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Riddle and AssociatesRESEARCH DESIGN AND Table 1—Forced weekly insulin titration scheduleMETHODS — Enrolled subjects weremen or women aged 30 –70 years, with Start with 10 IU/day bedtime basal insulin and adjust weeklydiabetes for Ն2 years, and treated withstable doses of one or two oral antihyper- Mean of self-monitored FPG values from Increase of insulin dosageglycemic agents (sulfonylureas, met- preceding 2 days (IU/day)formin, pioglitazone, or rosiglitazone) for Ն180 mg/dl (10 mmol/l) 8Ն3 months. Inclusion criteria included 140–180 mg/dl (7.8–10.0 mmol/l) 6BMI between 26 and 40 kg/m2, HbA1c 120–140 mg/dl (6.7–7.8 mmol/l) 4between 7.5 and 10.0%, and FPG Ն140 100–120 mg/dl (5.6–6.7 mmol/l) 2mg/dl (7.8 mmol/l) at screening. Exclu- The treat-to-target FPG was Յ100 mg/dl. Exceptions to this algorithm were 1) no increase in dosage ifsion criteria included prior use of insulin plasma-referenced glucose Ͻ72 mg/dl was documented at any time in the preceding week, and 2) in additionexcept for gestational diabetes or for Ͻ1 to no increase, small insulin dose decreases (2– 4 IU/day per adjustment) were allowed if severe hypoglyce-week, current use of an ␣-glucosidase in- mia (requiring assistance) or plasma-referenced glucose Ͻ56 mg/dl were documented in the precedinghibitor or a rapid-acting insulin secreta- week.gogue, use of other agents affectingglycemic control (including systemic glu- the abdomen), using a pen injector (Opti- ing fasting tests for 7 consecutive days andcocorticoids, nonselective ␤-sympathetic Pen Pro 1 for glargine or NovoPen 3 for 1-day eight-point glucose proﬁles (beforeblockers, and weight-loss drugs), history NPH) for 24 weeks. Oral antihyperglyce- and 2 h after breakfast, lunch, and dinner,of ketoacidosis or self-reported inability mic agents were continued at prestudy and at bedtime and 5 h after bedtime)to recognize hypoglycemia, serum ala- dosages. No dietary advice was given be- before each clinic visit.nine aminotransferase or aspartate ami- yond reinforcement of standard guide- Weight was measured, and venousnotransferase more than twofold above lines (15). The starting dose of both blood for FPG was collected betweenthe upper limit of normal or serum creat- insulins was 10 IU, and dosage was ti- 0700 and 0900 h at each visit. Blood forinine (Ն1.5 mg/dl for men and Ն1.4 trated weekly according to daily self- HbA1c was collected at baseline and 8, 12,mg/dl for women), and a history of drug monitored capillary fasting blood glucose 18, and 24 weeks. Glucose and HbA1cor alcohol abuse or inability to provide measurements using meters (Accu-Chek (Diabetes Control and Complicationsinformed consent. To minimize the like- Advantage; Roche Diagnostics) that pro- Trial referenced, normal range 4 – 6%)lihood of including patients with late- vide values corresponding closely to lab- were measured at the Diabetes Diagnosticonset type 1 diabetes, candidates with a oratory measurements of plasma glucose. Laboratory, University of Missouri-positive test for anti-GAD antibody A forced titration schedule was used, Columbia, Columbia, Missouri. Results of(Northwest Clinical Research, Seattle, seeking a target FPG of Յ100 mg/dl these tests were not disclosed to the inves-WA) or with fasting plasma C-peptide (Յ5.6 mmol/l) (Table 1). tigators until completion of the trial.