Emerging Treatments and Technologies ORIGINAL ARTICLE Less Hypoglycemia With Insulin Glargine in Intensive Insulin Therapy for Type 1 Diabetes ROBERT E. RATNER, MD THOMAS E. MECCA, PHD he Diabetes Control and Complica- IRL B. HIRSCH, MD CRAIG A. WILSON, PHD tions Trial (DCCT) (1)and other stud- JAMES L. NEIFING, MD FOR THE U.S. STUDY GROUP OF INSULIN ies (2,3) provide conclusive evidence SATISH K. GARG, MD GLARGINE IN TYPE 1 DIABETES T that maintaining tight glycemic control can prevent or delay microvascular complica- tions in individuals with type 1 diabetes. Attempts to achieve glycemic control are most often made by using multiple daily OBJECTIVE — Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analog with a prolonged duration of action compared with NPH human insulin injection (i.e., basal-bolus) therapy insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 or by using an insulin pump. Despite diabetes who had been previously treated with multiple daily injections of NPH insulin and reg- prodigious efforts, our ability to reach nor- ular insulin. mal GHb levels is hampered by the limiting occurrence of hypoglycemia (4). Variability RESEARCH DESIGN AND METHODS — This study was a multicenter randomized in absorption, delays in action, and pro- parallel-group study in which subjects were randomized to receive premeal regular insulin and longed insulin activity peaks in traditional either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily ther- insulin preparations contribute to difficulty apy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. in obtaining normoglycemia. Insulin Dose titration of both basal insulins was based on capillary fasting whole blood glucose (FBG) analogs have been developed to facilitate levels; the goal was a premeal blood glucose concentration of 4.4–6.7 mmol/l. successful basal-bolus therapy. A once-daily RESULTS — A total of 534 well-controlled type 1 diabetic subjects (mean GHb 7.7%, mean long-acting basal insulin analog that mim- fasting plasma glucose [FPG] 11.8 mmol/l) were treated. A small decrease in GHb levels was ics insulin secretion in nondiabetic sub- noted with both insulin glargine (Ϫ0.16%) and NPH insulin (Ϫ0.21%; P Ͼ 0.05). Significant jects to limit hepatic glucose production reductions in median FPG levels from baseline (Ϫ1.67 vs. Ϫ0.33 mmol/l with NPH insulin, has not been available for clinical use. P = 0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin The currently available longer-acting glargine. After the 1-month titration phase, significantly fewer subjects receiving insulin human ultralente insulin has a broad peak glargine experienced symptomatic hypoglycemia (39.9 vs. 49.2%, P = 0.0219) or nocturnal that lasts from 8 to 16 h, with a duration of Ͻ hypoglycemia (18.2 vs. 27.1%, P = 0.0116) with a blood glucose level 2.0 mmol/l compared action ranging from 20 to 36 h (5). Ultra- with subjects receiving NPH insulin. lente is the least consistently absorbed CONCLUSIONS — Lower FPG levels with fewer episodes of hypoglycemia were achieved insulin formulation available and has a with insulin glargine compared with once- or twice-daily NPH insulin as part of a basal-bolus wide intra- and interindividual variability regimen in patients with type 1 diabetes. in pharmacokinetics and pharmacody- namics (5,6). The intermediate-acting Diabetes Care 23:639–643, 2000 human NPH insulin has been the mainstay of insulin regimens used by subjects with type 1 diabetes (7). NPH insulin concen- trations rise to a peak after 4–6 h and then steadily decline. Because an NPH insulin dose is often limited by hypoglycemia at peak concentrations, using NPH insulin twice daily is often necessary. Furthermore, From the MedStar Clinical Research Center (R.E.R.), Washington, DC; the Diabetes Care Center (I.B.H.), the the action profile of NPH insulin, when University of Washington Medical Center, Seattle, Washington; the Portland Diabetes and Endocrine Center used with regular insulin in a basal-bolus ( J.L.N.), Portland, Oregon; the Barbara Davis Center for Childhood Diabetes (S.K.G.), the University of Col- regimen, leads to an increased risk of noc- orado Health Sciences Center, Denver, Colorado; and Quintiles, Inc. (T.E.M., C.A.W.), Kansas City, Missouri. turnal hypoglycemia, morning fasting Address correspondence and reprint requests to Robert E. Ratner, MD, MedStar Clinical Research Cen- hyperglycemia, or both (8). ter, 650 Pennsylvania Ave. S.E., Suite 50, Washington, DC. E-mail: [email protected]. A B Received for publication 27 September 1999 and accepted in revised form 28 December 1999. Insulin glargine (21 -Gly-30 a-L-Arg- R.E.R., I.B.H., and S.K.G. have received honoraria, consulting fees, and grant funding from and, at the time 30Bb-L-Arg-human insulin) is an