A Pilot Study to Examine the Feasibility of Insulin Glargine in Subjects with Impaired Fasting Glucose, Impaired Glucose Tolerance or New-Onset Type 2 Diabetes

Abstract

Objective: People with early type 2 diabetes and pre-diabetes (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) are at risk of hyperglycaemia-related complications, including cardiovascular disease. Insulin, traditionally reserved as late treatment in type 2 diabetes, may also be a useful therapy in this population. We examined the short-term efficacy and tolerability of insulin glargine (glargine) in individuals with early or pre-type 2 diabetes.

Research Design and Methods: In this multicentre, double-blind, placebo-controlled, randomized, parallel group, 12-day study, subjects with IGT/IFG (n=9), newly diagnosed type 2 diabetes (n=9) or normal glucose tolerance (n=3) (confined to a clinical research unit taking a prescribed diet) were randomized to once-daily glargine (n=16) or placebo (saline; n=5) at bedtime. Dose was titrated to achieve target fasting blood glucose (FBG) 80-95 mg/dL.

Results: Over the treatment period, mean FBG decreased in glargine-treated subjects (from 100.0±18.8 to 85.6±18.4 mg/dL), but was unchanged in placebo-treated subjects (from 112.5±10.6 to 111.3±17.5 mg/dL). Mean eight-point blood glucose value decreased by 9.7 mg/dL in the glargine group, but increased by 8.1 mg/dL in the placebo group. Mean post-exercise blood glucose was similar before and after glargine treatment, but increased after placebo treatment. Five subjects receiving glargine experienced 16 mild symptomatic hypoglycaemia episodes; however, no hypoglycaemia occurred during exercise. Mean body weight decreased in both the glargine (-0.44 kg) and placebo (-0.25 kg) groups, in line with dietary restrictions.

Conclusions: The results of this pilot study suggest that glargine can be used by people with IFG, IGT or new-onset type 2 diabetes for management of hyperglycaemia with low risk of hypoglycaemia. However titration of insulin in people on dietary restrictions should be more cautious as they may be more prone to hypoglycaemia. Further studies are warranted to determine the clinical benefits of this approach.

Key words

insulin glargine - type 2 diabetes - impaired fasting glucose - impaired glucose tolerance - exercise

References

• 1 American Diabetes Association . Clinical Practice Recommendations 2005.  Diabetes Care. 2005;  28 ((Suppl 1)) S1-S79
• 2 American Diabetes Association . , Diabetic retinopathy occurs in pre-diabetes. Available at www.diabetes.org/uedocuments/DPPrehnopathy.REV.pdf. Last accessed April 2008; 2005; 
• 3 Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.  Diabetes Care. 1999;  22 233-240
• 4 Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Subclinical states of glucose intolerance and risk of death in the U.S.  Diabetes Care. 2001;  24 447-453
• 5 Lim SC, Tai ES, Tan BY, Chew SK, Tan CE. Cardiovascular risk profile in individuals with borderline glycemia: the effect of the 1997 American Diabetes Association diagnostic criteria and the 1998 World Health Organization Provisional Report.  Diabetes Care. 2000;  23 278-282
• 6 Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.  Diabetes Care. 2004;  27 1647-1653
• 7 Sobel BE, Frye R, Detre KM. Burgeoning dilemmas in the management of diabetes and cardiovascular disease: rationale for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial.  Circulation. 2003;  107 636-642
• 8 Patel A, Chalmers J, Chaturvedi V, Currie R, Monaghan H, Neal B. Diabetes and vascular disease: a new international trial.  Asian Cardiovasc Thorac Ann. 2003;  11 180-184
• 9 Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H. Mortality prediction in diabetic patients with myocardial infarction: experiences from the DIGAMI study.  Cardiovasc Res. 1997;  34 248-253
• 10 Berghe G van den, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M. et al . Intensive insulin therapy in the critically ill patients.  N Engl J Med. 2001;  345 1359-1367
• 11 Alvarsson M, Sundkvist G, Lager I, Henricsson M, Berntorp K, Fernqvist-Forbes E. et al . Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients.  Diabetes Care. 2003;  26 2231-2237
• 12 Nathan DM. Initial management of glycemia in type 2 diabetes mellitus.  N Engl J Med. 2002;  347 1342-1349
• 13 Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo.  Diabetes Care. 2000;  23 644-649
• 14 Gerich J, Becker RH, Zhu R, Bolli GB. Fluctuation of serum basal insulin levels following single and multiple dosing of insulin glargine.  Diabetes Technol Ther. 2006;  8 237-243
• 15 Scholtz HE, Pretorius SG, Wessels DH, Becker RH. Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique.  Diabetologia. 2005;  48 1988-1995
• 16 Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group.  Diabetes Care. 2000;  23 1130-1136
• 17 Massi Benedetti M, Humburg E, Dressler A, Ziemen M. A One-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes.  Horm Metab Res. 2003;  35 189-196
• 18 Riddle M, Rosenstock J, Gerich J, Investigators IGS. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetes patients.  Diabetes Care. 2003;  26 3080-3086
• 19 Fritsche A, Schweitzer M, Haring H-U, Group S. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial.  Ann Intern Med. 2003;  138 952-959
• 20 Rathmann W, Haastert B, Riebel P, Schroeder-Bernhardi D, Kostev K, Huppertz E. et al . Prescription of insulin glargine in primary care practices in Germany.  Exp Clin Endocrinol Diabetes. 2007;  115 252-256
• 21 Siegmund T, Weber S, Blankenfeld H, Oeffner A, Schumm-Draeger PM. Comparison of insulin glargine versus NPH insulin in people with Type 2 diabetes mellitus under outpatient-clinic conditions for 18 months using a basal-bolus regimen with a rapid-acting insulin analogue as mealtime insulin.  Exp Clin Endocrinol Diabetes. 2007;  115 349-353
• 22 Standl E, Maxeiner S, Raptis S. Once-daily insulin glargine administration in the morning compared to bedtime in combination with morning glimepiride in patients with type 2 diabetes: an assessment of treatment flexibility.  Horm Metab Res. 2006;  38 172-177
• 23 DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balance overview.  Diabetes Care. 1992;  15 318-368
• 24 Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M. et al . Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency.  Diabet Med. 1994;  11 299-303
• 25 Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R. et al . Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care. 2006;  29 1963-1972
• 26 Oliver MF. Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes.  Am J Med. 2002;  112 305-311
• 27 Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes.  Diabetes. 2002;  51 ((Suppl 3)) S405-S413

APPENDIX 1 - LIST OF PARTICIPATING INVESTIGATORS

Participating investigators: USA: Marbury TC, Schwartz S, Rosenberg MA.

Correspondence