Currently Viewing:
The American Journal of Managed Care September 2014
Impact of Atypical Antipsychotic Use Among Adolescents With Attention-Deficit/Hyperactivity Disorder
Vanja Sikirica, PharmD, MPH; Steven R. Pliszka, MD; Keith A. Betts, PhD; Paul Hodgkins, PhD, MSc; Thomas M. Samuelson, BA; Jipan Xie, MD, PhD; M. Haim Erder, PhD; Ryan S. Dammerman, MD, PhD; Brigitte
Effective Implementation of Collaborative Care for Depression: What Is Needed?
Robin R. Whitebird, PhD, MSW; Leif I. Solberg, MD; Nancy A. Jaeckels, BS; Pamela B. Pietruszewski, MA; Senka Hadzic, MPH; Jürgen Unützer, MD, MPH, MA; Kris A. Ohnsorg, MPH, RN; Rebecca C. Rossom, MD
Is All "Skin in the Game" Fair Game? The Problem With "Non-Preferred" Generics
Gerry Oster, PhD, and A. Mark Fendrick, MD
Targeting High-Risk Employees May Reduce Cardiovascular Racial Disparities
James F. Burke, MD, MS; Sandeep Vijan, MD; Lynette A. Chekan, MBA; Ted M. Makowiec, MBA; Laurita Thomas, MEd; and Lewis B. Morgenstern, MD
HITECH Spurs EHR Vendor Competition and Innovation, Resulting in Increased Adoption
Seth Joseph, MBA; Max Sow, MBA; Michael F. Furukawa, PhD; Steven Posnack, MS, MHS; and Mary Ann Chaffee, MS, MA
Out-of-Plan Medication in Medicare Part D
Pamela N. Roberto, MPP, and Bruce Stuart, PhD
New Thinking on Clinical Utility: Hard Lessons for Molecular Diagnostics
John W. Peabody, MD, PhD, DTM&H, FACP; Riti Shimkhada, PhD; Kuo B. Tong, MS; and Matthew B. Zubiller, MBA
Should We Pay Doctors Less for Colonoscopy?
Shivan J. Mehta, MD, MBA; and Scott Manaker, MD, PhD
Currently Reading
Long-term Glycemic Control After 6 Months of Basal Insulin Therapy
Harn-Shen Chen, MD, PhD; Tzu-En Wu, MD; and Chin-Sung Kuo, MD
Quantifying Opportunities for Hospital Cost Control: Medical Device Purchasing and Patient Discharge Planning
James C. Robinson, PhD, and Timothy T. Brown, PhD
Effects of a Population-Based Diabetes Management Program in Singapore
Woan Shin Tan, BSocSc, MSocSc; Yew Yoong Ding, MBBS, FRCP, MPH; Wu Christine Xia, BS(IT); and Bee Hoon Heng, MBBS, MSc
Predicting High-Need Cases Among New Medicaid Enrollees
Lindsey Jeanne Leininger, PhD; Donna Friedsam, MPH; Kristen Voskuil, MA; and Thomas DeLeire, PhD
Cost-effectiveness Evaluation of a Home Blood Pressure Monitoring Program
Sarah J. Billups, PharmD; Lindsy R. Moore, PharmD; Kari L. Olson, BSc (Pharm), PharmD; and David J. Magid, MD, MPH

Long-term Glycemic Control After 6 Months of Basal Insulin Therapy

Harn-Shen Chen, MD, PhD; Tzu-En Wu, MD; and Chin-Sung Kuo, MD
The authors evaluate long-term glycemic control in a 5-year follow-up period after patients with newly diagnosed type 2 diabetes mellitus with severe hyperglycemia were treated with 6 months of basal insulin therapy in a randomized controlled trial.
Objectives
To compare the effects of a 6-month course of insulin therapy versus oral antidiabetic drugs (OADs) on long-term (5-year) glycemic control in patients newly diagnosed with type 2 diabetes mellitus (T2DM) with severe hyperglycemia.

