Emerging Treatments and Technologies ORIGINAL ARTICLE

Insulin Glulisine Provides Improved Glycemic Control in Patients With Type 2 Diabetes

1 3 GEORGE DAILEY, MD ROBERT G. MOSES, MD patients should mimic physiologic 2 4 JULIO ROSENSTOCK, MD KIRK WAYS, MD, PHD secretion, thereby maintaining levels as close to normoglycemia as possible at all times. Hence, there should be appropriate prandial replacement of the peaks in in- sulin activity to complement continuous OBJECTIVE — Insulin glulisine is a novel analog of human insulin designed for use as a 24-h basal insulin levels. rapid-acting insulin. This study compared the safety and efficacy of glulisine with regular human Regular human insulin (RHI) has insulin (RHI) in combination with NPH insulin. been used as a mealtime therapy for many years. However, its onset of action is rel- RESEARCH DESIGN AND METHODS — In total, 876 relatively well-controlled pa- atively slow and the action profile does tients with type 2 diabetes (mean HbA1c 7.55%) were randomized and treated with glulisine/ NPH (n ϭ 435) or RHI/NPH (n ϭ 441) for up to 26 weeks in this randomized, multicenter, not closely mimic physiologic mealtime multinational, open-label, parallel-group study. Subjects were allowed to continue the same insulin secretion, necessitating its recom- dose of prestudy regimens of oral antidiabetic agent (OAD) therapy (unless hypoglycemia ne- mended administration 30–45 min be- cessitated a dose change). fore meals (4). This requires meal planning that can be restrictive to pa- RESULTS — A slightly greater reduction from baseline to end point of HbA1c was seen in the tients’ lifestyles; indeed, most patients ad- Ϫ Ϫ ϭ glulisine group versus RHI ( 0.46 vs. 0.30% with RHI; P 0.0029). Also, at end point, lower minister RHI Ͻ30 min before mealtime postbreakfast (156 vs. 162 mg/dl [8.66 vs. 9.02 mmol/l]; P Ͻ 0.05) and postdinner (154 vs. 163 Ͻ (5). RHI is, therefore, unlikely to provide mg/dl [8.54 vs. 9.05 mmol/l]; P 0.05) blood glucose levels were noted. Symptomatic hypo- optimal glycemic control in most patients. glycemia (overall, nocturnal, and severe) and weight gain were comparable between the two treatment groups. There were no between-group differences in baseline–to–end point changes Glulisine is a novel rapid-acting insu- in insulin dose. lin analog that differs from human insulin by the replacement of the amino acid as- CONCLUSIONS — Twice-daily glulisine associated with NPH can provide small improve- paragine with at position 3 and ly- ments in glycemic control compared with RHI in patients with type 2 diabetes who are already sine with at position 29 of relatively well controlled on insulin alone or insulin plus OADs. The clinical relevance of such a the B-chain. Compared with RHI, glu- difference remains to be established. lisine has a more rapid onset of action and a shorter duration of action (6). The time- Diabetes Care 27:2363–2368, 2004 action profile of glulisine thus lends itself to greater treatment convenience com- pared with RHI, as its use requires less ttaining and maintaining normo- may initially control hyperglycemia, most mealtime planning. glycemic control are the treatment patients with type 2 diabetes will ulti- This study compared the effects of A goals in type 2 diabetes in order to mately require insulin therapy, as ␤-cell glulisine (Aventis Pharma) and RHI (Eli minimize long-term clinical risk (1). Al- function progressively declines (2,3). Ide- Lilly) on HbA1c, self-monitored blood though oral antidiabetic agents (OADs) ally, glycemic control in insulin-treated glucose profiles, hypoglycemia, and safety in patients with type 2 diabetes. ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1Scripps Clinic, La Jolla, California; the 2Dallas Diabetes and Endocrine Center, Dallas, Texas; 3Wollongong Hospital, Wollongong, NSW, Australia; and 4Aventis Pharma, Bridgewater, New Jersey. RESEARCH DESIGN AND Address correspondence and reprint requests to George Dailey, MD, Scripps Clinic, 10666 North Torrey METHODS — Subjects with estab- Pines Rd., La Jolla, CA 92037. E-mail: [email protected]. Ն Received for publication 22 January 2004 and accepted in revised form 19 July 2004. lished type 2 diabetes, aged 18 years, G.D. has received honoraria, research grants, and served as an occasional consultant for Aventis, Bristol- who had been on insulin therapy for Ն6 Myers Squibb, Merck, Novo Nordisk, Pfizer, Eli Lilly, GlaxoSmithKline, and ; has served on a months before the study, with an HbA1c speakers bureau only for Merck Sante; and has been an investigator for Schering-Plough, Takeda, Kowa, level between 6.0 and 11.0%, were en- ACON, Forest, and Becton-Dickinson. J.R. has served as a consultant and/or on a speakers bureau for Aventis, Pfizer, Novo Nordisk, Takeda, GlaxoSmithKline, and Johnson & Johnson; and has received research rolled in the study. support from Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Novo Nordisk, Pfizer, Aventis, Novartis, This was a phase III, 1:1 randomized, Takeda, AstraZeneca, and Merck. K.W. holds stock in Bristol-Myers Squibb and Lilly. multicenter, multinational, controlled, Abbreviations: ITT, intention to treat; OAD, oral antidiabetic agent; RHI, regular human insulin; TEAE, open-label, parallel-group study with a treatment-emergent adverse event. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion 1-week screening, 4-week run-in, and factors for many substances. 26-week treatment phase. During run-in, © 2004 by the American Diabetes Association. all subjects received RHI and NPH insulin

