Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) on Insulin Secretion and Action in Type 2 Diabetes

Type 2 Diabetes Clinical Trial

Official title:

Effect of a Basal/Pre-Meal Insulin Strategy (Detemir/Aspart) to Improve Insulin Secretion and Action in Subjects With Type 2 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00998335
• Other study ID #: 20060167
• Status: Completed
• Phase: Phase 4
• First received: October 19, 2009
• Last updated: April 26, 2012
• Start date: June 2007
• Est. completion date: February 2010

Study information

• Verified date: April 2012
• Source: The University of Texas Health Science Center at San Antonio
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The optimal insulin therapy in T2DM is controversial and its impact on nonalcoholic fatty liver disease (or NAFLD, a common condition in T2DM; Cusi K, Current Diabetes Reports 2009) has not been systematically studied before, and in particular, never when using the new insulin formulations detemir (Levemir®) or aspart (Novolog®). This study was 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.

Description:

Clinical studies suggest that 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 (i.e, long-acting insulins detemir or glargine, alone or combined with pre-meal short-acting insulins). Most studies have focused on glycemic control without a careful examination to the underlying mechanisms, with some studies reporting on improved hepatic and muscle insulin sensitivity. We have found in our 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 (see attached articles). 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 (as suggested by a growing body of literature, see Cusi K, Current Diabetes Reports 2009) we speculate that if reversed by a strategy of basal long-acting insulin (i.e., insulin detemir) alone, or combined with a rapid-acting analog (i.e., pre-meal insulin aspart) may be a good strategy for the treatment of T2DM. However, the effects of intensive insulin therapy on NAFLD in T2DM (measured by the gold-standard magnetic resonance and spectroscopy or MRS) or on insulin action and insulin secretion using gold-standard metabolic techniques.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: February 2010
• Est. primary completion date: February 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

To participate patients must:

1. Be able to communicate meaningfully with the Investigator and be legally competent to provide written informed consent.

2. Female patients must be non-lactating and must either be at least two years post-menopausal, or be using adequate contraceptive precautions (i.e. oral contraceptives, approved hormonal implant, intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period.

3. Age range of 18 to 70 years (inclusive).

4. Patients must have been on a stable dose of allowed chronic medications for two months prior to entering the double-blind treatment period.

5. All participants must have the following laboratory values:

• Hemoglobin = 12 g/dl in males or = 11 g/dl in females

• Serum creatinine = 1.5 mg/dl

• AST (SGOT) = 2.5 times upper limit of normal

• ALT (SGPT) = 2.5 times upper limit of normal

• Alkaline phosphatase = 2.5 times upper limit of normal

Exclusion Criteria:

Patients will be excluded if any of the following criteria are present:

1. Individuals with type 1 diabetes or type 2 diabetes and a FPG = 300 mg/dl.

2. Subjects on sulfonylureas, metformin and/or TZDs unless the dose has been stable for at least 2 months prior to study entry.

3. Patients on any of the following medications: thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on stable doses of such agents for the past two months before entry into the study. Patients may be taking stable doses of estrogens or other hormonal replacement therapy if the patient has been on these agents for the prior two months. Patients taking systemic glucocorticoids will be excluded.

4. Past (within 1 year) or current history of alcohol abuse.

5. Patients will be excluded if there is a history of clinically significant heart disease (New York Heart Classification greater than grade II), peripheral vascular disease (history of claudication), or pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation) or chronic renal failure (serum creatinine greater than 1.5 mg/dl).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Long-acting bedtime insulin detemir (Levemir)
Insulin detemir is given at bedtime aiming at a fasting plasma glucose between 80-100 mg/dl.
• Insulin detemir and pre-meal insulin aspart.
Insulin detemir at bedtime. Insulin aspart before breakfast, lunch and dinner.

Locations

Country	Name	City	State
United States	The University of Texas H.S.C. at San Antonio and the San Antonio Audie L. Murphy VA Hospital	San Antonio	Texas

Sponsors (3)

Lead Sponsor	Collaborator
The University of Texas Health Science Center at San Antonio	Novo Nordisk A/S, VA Office of Research and Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hepatic steatosis measured by magnetic resonance spectroscopy (MRS).		3 and 6 months.	No
Secondary	Metabolic control as measured by the fasting and postprandial plasma glucose (mixed meal, day-long plasma glucose profile) and A1c.		3 and 6 months.	No
Secondary	Insulin secretion and insulin sensitivity.		3 and 6 months.	No
Secondary	Intramyocellular (IMCL) by MRS and visceral fat content by magnetic resonance imaging (MRI).		3 and 6 months.	No
Secondary	Plasma lipids.		3 and 6 months.	No
Secondary	Vascular inflammatory markers (hsCRP, ICAM, VCAM, etc.)		3 and 6 months.	No
Secondary	Anthropometric measures (body weight, body mass index (BMI), total body fat by DXA).		3 and 6 months.	No
Secondary	Rate of hypoglycemia.		6 months.	Yes