Study Design
5 years’ follow-up of a randomized controlled trial.

Methods
Newly diagnosed patients with T2DM and severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10 to 14 days. Fifty patients were randomized to receive either insulin injections or OADs for an additional 6 months. Subjects were followed for 5 years to evaluate long-term glycemic control. We compared the glycated hemoglobin (A1C) levels of the treatment groups and the proportion of patients in each group who reached the treatment targets. We also examined the remission rate (A1C ≤6.5% without antidiabetic medication) at the end of the 5 years. The mechanisms of improved glycemic control and possible mechanism of remission were also investigated.

Results
At 5 years, A1C levels remained lower in the insulin group than in the OAD group (6.49 ± 0.72% vs 7.72 ± 1.06%; P = .012). The proportion of subjects with A1C levels ≤6.5% was significantly higher in the insulin group than in the OAD group (63.6% vs 23.5%; P = .013). The remission rate was 27.3% in the insulin group and 5.9% in the OAD group (P = .048).

Conclusions
This randomized trial demonstrated that a 6-month course of insulin therapy led to better 5-year glycemic control, reflected by lower A1C levels, than did oral antidiabetic agent therapy. Moreover, the insulin-treated group had a significantly higher rate of remission from diabetes.

Am J Manag Care. 2014;20(9):e369-e379
When a patient presents with new-onset type 2 diabetes mellitus (T2DM) with severe hyperglycemia, the optimal treatment is aggressive insulin therapy. Some patients may be withdrawn from insulin and shifted to oral antidiabetic agents after the symptoms decline in 10 to 14 days. We designed an interventional trial to compare the effects of 6 further months of insulin therapy versus oral antidiabetic drugs (OADs) on long-term (5-year) glycemic control in these patients. We found that a 6-month course of insulin therapy led to better 5-year glycemic control than did OAD therapy in newly diagnosed T2DM patients with severe hyperglycemia.
Type 2 diabetes mellitus (T2DM) is characterized by declining β-cell function in the presence of increasing hyperglycemia and relatively constant insulin resistance.1 This process begins early in the natural course of the disease, accelerates markedly after reaching a compensatory threshold, and drives disease progression.1 Accumulating evidence suggests that this decline can be slowed or even reversed, potentially at an early stage of disease.2 Studies have shown that short-term intensive insulin therapy at the time of diagnosis can lead to rapid improvement in β-cell function and maintenance of glycemic control for months after therapy is stopped.3-6

Recently, investigators in China and Taiwan reported the results from 2 independent randomized controlled trials in patients with newly diagnosed T2DM. Both trials compared the effects of short-term intensive insulin therapy with those of oral antidiabetic agents (OADs) on glycemic control and β-cell function: insulin therapy led to more effective glycemic control and significantly greater improvement in β-cell function than did oral antidiabetic agents.7,8 However, data on the effects of short-term insulin on maintaining long-term glycemic control are scarce, especially in patients with severe hyperglycemia.

When a patient presents with new-onset T2DM with severe hyperglycemia, the optimal treatment is aggressive insulin therapy.9,10 Once symptomatic relief has been achieved, it may be possible to withdraw insulin and shift to oral agents. We hypothesized that continuous insulin therapy in patients with new-onset T2DM with severe hyperglycemia may achieve prolonged glycemic control. We designed a 6-month interventional trial to compare the benefits of basal insulin therapy with those of OADs; patients would pursue one course or the other after correction of the glucose toxicity with a short period of intensive insulin therapy. The current study is the continuation of our previous published trial8 to evaluate the long-term maintenance (5 years) of glycemic control in newly diagnosed individuals with T2DM with severe hyperglycemia. We also investigated the possible mechanisms responsible for the development of long-term glycemic remission.