Յ0.25 pmol/ml (Clinical Reference Lab- Subjects visited the research site atoratory, Lenexa, KS) were excluded. baseline and 2, 4, 8, 12, 18, and 24 weeks Outcome measures and were contacted by telephone at 1, 3, The primary outcome measure was theStudy design 5, 6, 7, 10, 15, and 21 weeks to discuss percentage of subjects achieving HbA1cThis multicenter, open-label, random- dosage changes. Glucose values and insu- Յ7.0% without a single instance of symp-ized, parallel, 24-week comparative study lin changes were transmitted to a central tomatic nocturnal hypoglycemia con-was performed at 80 sites in the U.S. and coordinating center. Failure to follow the ﬁrmed by plasma-referenced glucoseCanada between 7 January 2000 and 22 algorithm was investigated by coordinat- Յ72 mg/dl (4 mmol/l) and/or meetingOctober 2001. It was conducted in accor- ing center personnel or members of a ti- criteria for severe hypoglycemia. This glu-dance with the Declaration of Helsinki tration monitoring committee. Subjects cose threshold was chosen because lowerand approved by local ethical review were asked to test glucose whenever they levels can induce hypoglycemia unaware-committees. All subjects provided in- experienced symptoms that might be re- ness (16). Severe hypoglycemia was de-formed consent. A randomization sched- lated to hypoglycemia and to record the ﬁned as symptoms consistent withule generated by Quintiles (Kansas City, results. Hypoglycemia documented by hypoglycemia during which the subjectMO) linked sequential numbers to ran- glucose levels Յ72 mg/dl (4 mmol/l) or required the assistance of another persondom treatment codes and assured an requiring assistance called for cessation of and was associated with either a glucoseϳ1:1 ratio at each site. Randomization titration for a week, but subjects were level Ͻ56 mg/dl (3.1 mmol/l) or promptwas performed in the order in which sub- asked to resume upward titration the next recovery after oral carbohydrate, intrave-jects qualiﬁed, using a centralized tele- week if hypoglycemia did not recur. nous glucose, or glucagon. Nocturnal hy-phone system. When mean glucose values in the 100 – poglycemia was deﬁned as occurring after 120 mg/dl (5.6 – 6.7 mmol/l) range were the bedtime injection and before the mea-Study protocol and treatment obtained, investigators were allowed to surement of glucose, eating breakfast, orPatients were randomized to either stop titration or temporarily reduce dos- administration of any oral antihypergly-glargine (Lantus; Aventis) or human NPH age when they believed further titration cemic agent in the morning.insulin (Novolin; Novo Nordisk) to be ad- would be hazardous. In addition to glu- Other measures included changesministered subcutaneously at bedtime, at cose tests to guide titration and document from baseline for HbA 1c , FPG, anda site preferred by the individual (usually hypoglycemia, subjects performed morn- weight; percentage of subjects achievingDIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 3081
The Treat-to-Target TrialHbA1c Յ7% or FPG Յ100 mg/dl (5.6 Table 2—Baseline characteristics of subjects in the studymmol/l) independent of the occurrence ofhypoglycemia; the percentage of subjects Glargine NPHachieving FPG Յ100 mg/dl (5.6 mmol/l)without conﬁrmed hypoglycemia; with- n 367 389in-subject variability between seven se- Sex (F/M) (%) 45/55 44/56quential fasting glucose measures; and Age (years) 55 Ϯ 9.5 56 Ϯ 8.9overall rates of symptomatic hypoglyce- Duration of diabetes (years) 8.4 Ϯ 5.55 9.0 Ϯ 5.57mia including unconﬁrmed, conﬁrmed, BMI (kg/m2) 32.5 Ϯ 4.64 32.2 Ϯ 4.80and severe hypoglycemia. FPG (mg/dl [mmol/l]) 198 (11.0) Ϯ 49 (2.71) 194 (10.8) Ϯ 47 (2.61) HbA1c (%) 8.61 Ϯ 0.9 8.56 Ϯ 0.9 Ethnicity (%)Statistical analyses White 84 83Based on previous data (17), randomiza- Black 11 13tion of 750 subjects had the power to pro- Asian 3 3vide an 85% chance of detecting, with Multiracial 1 1␣ ϭ 5%, a 10% treatment effect for the Hispanic heritage (%) 10 6primary outcome measure. The intent-to- Prior therapy (%)treat (ITT) population included all sub- SU ϩ metformin 71 74jects randomized who received at least SU only 11 10one dose of study medication. The last Metformin only 8 7measurement before discontinuation or SU ϩ TZD 6 5completion of the protocol was consid- Metformin ϩ TZD 3 3ered