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2363 Glycemic control with insulin glulisine injections, both given twice daily. The fasting [prebreakfast], before lunch and sided ANCOVA at a significance level of study was conducted in accordance with dinner, after all three meals, and at bed- ␣ϭ2.5%; all other statistical tests were Good Clinical Practice and conformed to time) were measured on 3 different days two sided, at a significance level of ␣ϭ the ethical principles of the Declaration of in the weeks preceding clinic visits at 5%. To assess noninferiority, the upper Helsinki. All study materials were re- baseline and weeks 12 and 26. All blood bound of the CI for the between- viewed and approved by an independent glucose values were converted to whole- treatment difference in the adjusted mean ethics committee or institutional review blood–referenced blood glucose for con- baseline to end point change in HbA1c board. sistency in data reporting. was compared with the predefined non- Randomization was stratified accord- inferiority margin of 0.4% HbA1c. Nonin- ing to whether subjects were treated with Hypoglycemia feriority was demonstrated if the upper OADs at randomization. Subjects were Overall, nocturnal and severe symptom- bound of CI was Ͻ0.4%. If noninferiority randomized to subcutaneous injections of atic hypoglycemia were monitored. was demonstrated, a corresponding glulisine or RHI 0–15 and 30–45 min, Symptomatic hypoglycemia was defined check of statistical superiority (upper respectively, before breakfast and dinner. as an event with clinical symptoms con- bound of CI Ͻ0.0%) was performed If required, based on the clinical judg- sidered to result from hypoglycemia. without an ␣ penalty because this is a ment of the investigator, more than two Nocturnal symptomatic hypoglycemia closed procedure. Changes in HbA1c from injections of glulisine or RHI were permit- was defined as symptomatic hypoglyce- baseline to weeks 12 and 26, self- ted. Both treatment groups received mia occurring while the patient was monitored blood glucose, and insulin twice-daily injections of NPH insulin as asleep (between bedtime and rising in the dose were evaluated by ANCOVA. Base- basal therapy. The number of meal time morning). Severe symptomatic hypogly- line between-treatment comparisons for insulin injections and the timing of NPH cemia was defined as symptomatic hypo- continuous variables were analyzed by insulin administration were established glycemia requiring assistance from ANOVA. Comparisons of hypoglycemia during run-in and maintained during the another person and confirmed by blood incidence were conducted using the treatment phase. Mixing of glulisine or glucose Ͻ36 mg/dl (Ͻ2.0 mmol/l) or as- Cochran-Mantel-Haenszel test. Mean val- RHI with NPH insulin just before injec- sociated with prompt recovery following ues were adjusted for center, stratum, tion was allowed. No formal insulin dose oral carbohydrate, intravenous glucose, baseline, and OAD use at randomization. algorithms were given. Adjustment of or administration. The intention-to-treat (ITT) population glulisine and RHI doses was at the inves- (all randomized subjects who received tigator’s discretion if necessary to achieve Insulin dose study ) was evaluated for all 2-h postprandial