METHODS

Study Design and Subjects

This study was a randomized, open-label, controlled trial and was designed a priori in 2 parts. The first part was a 6-month interventional study to test the effects of insulin on insulin resistance and b-cell function in patients with newly diagnosed T2DM with severe hyperglycemia.8 The second part was a 5-year follow-up study to test the effects of insulin on the durability of long-term glycemic control, which was conducted in response to an inquiry from our Institutional Review Board. The mechanisms of improved glycemic control and possible mechanism of remission were also investigated.

We recruited consecutive newly diagnosed T2DM patients with severe hyperglycemia (fasting plasma glucose >300 mg/dL or random plasma glucose >400 mg/dL) who had been admitted to Taipei Veterans General Hospital. Randomization was performed after 10 to 14 days of intensive insulin therapy by using an insulin-treatment to OAD-treatment ratio of 3:2. Therefore, 30 patients were randomly assigned to the insulin group and 20 to the OAD group. Forty-two patients completed the 6-month intervention, and 5-year follow-up data were available for 39 patients (Figure 1). The study was approved by the Institutional Review Board of Taipei Veterans General Hospital, and written informed consent was obtained from all participants.

Hospitalization Procedures

Bedtime neutral protamine Hagedorn (NPH) insulin (Insulatard, Novo Nordisk, Denmark) and regular insulin taken before meals (Actrapid, Novo Nordisk, Denmark) were used for intensive insulin therapy. The target glucose levels were fasting blood glucose (FBG) 90 to 130 mg/dL and bedtime blood glucose 100 to 160 mg/dL.9 All subjects received a 75g oral glucose tolerance test (OGTT) when their fasting blood glucose levels were between 100 and 140 mg/dL. Blood samples were collected for glucose and insulin analysis at 30, 60, 90, and 120 minutes, and for C-peptide analysis at 120 minutes.

Outpatient Clinic Follow-up

All subjects were discharged after 10 to 14 days of intensive insulin therapy, and were subsequently randomized to either continue with insulin treatment or shift to OADs. Subjects were then followed as outpatients; they visited our clinic every 2 weeks for the first 2 months, then every 4 weeks for another 4 months.

Subjects in the insulin group were instructed in the technique of glucose monitoring. Two-thirds of the daily dose was administered before breakfast and the remaining third was administered at bedtime. Both morning and bedtime insulin doses were titrated every 3 days to achieve target FPG values between 90 and 130 mg/dL.

The titration method of OADs in our protocol was modified from that of the Steno-2 Study published in 2003.10 As the initial step, overweight or obese patients (defined as having a body mass index [BMI] >25) received metformin (daily doses ranged from 500 mg once a day to 500 mg 3 times a day), and lean patients received a drug in the sulfonylurea class, gliclazide-MR (with doses ranging from 30 mg to 90 mg per day). The dosage was titrated based on FPG results on the visiting day to achieve target values between 90 and 130 mg/dL. As the second step, metformin was added to the regimen of the lean patients, and gliclazide-MR to the regimens of overweight and obese patients. As a possible third step, gliclazide-MR could be up-titrated to a maximum dose of 120 mg per day and metformin to 2550 mg per day (with split dosing).

Clinical Examination

Glycated hemoglobin (A1C) measurements were per formed at 3 and 6 months, and the OGTT was repeated 6 months after randomization. We stopped pharmacologic treatment approximately 12 hours (metformin) and 24 hours (gliclazide-MR and insulatard) before performing the OGTT. Areas under the glucose and insulin curves during the OGTT were calculated by the trapezoid rule. Early-phase insulin secretion (insulinogenic index) was calculated as the ratio between the incremental plasma insulin and glucose concentrations during the first 30 minutes of the OGTT. Total insulin secretion was calculated as the ratio between the incremental areas under the insulin and glucose curves during the OGTT. The Matsuda index was calculated for insulin resistance as previously reported.11 Homeostasis model assessment was used to estimate insulin resistance (HOMA-IR) and b-cell function (HOMA-B).12