the end point measurement (last ob- TZD only Ͻ1 Ͻ1servation carried forward). For all center- Data are means Ϯ SD, unless otherwise noted. SU, sulfonylurea; TZD, thiazolidinedione.stratiﬁed analyses, centers with Ͻ24randomized and treated subjects werepooled on a geographical basis, indepen- and protocol violation, loss to follow-up, Mean daily dosages at end point adjusteddently of treatment identiﬁcation. Be- or other reasons (glargine 6, NPH 6). for body weight were 0.48 Ϯ 0.01 IU/kgtween-treatment differences in the No between-treatment differences were for glargine vs. 0.42 Ϯ 0.01 IU/kg forpercentages of subjects achieving the pri- apparent at baseline in the ITT population NPH (P Ͻ 0.001; between-treatment dif-mary end point or other HbA1c or FPG (Table 2), except that slightly more sub- ference 0.06 IU/kg [0.02– 0.09]). Weighttargets or experiencing hypoglycemia jects in the glargine group were of His- increased similarly from baseline to endwere assessed by the Cochran-Mantel- panic descent. Over 70% were taking point in both groups: 3.0 Ϯ 0.2 kg withHaenszel test stratiﬁed by pooled center. both a sulfonylurea and metformin. Initial glargine and 2.8 Ϯ 0.2 kg with NPH (P ϭFor the continuous variables, the change HbA1c averaged 8.6%. NS; between-treatment difference 0.2 kgfrom baseline was examined by ANCOVA [Ϫ0.24 to 0.68]).with treatment and pooled center as ﬁxed Glycemic response, insulin dosage,effects and the corresponding baseline as and weight Self-measured glycemic patternsa covariate. All statistical tests were two Fasting glucose decreased smoothly in Eight-point glucose proﬁles were com-sided, and results are presented as means both groups, reaching a plateau by 12 pared at baseline and end point. Meanand SE unless otherwise speciﬁed. weeks. Mean FPG at end point was 117 values at all times of day declined after mg/dl (6.5 mmol/l) for glargine and 120 addition of insulin, without alteration ofRESULTS — In total, 1,381 subjects mg/dl (6.7 mmol/l) for NPH (P ϭ NS; the postmeal increments and without dif-were screened. After a 4-week run-in pe- between-treatment difference Ϫ3.6 ferences between treatments. Althoughriod, 764 qualifying subjects were ran- mg/dl [Ϫ0.2 mmol/l] [95% CI Ϫ8.82 to population mean values for fasting glu-domized to either glargine or NPH. Eight 1.62]) (Fig. 1A). HbA1c declined at a pre- cose were similar, with glargine there was(ﬁve glargine and three NPH) withdrew dictably slower rate, stabilizing after 18 less within-subject variability betweenbefore receiving an insulin injection. The weeks (Fig. 1B). Mean HbA1c at end point seven sequential fasting measurementsremaining 756 subjects comprised the was 6.96% with glargine and 6.97% with over the course of treatment. At 24 weeks,ITT population. Equivalent numbers NPH (P ϭ NS; between-treatment differ- the mean deviation from the median ofwithdrew from the two groups during the ence Ϫ0.03%; [Ϫ0.13 to 0.08]). fasting values for individual subjects wastrial: 33 of 367 (9.0%) from glargine and Insulin dosage increased in similar greater with NPH than glargine (20.3632 of 389 (8.2%) from NPH. Reasons for patterns in both groups, but was higher mg/dl [1.13 mmol/l] vs. 18.38 mg/dlwithdrawal included subject preference with glargine than with NPH from week 2 [1.02 mmol/l]; between-treatment P ϭ(glargine 15, NPH 3); investigator’s dis- until the study’s end (P Ͻ 0.05– 0.001). 0.013, after adjustment for baseline).cretion, poor adherence, or lack of efﬁ- Mean daily dosages at end point werecacy (glargine 3, NPH 14); hypoglycemia 47.2 Ϯ 1.3 IU for glargine vs. 41.8 Ϯ 1.3 Rates of hypoglycemia(glargine 1, NPH 3); adverse events other for NPH (P Ͻ 0.005; between-treatment Figure 2 shows the cumulative incidencethan hypoglycemia (glargine 6, NPH 4); difference 5.3 IU [95% CI 1.8 – 8.9]). of hypoglycemic events. Fewer events oc-3082 DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003
