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Published online August 23, 2007
Diabetes Care 30:3031-3032, 2007
DOI: 10.2337/dc07-0397
© 2007 by the American Diabetes Association
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Clinical Care/Education/Nutrition/Psychosocial Research
Original Research

Flexible Intensive Versus Conventional Insulin Therapy in Insulin-Naive Adults With Type 2 Diabetes

An open-label, randomized, controlled, crossover clinical trial of metabolic control and patient preference

Christof Kloos, MD1, Alexander Sämann, MD1, Thomas Lehmann, DSC2, Anke Braun, MD3, Barbara Heckmann4 and Ulrich A. Müller, MD1

1 Department of Internal Medicine III, Friedrich-Schiller-University, Jena, Germany
2 Industrie und Handelskammer (Chamber of Commerce) Thuringia, Erfurt, Germany
3 Bethanien-Hospital, Heidelberg, Germany
4 Hospital-Fulda, Fulda, Germany

Address correspondence and reprint requests to Christof Kloos, MD, Klinik für Innere Medizin, Erlanger Allee 101, Friedrich-Schiller-Universität, 07740 Jena, Germany. E-mail: christof.kloos{at}med.uni-jena.de

Abbreviations: CIT, conventional insulin therapy • FIT, flexible intensive insulin therapy


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Improving metabolic control can reduce complications in type 2 diabetes (1–4). Conventional insulin therapy (CIT) and flexible intensive insulin therapy (FIT) are treatment options in insulin-dependent type 2 diabetic patients. In CIT, participants inject premixed human insulin (30% regular insulin, 70% NPH insulin) before breakfast and dinner and follow individually adjusted diet plans with fixed amounts of carbohydrates (5). In FIT, human regular insulin is adjusted before main meals according to current blood glucose readings and desired carbohydrate intake. When necessary, NPH insulin is added at bedtime. CIT can be easy to handle and requires less active diabetes self-management. In FIT, patients benefit from dietary freedom and improvement in quality of life (6). In pilot studies, FIT has shown good metabolic control and low risk of hypoglycemia (7). FIT may have additional advantages due to better postprandial blood glucose control (8).


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
We tested the hypothesis that FIT and CIT in insulin-naive adults with type 2 diabetes are equally effective in regard to metabolic outcomes. We hypothesized that younger participants, in employment, would prefer FIT.

The trial was designed as a clinical, prospective, randomized, open-label, single-center, crossover study. The primary end point was glycosylated hemoglobin A1c (GHb); secondary end points were mild and severe hypoglycemia, insulin dosage, blood pressure, BMI, and therapy preference. Participants started insulin therapy either with CIT (group A) or FIT (group B), randomly. Individual insulin dosage and carbohydrate intake were determined over a 4-week run-in period with weekly visits. All visits were the same in both groups and were held in the study center. In CIT, daily blood glucose self-control was performed before breakfast and dinner; in FIT, this was done before main meals. Oral antidiabetes drugs were not permitted. The participants completed an outpatient Diabetes Treatment and Teaching Program with five lessons (90–120 min) during run-in. The run-in was followed by an 8-week study sequence until crossover. At crossover, participants were given one structured teaching session for refreshing and switched from CIT to FIT or from FIT to CIT. After a 1-week run-in period for insulin dose adjustment, participants completed the second 8-week study sequence. At trial end, therapeutic preference was investigated with a structured interview.

Eligible participants who failed therapeutic goals under oral antidiabetes therapy were consecutively recruited (outpatient clinic, Friedrich-Schiller-University). Exclusion criteria were not having type 2 diabetes, diabetes duration <2years, not insulin naive, ineffective oral antidiabetes therapy <3 months, GHb <7 or >11%, and age <40 or >65 years.

GHb was measured using high-performance liquid chromatography (normal range 1.6–5.9%; mean 5.2 ± 0.33%; TOSOH-Glykohämoglobin-Analyzer-HLC-723-GHbV; Tosoh, Tokyo, Japan). Mild hypoglycemia was defined as symptomatic neuroglycopenia or blood glucose readings <3.3 mmol/l. Severe hypoglycemia required intravenous glucose or subcutaneous/intramuscular glucagon injection.

To have a 90% chance of detecting as significant (at the two-sided 5% level), a 0.5% difference in GHb between the two groups with an assumed SD of 0.8%, 38 participants were required. Intent-to-treat analysis was carried out according to a preestablished analysis plan. Means and SDs were calculated. The t test for paired and nonpaired samples was used where appropriate. For statistical analysis of associations of GHb and participant's characteristics, linear mixed-effects models were used. P < 0.05 was regarded as statistically significant. Statistical analysis was performed with SPSS (version 15; SPSS, Chicago, IL).

The study was approved by the local ethics committee and was performed according to the principles of the Declaration of Helsinki. Written informed consent was obtained before participants took part. The trial was registered with clinicaltrials.gov (NCT00440284).