Follow-up Examination

After 6 months of randomization, patients in the insulin group stopped insulin and started OADs for further management. The dose titration procedure was the same as that used during the intervention period in the OAD group. After 12 months, all patients were treated in our clinics according to national guidelines. The dosage was titrated based on the A1C value to achieve a target value –6.5%. A third medication was considered when the A1C value was greater than 7.5%. Our protocol also recommended decreasing the dose of medication when the A1C value was less than 6.0% and the FPG level was less than 100 mg/dL. All subjects were continually followed in our clinics for 5 years to evaluate long-term glycemic control.

Outcomes

The overall goal of this follow-up study was to investigate long-term glycemic control. The primary end points were the A1C levels and the proportion of patients who reached the treatment targets (A1C –6.5% or –7.0% at 5 years) between the treatment groups. The secondary end points were the remission rate (A1C –6.5% without antidiabetic medication) at the end of the 5 years of follow-up, and severe hypoglycemia, defined as a recorded blood glucose value less than 40 mg/dL. We also examined the possible mechanism for remission from the biochemical measurements over the course of interventions.

Statistical Analyses

This is a 5-year follow-up study from a randomized controlled trial. We analyzed the outcomes of the intent-to-treat population defined as all randomized patients who had received the second OGTT at the end of intervention. Statistical analyses were performed using SPSS for Windows version 18.0 (SPSS, Inc, Chicago, IL). Normally distributed and continuous variables are presented as mean ± SD, and non-normally distributed variables are expressed as median (interquartile range). The paired Student’s t test was used to analyze differences from baseline to end point, and the independent Student’s t test was used to compare differences between the treatment arms. Changes from baseline in A1C, insulin dose, OAD dose, body weight, and hypoglycemic events were analyzed using 1-way analysis of variance (ANOVA). A Mann-Whitney U test was used to analyze the nonnormally distributed variables, and c2 tests were used to analyze the differences in remission rates between the 2 intervention groups. A1C levels were measured every 3 to 4 months, and the median value was determined for each year. All doses of sulfonylureas were calculated as equivalent gliclazide dose at the last visit. The average doses of insulin and OADs were calculated as total dose divided by patient number in each group. A P value of less than .05 was considered statistically significant.

RESULTS

Demographic, Clinical, and Biochemical Characteristics

Demographic, clinical, and biochemical characteristics of the patients at baseline, at the end of intervention (6 months), and at the end of follow-up (5 years) are shown in Table 1. The baseline data presented in Table 1, except for the fasting plasma glucose (FPG) levels, were obtained after 10 to 14 days of intensive insulin therapy. The mean age was 57.5 ± 16.3 years; mean body weight was 72.4 ± 17.3 kg; mean BMI was 26.5 ± 5.3 kg/m2; mean peak plasma glucose was 531 ± 156 mg/dL; mean FPG was 333 ± 88 mg/dL; and mean A1C was 11.77 ± 2.08%.

Glycemic Control

Glycemic control, including A1C values and FPG levels, was similar at baseline in the 2 groups. At the end of the 6-month intervention, the mean FPG was 122.6 ± 29.5 mg/dL in the insulin group and 130.2 ± 19.9 mg/dL in the OAD group, a difference that was not statistically significant (P = .333). However, at the end of 5 years, the FPG was significantly lower in the insulin group than the OAD group (120.3 ± 22.0 vs 145.0 ± 33.6 mg/dL; P = .019).

Figure 1A shows the A1C changes in both groups during the study period and follow-up visits. After 6 months of intervention, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 ± 0.70% vs 7.50 ± 1.50%; P < .001), and the differences were maintained through to the end of 5 years of follow-up (6.49 ± 0.72% vs 7.72 ± 1.06%; P = .001).

 
Copyright AJMC 2006-2017 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up
×

Sign In

Not a member? Sign up now!