Riddle and Associates evident for the rates of conﬁrmed hypo- glycemic events per patient-year (Fig. 3B) except for slightly more events at a single daytime time point (11.00 –12.00 h) with glargine. With either way of displaying the temporal distribution of hypoglyce- mia, a peak was evident in the early morn- ing for NPH. Expressed as events per patient year, the rates of nocturnal hypo- glycemia with glargine versus NPH were 4.0 vs. 6.9 (P Ͻ 0.001) for all reported events, 3.1 vs. 5.5 (P Ͻ 0.001) for con- ﬁrmed events of Յ72 mg/dl (4.0 mmol/l), and 1.3 vs. 2.5 (P Ͻ 0.002) for conﬁrmed events of Յ56 mg/dl (3.1 mmol/l). The risk reduction with glargine for these cat- egories of hypoglycemia was 42, 44, and 48%, respectively. Treatment success The two insulins were equally effective in achieving target levels of glycemic con- trol. The Յ7% HbA1c target was reached by 58.0% of subjects with glargine and 57.3% with NPH. However, complete treatment success, rigorously deﬁned as reaching target HbA1c without an episode of documented nocturnal hypoglycemia, was achieved by more subjects with glargine (33.2 vs. 26.7%, P Ͻ 0.05). The 100-mg/dl (5.6-mmol/l) FPG titration target was reached by 36.2% of subjects with glargine and 34.4% with NPH. How- ever, this target was more often achieved without hypoglycemia using glargine. With glargine, 22.1% of patients reached FPG Յ100 mg/dl and 33.2% reached FPG Յ120 mg/dl without documentedFigure 1—FPG (A) and HbA1c (B) during the study. Values in both ﬁgures are means; error bars nocturnal hypoglycemia compared withindicate SE. 15.9% and 25.7% with NPH, respectively (both P Ͻ 0.03).curred with glargine than NPH, especially with the two treatments. Nine patients CONCLUSIONS — This trial was de-those conﬁrmed by glucose tests (Fig. 2A taking glargine (2.5%) reported 14 severe signed to clarify two issues. First, it was aand B), with no tendency for the between- events and seven taking NPH (1.8%) re- proof-of-concept trial testing the hypoth-treatment difference to decline over time. ported 9 severe events. None of these ep- esis that supplementing oral therapy with Expressed as events per patient year, isodes resulted in unconsciousness or a bedtime injection of basal insulin canthe rates of hypoglycemia with glargine seizures. Severe hypoglycemia was the routinely achieve the recommended 7%versus NPH were 13.9 vs. 17.7 (P Ͻ 0.02) only serious adverse event considered HbA1c target in this population. Second,for all symptomatic events, 9.2 vs. 12.9 possibly related to treatment. it tested whether glargine is better suited(P Ͻ 0.005) for conﬁrmed events of Յ72 than NPH to provide this supplement.mg/dl (4.0 mmol/l), and 3.0 vs. 5.1 (P Ͻ Daily pattern of hypoglycemia In support of our ﬁrst hypothesis,0.003) for conﬁrmed events of Յ56 mg/dl Signiﬁcantly more patients experienced both insulins reduced mean HbA1c from(3.1 mmol/l). These P values were derived hypoglycemia at night with NPH, but 8.6% at baseline to 7% at end point, withfrom an analysis of ranks due to the skew there were no between-treatment differ- nearly 60% of patients reaching 7% orin distribution of the observed values. The ences in the percentage of patients with less. This exceptional success exceededrisk reduction with glargine relative to symptomatic hypoglycemia conﬁrmed by the results of other trials in which basal orNPH for these categories of hypoglycemia a measurement of glucose Յ72 mg/dl (4.0 premixed insulin was added to oral ther-was 21, 29, and 41%, respectively. Severe mmol/l) through the day and early apy when mean HbA1c was Ͼ8% (17–hypoglycemia was similarly uncommon evening (Fig. 3A). Similar patterns were 21), and several factors probablyDIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 3083