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
Baseline clinical data between groups were not significantly different (Table 1, group A [first CIT, n = 20] vs. group B [first FIT, n = 19]): age 56.6 ± 7.3 vs. 54.7 ± 6.6 years, diabetes duration 7.5 ± 4 vs. 8.2 ± 4.2 years, total cholesterol 5.3 ± 1.1 vs. 5.3 ± 1.1 mmol/l, creatinine 82 ± 18.4 vs. 77 ± 16.3 µmol/l, peripheral neuropathy 9 vs. 4 participants, and number of participants employed 12 vs. 15, respectively.


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  		Table 1— Main outcomes (intent-to-treat analysis)

 
All participants completed both study sequences except for one person who refused to switch. After initiation of insulin therapy, GHb declined from 8.9 ± 1.7 to 7.3 ± 0.9% (P < 0.0001), and BMI increased from 29.4 ± 4.4 to 30 ± 4.2 kg/m2 (P < 0.01). Blood pressure and lipid profiles remained unchanged. There was no significant difference between CIT and FIT regarding GHb, BMI, blood pressue, insulin dosage, and hypoglycemia (Table 1). In linear mixed-effects models, GHb after CIT and GHb after FIT were not associated with age, sex, diabetes duration, initial GHb, blood pressure, lipid profiles, comorbidity, and occupation.

Twenty participants preferred to continue CIT, whereas 18 opted for FIT. Reasons to opt for FIT were therapy flexibility (n = 9), easier therapy (n = 1), and metabolic control (n = 1). Arguments in favor of CIT were easier therapy (n = 8), fewer injections (n = 8), and metabolic control (n = 3). In a binary logistic regression model, 88% of therapy decisions were explained by the last therapy option. The model was not improved when additional variables like age, sex, diabetes duration, GHb after CIT or FIT, initial GHb, blood pressure, lipid profiles, and occupation were added.


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
Initiation of insulin therapy in type 2 diabetes was safe and effective. Metabolic control improved during the first study sequence in FIT and CIT but did not further improve in the second sequence. Participants did not reach GHb levels below 7%. After having practiced CIT and FIT for 8 weeks each, participants preferred their last therapy. This indicates that clinical advantages of CIT or FIT were of minor importance for participants irrespective of age or whether they were employed. Interestingly, in contrast to patients with type 1 diabetes, gaining more dietary freedom seems not to be a prevalent motive in type 2 diabetes (6).

There are several limitations to consider. The sample size of this randomized controlled trial was too small and the study period too short to detect minor differences. Carry-over effects of the crossover design can reduce the effect of the second trial sequence. The primary outcome measure of this trial (GHb) was a surrogate parameter. Comparison of side effects may be limited by different definitions of mild and severe hypoglycemia. Participants were young and had early manifestation of type 2 diabetes compared with the general population (9). Older patients with impaired cognitive function might be unable to practice effective diabetes self-management using insulin therapy or might be disinterested in the clinical advantages of FIT and CIT (10).


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 23 August 2007. DOI: 10.2337/dc07-0397. Clinical trial reg. no. NCT00440284, clinicaltrials.gov.

U.A.M. has received lecture and other fees from Takeda, Novo Nordisk, Berlin Chemie, Roche Diagnostics, Deutsche BKK, Diabeteszentrum Thüringen, Merck, and Reha aktiv 2000.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication February 27, 2007. Accepted for publication August 19, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

  1. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998[Medline]
  2. Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353:617–622, 1999[Medline]
  3. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O: Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 348:383–393, 2003[Abstract/Free Full Text]
  4. Shichiri M, Kishikawa H, Ohkubo Y, Wake N: Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 23(Suppl. 2):B21–B29, 2003
  5. Gruesser M, Hartmann P, Schlottmann N, Joergens V: Structured treatment and teaching programme for type 2 diabetic patients on conventional insulin treatment: evaluation of reimbursement policy. Patient Educ Couns 29:123–130, 1996[Medline]
  6. DAFNE Study Group: Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomised controlled trial. BMJ 325:746, 2002[Abstract/Free Full Text]
  7. Kalfhaus J, Berger M: Insulin treatment with preprandial injections of regular insulin in middle-aged type 2 diabetic patients: a two year observational study. Diabetes Metab 26:197–201, 2000[Medline]
  8. Robertson C: Physiologic insulin replacement in type 2 diabetes: optimizing postprandial glucose control. Diabetes Educ 32:423–432, 2006[Abstract/Free Full Text]
  9. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197, 1997[Medline]
  10. Braun A, Muller UA, Muller R, Leppert K, Schiel R: Structured treatment and teaching of patients with type 2 diabetes mellitus and impaired cognitive function: the DICOF trial. Diabet Med 21:999–1006, 2004[Medline]

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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