insulin of this study, T.E.M. and C.A.W. were employed by Hoechst Marion Roussel, a company that manufactures analog produced by recombinant DNA and markets pharmaceuticals related to the treatment of diabetes, including insulin glargine. technology. Amino acid changes shift the Abbreviations: ANCOVA, analysis of covariance; DCCT, Diabetes Control and Complications Trial; FBG, fasting whole blood glucose; FPG, fasting plasma glucose. isoelectric point (which reduces the solu- A table elsewhere in this issue shows conventional and Système International (SI) units and conversion bility of insulin glargine at physiological pH factors for many substances. levels) and stabilize the hexamer (which DIABETES CARE, VOLUME 23, NUMBER 5, MAY 2000 639 Insulin glargine in type 1 diabetes delays its dissociation into monomers) time and before breakfast), depending on changes in insulin glargine or human (9,10). Consequently, insulin glargine has a their pretreatment insulin regimens. Sub- insulin antibodies as measured by the delayed and prolonged absorption after jects in the insulin glargine group were to Global Preclinical Laboratory (Hoechst subcutaneous administration (11). Eugly- be switched from once-daily NPH insulin Marion Roussel). cemic clamp data in healthy volunteers on a unit-for-unit basis, whereas a slight indicate that the absorption of insulin dose decrease was recommended for sub- Statistics glargine is prolonged and without peaks jects who switched from twice-daily NPH All analyses were performed by using an (6,12–14). Short-term (4-week) compara- insulin. Dose titration of both basal insulins intent-to-treat population with the last tive trials in subjects with type 1 or type 2 was based on capillary fasting blood glu- observation carried forward. An estimated diabetes have demonstrated that once-daily cose (FBG) levels; the goal was a premeal 440 subjects (220 in each treatment group) insulin glargine doses reduce fasting plasma blood glucose concentration of 4.4–6.7 were required to detect a mean difference of glucose (FPG) levels to a similar extent or mmol/l (80–120 mg/dl). Dose increases 0.5% in GHb levels between treatments to a significantly greater extent than once- were made if morning capillary FBG levels with a type 1 error of ␣ = 5% and a statis- or twice-daily NPH insulin with a compa- were consistently Ͼ6.7 mmol/l with no tical power of 90%. rable or (in some studies) a significantly symptomatic nocturnal hypoglycemia. Baseline demographics were compared lower incidence of nocturnal hypoglycemia Dose decreases were made if morning cap- by using an analysis of variance model with (15–18). This long-term study examines illary FBG levels were Ͻ4.4 mmol/l or if treatment and investigative site as fixed the safety and efficacy of once-daily insulin symptomatic nocturnal hypoglycemia was effects for continuous variables and the glargine versus once- or twice-daily NPH evident. Subjects in both treatment groups Cochran-Mantel-Haenszel test controlled insulin as part of basal-bolus insulin regi- used regular insulin ϳ30 min before meals for investigative site for categorical vari- mens for subjects with type 1 diabetes. to meet prandial insulin requirements. ables. Capillary FBG values were calculated The study included 8 visits: screening by using the mean of the 7 consecutive RESEARCH DESIGN AND (1–4 weeks before randomization); ran- daily measurements taken before each visit. METHODS domization (week 0); and weeks 1, 4, 8, 12, Changes in GHb and capillary FBG values 20, and 28. Subjects self-measured capillary from baseline to end point were assessed by Subjects FBG levels (LifeScan One Touch; Johnson using analysis of covariance (ANCOVA) A total of 534 men and women 18–80 & Johnson, Milpitas, CA) at home on 7 models with terms for treatment and inves- years of age with type 1 diabetes (post- consecutive days preceding the baseline and tigative site and with the baseline measure prandial C-peptide levels of Յ0.5 nmol/l) at visits at weeks 8, 20, and 28. FPG levels as a covariate. A skewed distribution of for at least 1 year and GHb levels of were assessed at all clinic visits. GHb levels residuals from the fitted ANCOVA model Յ12.0% were eligible. Exclusion criteria were measured at baseline and at weeks 8, was observed for FPG data; therefore, an included treatment with antidiabetic drugs 20, and 28 at the Diabetes Diagnostics Lab- analysis of rank change from baseline in other than insulin within 1 month of study oratory (University of Missouri, Columbia, FPG level was performed by using median entry, pregnancy, impaired hepatic func- MO; normal values 4.2–5.8%). values in a ranked ANCOVA model. tion, and impaired renal function. Subjects The incidence of hypoglycemia was could not work a night shift.