The Treat-to-Target Trial pecially more common with NPH. The rates of hypoglycemia by clock time, fol- lowing a bedtime injection of NPH (Fig. 3), closely resembled the action proﬁle of NPH in pharmacodynamic studies (22), highlighting the main limitation of this insulin as a basal supplement—its char- acteristic peak of glucose-lowering activ- ity between 4 and 8 h after injection. The 42– 48% reduction of nocturnal hypogly- cemia with glargine provides clinical sup- port for the theoretical superiority of glargine, based on its ﬂatter action proﬁle (23). Rates of daytime hypoglycemia were reassuringly low, showing that the reduc- tion of nocturnal hypoglycemia with glargine did not come at the expense of more hypoglycemia throughout the day. Severe hypoglycemia was similarly infre- quent with the two insulins. These hypo- glycemia data conﬁrm the hypothesis that glargine is better suited to this basal insu- lin regimen than NPH by allowing pa- tients to reach recommended levels of glycemic control more safely. Some important questions are not ad- dressed by these ﬁndings. For example, which subgroups of patients are most likely to reach target with this regimen, and which will have the greatest relative beneﬁt from glargine? If patients are less strongly encouraged to increase insulin after mild hypoglycemia, will they have higher HbA1c values when NPH is used than with glargine? How clinically impor- tant is the 3-kg weight gain after starting insulin, which was not reduced in the glargine group, and how can it be mini- mized? How should patients not reachingFigure 2—Cumulative number of hypoglycemia events. Events with plasma-referenced glucose(PG) Յ72 mg/dl (4.0 mmol/l) (A) and with PG Յ56 mg/dl (3.1 mmol/l) (B) are depicted. or maintaining the HbA1c target with a single basal insulin injection subse- quently advance to intensiﬁed therapy in- cluding mealtime rapid-acting insulin?contributed. First, baseline HbA1c was col exceeded 90%, suggesting that this What approach should be used for cate-lower in this study than in most other regimen was easy to follow. gories of patients who were not includedstudies. Second, over two-thirds of the The comparison of glargine with NPH in this trial, such as those with late-onsetsubjects were taking two oral agents, and added important information about hy- type 1 diabetes or with HbA1c valuesalthough poor control on two agents sug- poglycemia occurrence and timing. Al- Ͼ10%, many of whom may need addi-gests advanced diabetes, potentially re- though the two insulins achieved similar tional injections of short-acting insulin ifquiring multiple injections of insulin, FPG and HbA1c levels, glargine did so levels of HbA1c remain above target de-continuation of these agents probably en- with considerably less symptomatic hy- spite optimization of basal insulin? Fur-hanced the effects of remaining endoge- poglycemia. This indicates the success of ther analyses and more studies are clearlynous insulin. Third, the titration target the effort devoted to titration but reveals needed.was ambitiously low (100 mg/dl [5.6 that the equivalent success with NPH Despite these limitations, the Treat-mmol/l] using a plasma-referenced sys- came with more risk and inconvenience to-Target Trial offers the basis for a sim-tem, corresponding to ϳ90 mg/dl [5.0 related to this side effect. The lower rates ple, standardized way to initiate basalmmol/l] with a whole-blood system). Fi- of hypoglycemia with glargine were ac- insulin in routine practice for an impor-nally, insulin dosage was systematically companied by less variability of FPG, tant group of patients, those overweighttitrated to target. The reported levels of which presumably contributed to this ad- patients with type 2 diabetes who havepatient adherence to the treatment proto- vantage. Nocturnal hypoglycemia was es- HbA1c between 7.5 and 10% despite us-3084 DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003
