 18 ± 63 | NA ± NA |
| Adiponectin (6 months) | 65 ± 71 | 5 ± 30 |
| MMP-9 (3 months) | 32 ± 59 | NA ± NA |
| MMP-9 (6 months) | 30 ± 115 | 49 ± 73 |
| E-selectin (3 months) | -6 ± 25 | NA ± NA |
| E-selectin (6 months) | 34 ± 34 | 19 ± 29 |
| sICAM (3 months) | -4 ± 22 | NA ± NA |
| sICAM (6 months) | 2 ± 12 | -1 ± 15 |
| sVCAM (3 months) | 1 ± 8 | NA ± NA |
| sVCAM (6 months) | 14 ± 13 | 7 ± 11 |
Collected over Up to 6 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Insulin Detemir Only | — | 0/30 (0%) | 0/30 (0%) |
| Insulin Detemir Plus Aspart | — | 0/22 (0%) | 0/22 (0%) |
All participants were started in the "Insulin detemir only" arm. At week 12 the participants were randomized in a 2:1 ratio between the two arms.
| Age, Categorical(Participants) | Insulin Detemir Only | Insulin Detemir Plus Aspart | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 8 | 22 | 30 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Insulin Detemir Only | Insulin Detemir Plus Aspart | Total |
|---|---|---|---|
| Mean | 50 ± 8 | 59 ± 8 | 57 ± 9 |
| Sex: Female, Male(Participants) | Insulin Detemir Only | Insulin Detemir Plus Aspart | Total |
|---|---|---|---|
| Female | 0 | 3 | 3 |
| Male | 8 | 19 | 27 |
| Region of Enrollment(participants) | Insulin Detemir Only | Insulin Detemir Plus Aspart | Total |
|---|---|---|---|
| United States | 8 | 22 | 30 |
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