blood glucose 120–160 Bolus and basal daily insulin doses and efficacy and safety variables. mg/dl (6.7–8.9 mmol/l), while avoiding total daily number of injections were hypoglycemia. NPH insulin doses were recorded. RESULTS — A total of 1,186 patients adjusted according to a predefined insulin entered screening; 878 were randomized titration regimen to achieve preprandial Safety and 876 received study medication (glu- blood glucose 90–120 mg/dl (5.0–6.7 Local and systemic treatment-emergent lisine: n ϭ 435; RHI: n ϭ 441). This com- mmol/l), while avoiding hypoglycemia. adverse events (TEAEs) were investigator prised the ITT population. Of the 876 Continuation of prestudy OAD dose and and patient reported. Severe symptomatic treated patients, 64 withdrew (glulisine: regimen was permitted, unless hypogly- hypoglycemia was systematically re- n ϭ 28; RHI: n ϭ 36) after treatment start. cemia necessitated a dose reduction for ported as a possibly related serious TEAE. Main reasons for withdrawal included did safety reasons. Lipid levels, Escherichia coli antibody lev- not wish to continue (glulisine: n ϭ 12; els, hematologic parameters, and clinical RHI: n ϭ 13), lost to follow-up (glulisine: Glycemic control parameters chemistry were analyzed. Changes from n ϭ 5; RHI: n ϭ 6), and TEAEs (glulisine: ϭ ϭ HbA1c levels. Glycated hemoglobin in baseline in insulin antibody levels (cross- n 5; RHI: n 6). whole blood was analyzed by a single cen- reactive, glulisine specific, and human in- Baseline characteristics (Table 1) tral laboratory (Diabetes Diagnostic Lab- sulin specific) were evaluated as were similar between the two treatment oratory, Columbia, MS), which was percentage bound radiolabeled insulin of groups, except for age and duration of di- certified by the U.S. National Glycohemo- total radiolabeled insulin (% B/T). abetes. Patients randomized to glulisine globin Standardization Program. GHb re- were older (mean age 58.9 Ϯ 10.20 years Ϯ ϭ sults were reported as “HbA1c Statistical methods vs. 57.7 9.90 with RHI; P 0.04) and equivalents” and are directly traceable to Based on 1:1 randomization and assum- had a significantly longer mean duration the Diabetes Control and Complications ing a nonevaluable rate of 20%, 846 sub- of diabetes versus the RHI group (14.7 Ϯ Trial reference. Measurements were taken jects (423 per treatment group) needed to 8.12 vs. 13.4 Ϯ 7.55 years; P ϭ 0.02). at baseline and weeks 12 and 26. be randomized to demonstrate noninferi- The majority of subjects in the glulisine ority of glulisine versus RHI (upper con- and RHI treatment groups used NPH in- Self-monitored blood glucose profiles. fidence limit of the two-sided 95% CI for sulin before entry into the study (388 Using self-monitoring devices (plasma- the between-treatment adjusted mean [89.2%] and 386 [87.5%] subjects, re- Յ referenced [North America] and whole- difference 0.4% HbA1c) with at least spectively). Before the study, premixed blood–referenced [Australia] meters were 90% power. The primary analysis was insulin was being used by 169 (38.9%) provided by the study sponsor), seven- comparison of baseline to end point– patients in the glulisine group and 169 point blood glucose profiles (morning adjusted change in HbA1c using one- (38.3%) subjects in the RHI group.