Riddle and Associates trial, including his work on the Titration Mon- itoring Committee. APPENDIX Investigators in the Insulin Glargine 4002 Study Group U.S. Bell D, Berlin C, Bernene J, Bloom- garden ZT, Bode B, Boden G, Bohannon N, Boyle PJ, Braunstein S, Burris A, Buse J, Calle R, Cannon R, Chaykin L, Crow D, Dailey G, Davidson J, Davis S, Drexler AJ, Drummond W, Dwarakanathan A, Faj- tova V, Falko J, Feinglos M, Fink R, Firek A, Fonseca V, Gallup B, Gerich J, Graf RJ, Grunberger G, Guthrie R, Henry R, Her- shon K, Juneja R, Kaye W, Kayne DM, Kent A, Khairi R, Khan M, Kim J, Kitabchi A, Klaff L, Leahy J, Levy P, Lorber D, Madhun Z, Malchoff C, Marks J, Mc- Clanahan M, McGill J, Mehta A, Meredith M, Mersey J, Miles J, Montgomery C, Ne- iﬁng JL, Podlecki DA, Radparvar A, Raskin P, Ratner R, Reeves M, Rendell MS, Reynolds R, Riddle MC, Rikalo N, Roberts V, Rodriguez A, Rosenstock J, Ross P, Schneider SH, Schwartz SL, Seibel JA, Short B, Taylon A, Teague RJ, Trippe B, Troupin B, Trujillo A, Vaswani A, Warren M, Weinstein RL, and Weinstock RS. Canada. Dawkins K, Edwards A, Hardin P, Hramiak I, Josse R, Ross S, Ur E, and Woo V. References 1. Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS: Racial and ethnic dif- ferences in glycemic control in adults with type 2 diabetes. Diabetes Care 22:403–Figure 3—Distribution of hypoglycemia by time of day. A: The proportion of patients experienc- 408, 1999ing at least one episode of hypoglycemia documented with plasma-referenced glucose Յ72 mg/dl 2. Turner RC, Cull CA, Frighi V, Holman(4.0 mmol/l). B: The hourly hypoglycemia rates, expressed as events per patient-year at the same RR, UK Prospective Diabetes Studyplasma-referenced glucose cutoff. Group: Glycemic control with diet, sulfo- nylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressiveing one or two oral agents. The regimen in its design and conduct, the collection and requirement for multiple therapiesrequires just one daily injection added to statistical analysis of data, and providing study (UKPDS 49). JAMA 281:2005–2012,oral therapy and one daily fasting glucose medications. The primary authors partici- 1999test to guide adjustment of dosage. In this pated in the design and monitoring of the 3. UK Prospective Diabetes Study Group:trial, it achieved the 7% HbA1c target for a study, controlled data evaluation and interpre- UK Prospective Diabetes Study 16: over- tation, and prepared the manuscript. view of 6 years’ therapy of type II diabetes:majority of patients. Furthermore, the Data from this study have been previously a progressive disease. Diabetes 44:1249 –lower risk of nocturnal hypoglycemia 1258, 1995with glargine relative to NPH reduces the published in abstract form (in Diabetes 50 4. Stratton IM, Adler AI, Neil HA, Matthewsleading barrier to starting insulin therapy: [Suppl. 2]:A129, 2001; Diabetes 51 [Suppl. DR, Manley SE, Cull CA, Hadden D,the fear of hypoglycemia. This study 2]:A113, A482, 2002; Diabetologia 45 [Suppl. Turner RC, Holman RR: Association ofbrings us one step closer to a widely ap- 2]:A52, A259, 2002) and presented at the glycaemia with macrovascular and micro-plicable clinical algorithm. 2002 congresses for the American Diabetes vascular complications of type 2 diabetes Association and the European Association for (UKPDS 35): prospective observational the Study of Diabetes. study. BMJ 321:405– 411, 2000Acknowledgments — This study was spon- The authors express their gratitude to 5. Klein R, Klein BEK, Moss SE: Relation ofsored by Aventis Pharma, which was involved George Dailey for his important role in the glycemic control to diabetic microvascu-DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 3085
The Treat-to-Target Trial lar complications of diabetes mellitus. NIDDM. Diabetes 44:165–172, 1995 Ryysy L, Salo S, Seppala P, et al: Compar- Ann Intern Med 124:90 –96, 1996 13. Bolli GB, Owens DR: Insulin glargine ison of insulin regimens in patients with 6. UK Prospective Diabetes Study (UKPDS) (Commentary). Lancet 356:443– 444, non-insulin-dependent diabetes mellitus. Group: Intensive blood-glucose control 2000 N Engl J Med 327:1426 –1433, 1992 with sulphonylureas or insulin compared 14. Rosenstock J, Schwartz SL, Clark CM Jr, 20. Yki-Jarvinen H, Ryysy L, Nikkila K, Tulo- ¨ with conventional treatment and risk of Park GD, Donley DW, Edwards MB: Basal kas T, Vanamo R, Heikkila M: Compari- complications in patients with type 2 di- insulin therapy in type 2 diabetes: 28- son of bedtime insulin regimens in patients abetes (UKPDS 33). Lancet 352:837– 853, week comparison of insulin glargine with type 2 diabetes mellitus. Ann Intern 1998 (HOE901) and NPH insulin. Diabetes Med 130:389 –396, 1999 7. Wright A, Burden ACF, Paisey RB, Cull Care 24:631– 636, 2001 21. Abraira C, Henderson WG, Colwell JA, CA, Holman RR, UK Diabetes Study 15. American Diabetes Association: Nutrition Nuttall FQ, Comstock JP, Emanuele NV, Group: Sulfonylurea inadequacy: efﬁcacy recommendations and principles for peo- Levin SR, Sawin CT, Silbert CK: Response of addition of insulin over 6 years in pa- ple with diabetes mellitus (Position State- to intensive therapy steps and to glipizide tients with type 2 diabetes in the UK Pro- ment). Diabetes Care 23:S43–S49, 2000 dose in combination with insulin in type 2 spective Diabetes Study (UKPDS 57). 16. Davis SN, Shavers C, Mosqueda-Garcia R, diabetes: VA feasibility study on glycemic Diabetes Care 25:330 –336, 2002 Costa F: Effects of differing antecedent control and complications (VA CSDM). 8. Hayward RA, Manning WG, Kaplan SH, hypoglycemia on subsequent counter- Diabetes Care 21:574 –579, 1998 Wagner EH, Greenﬁeld S: Starting insulin regulation in normal humans. Diabetes 22. Lepore M, Pampanelli S, Fanelli C, Por- therapy in patients with type 2 diabetes: 46:1328 –1335, 1997 effectiveness, complications, and resource 17. Yki-Jarvinen H, Dressler A, Ziemen M, ¨ cellati F, Bartocci L, Di Vincenzo A, Cor- utilization. JAMA 278:1663–1669, 1997 HOE 901/3002 Study Group: Less noc- doni C, Costa E, Brunetti P, Bolli GB: 9. Cryer PE: Hypoglycemia is the limiting turnal hypoglycemia and better post-din- Pharmacokinetics and pharmacodynam- factor in the management of diabetes. ner glucose control with bedtime insulin ics of subcutaneous injection of long-act- Diabete Metab Res Rev 15:42– 46, 1999 glargine compared with bedtime NPH in- ing human insulin analog glargine, NPH10. Taskinen M-R, Sane T, Helve E, Karonen sulin during insulin combination therapy insulin, and ultralente human insulin and S-L, Nikkila EA, Yki-Jarvinen H: Bedtime in type 2 diabetes. Diabetes Care 23:1130 – continuous subcutaneous infusion of insulin for suppression of overnight free 1136, 2000 insulin lispro. Diabetes 49:2142–2148, fatty acid, blood glucose, and glucose pro- 18. Riddle MC, Schneider J, Glimepiride 2000 duction in NIDDM. Diabetes 38:580 – Combination Group: Beginning insulin 23. Heinemann L, Linkeschova R, Rave K, 588, 1989 treatment of obese patients with evening Hompesch B, Sedlak M, Heise T: Time-11. Riddle MC: Evening insulin strategy. Di- 70/30 insulin plus glimepiride versus in- action proﬁle of the long-acting insulin abetes Care 13:676 – 686, 1990 sulin alone. Diabetes Care 21:1052–1057, analog insulin glargine (HOE901) in12. Shank ML, DelPrato S, DeFronzo RA: 1998 comparison with those of NPH insulin Bedtime insulin/daytime glipizide: effec- 19. Yki-Jarvinen H, Kauppila M, Kujansuu E, ¨ and placebo. Diabetes Care 23:644 – 649, tive therapy for sulfonylurea failures in Lahti J, Marjanen T, Niskanen L, Rajala S, 20003086 DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003