2364 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Dailey and Associates

Table 1—Demographics and baseline characteristics of patients with type 2 diabetes receiving glulisine and RHI (ITT population)

Variable Glulisine RHI P n 435 441 — Sex Male 244 (56.1) 219 (49.7) 0.07 Female 191 (43.9) 222 (50.3) — Age (years) 58.9 Ϯ 10.20 57.7 Ϯ 9.90 0.04 BMI (kg/m2) 34.60 Ϯ 6.88 34.51 Ϯ 7.02 0.79 Duration of diabetes (years) 14.7 Ϯ 8.12 13.4 Ϯ 7.55 0.02 Age at diagnosis of diabetes (years) 44.8 Ϯ 10.30 44.8 Ϯ 9.68 0.86 Ϯ Ϯ HbA1c (%) 7.58 0.937 7.52 0.959 0.51 Mean daily insulin dose (units) Basal 59.6 Ϯ 34.70 57.1 Ϯ 31.18 0.40 Short acting 32.5 Ϯ 25.36 31.3 Ϯ 23.57 0.46 OAD use at randomization 245 (56.3) 263 (59.6) 0.32 Race White 372 (85.5) 376 (85.3) — Black 48 (11.0) 51 (11.6) — Asian 8 (1.8) 9 (2.0) — Multiracial 7 (1.6) 5 (1.1) — Hispanic origin 34 (7.8) 26 (5.9) — Data are means Ϯ SD or n (%), unless otherwise indicated.

Glycemic control statistical significance reached at 2 h post- dences or monthly rates of overall, Ͻ Baseline to end point change in HbA1c. breakfast and 2 h postdinner (P 0.05) nocturnal, or severe symptomatic hypo- Baseline HbA1c was comparable between (Fig. 2). glycemia from month 4 to treatment end, the treatment groups (Table 1), and both a time at which patients were fully accli- groups showed significant baseline to end Symptomatic hypoglycemia mated to the study. In both the glulisine point reductions in mean HbA1c levels There were no statistically significant be- and RHI groups, a similar proportion of (Ϫ0.46 and Ϫ0.30%, for glulisine and tween-treatment differences in the inci- patients experienced at least one episode RHI, respectively). Noninferiority of glu- lisine compared with RHI was demon- strated by virtue of the fact that the upper bound of the 95% CI was Ͻ0.4% (base- line-adjusted mean difference Ϫ0.16, 95% CI Ϫ0.26 to Ϫ0.05). The upper limit of the 95% CI was Ͻ0.0%, which established statistical superiority for glu- lisine (P ϭ 0.0029). In both groups, just over one-half of the patients reached Յ HbA1c 7% (53.5 and 50.6% of patients on glulisine and RHI, respectively). Change in HbA1c over the course of the study. There was a significant reduction from baseline in HbA1c in both groups over the course of the study (Fig. 1), with statistically significantly greater reduc- tions from baseline observed with glu- lisine versus RHI from 12 weeks onwards (P Ͻ 0.05 for all time points measured) (Fig. 1). Self-monitored blood glucose profile. At baseline, self-monitored seven-point blood glucose profiles were comparable in the two groups. However, blood glu- Ͻ cose values were lower with glulisine ver- Figure 1—Mean HbA1c over time. *Between-treatment difference: P 0.05. HbA1c is measured sus RHI at all on-treatment points, with as HbA1c equivalents.

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2365 Glycemic control with insulin glulisine

Safety Adverse events. A total of 358 glulisine- treated patients (82.3%) and 351 RHI- treated patients (79.6%) experienced TEAEs during the treatment phase. Fifty- five (12.6%) patients in the glulisine group and 51 (11.6%) patients in the RHI group experienced serious TEAEs. Seri- ous nonhypoglycemia TEAEs were re- ported in 80 (9.1%) of the 876 patients during the study (glulisine: n ϭ 40 [9.2%]; RHI: n ϭ 40 [9.1%]); none of these were considered possibly related to study medication. There were three deaths (glulisine: n ϭ 1 [0.2%]; RHI: n ϭ 2 [0.5%]), none of which were deemed to be treatment related or associated with a severe hypoglycemic event. The inci- dences of potential systemic hypersensi- tivity (6.9% with glulisine vs. 5.2% with Figure 2—-Mean daily blood glucose profiles at study end point. *Between-treatment difference: P Ͻ 0.05. RHI) and injection site reactions (3.2% with glulisine vs. 2.3% with RHI) were similar in both treatment groups. Laboratory and other safety data. The of symptomatic (51.7 vs. 53.6%, respec- short-acting injections per day was also two groups were similar in terms of he- tively; P ϭ 0.600), nocturnal (21.4 vs. similar in both groups at end point (2.27 matology, clinical chemistry, and lipids in 24.5%, respectively; P ϭ 0.303), or severe with glulisine vs. 2.24 with RHI). the change from baseline, predefined ab- hypoglycemia (1.4 vs. 1.2%, respectively; A total of 78.7% of patients reported normal values, and clinically noteworthy P ϭ 0.645). Symptomatic hypoglycemia mixing the short-acting insulin with NPH values. A rise in E. coli antibody levels rates were similar in the insulin glulisine insulin (glulisine: 74.1%; RHI: 83.1%) from negative or borderline to positive and RHI groups (0.95 vs. 1.04 events/ before injection by syringe; 25.7% mixed was similarly infrequent in both treat- patient-month, respectively; P ϭ 0.186), their once daily and 53.0% ment groups and not associated with the as were nocturnal hypoglycemia rates mixed twice daily. The proportion of pa- reporting of potential systemic hypersen- (0.14 vs. 0.21 events/patient-month, re- tients mixing the insulins in a syringe sitivity TEAEs. The adjusted mean change spectively; P ϭ 0.109). Severe hypoglyce- once and twice daily was similar in the in body weight at end point was similar in mia rates were low at 0.0041 events/ two treatment groups. both treatment groups (glulisine: 1.8 kg; patient-month for glulisine and 0.0037 RHI: 2.0 kg; P ϭ 0.369). events/patient-month for RHI, and simi- OAD use lar between treatment groups (between- Subjects were allowed to continue taking Insulin antibodies treatment P ϭ 0.353). This between- OADs during the treatment period, and At baseline, median cross-reactive insulin treatment similarity was consistent over randomization was stratified according to antibody levels were comparable in the the entire treatment period (data not whether the subjects were already being glulisine (0.13% B/T) and RHI (0.20% shown). treated with OADs before the study. At B/T) groups. Baseline to end point randomization, OADs were being used by changes in cross-reactive insulin antibody Insulin dose 508 (58%) subjects (245 in the glulisine levels were not statistically significant in No between-treatment differences in in- group and 263 in the RHI group). Of either group. Mean change from baseline sulin doses were detected throughout the these, 133 (26.2%) were taking a sulfo- in the glulisine group was 0.298 Ϯ 2.01% study. Total daily insulin dose was similar nylurea (61 [14%] patients in the glu- B/T, with a median value of 0.01% B/T with glulisine versus RHI at baseline (91.6 lisine group and 72 [16.3%] patients in and 5, 10, and 95% quartiles of Ϫ1.12, vs. 88.6 units; P ϭ 0.3770). The same was the RHI group), and the treatments were Ϫ0.59, and 3.22, respectively. Mean true of daily basal (59.1 vs. 57.3 units; balanced for use at baseline. change from baseline in the RHI group P ϭ 0.4025) and short-acting insulin At end point, 512 (58.4%) patients were was 0.093 Ϯ 1.5321% B/T, with a median (32.5 vs. 31.3 units; P ϭ 0.4644) doses at taking OADs (4 patients began OAD ther- value of 0.02% B/T and 5, 10, and 95% baseline. At end point, total daily insulin apy and 4 stopped their OAD therapy quantiles of Ϫ1.37, Ϫ0.57, and 1.30, dose increased similarly with glulisine during the course of the study). Consis- respectively. versus RHI (9.3 vs. 11.1 units; P ϭ tent with the overall results, a subgroup 0.2427), as did the daily basal insulin comparison of patients using OADs at CONCLUSIONS — This is the largest dose (5.7 vs. 6.0 units; P ϭ 0.7741) and baseline versus those who did not showed study described to date that compares a the daily short-acting insulin dose (3.7 vs. a larger decrease in HbA1c in the glulisine rapid-acting with RHI in 5.0 units; P ϭ 0.1756). The number of group versus RHI. patients with type 2 diabetes. There is a

2366 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Dailey and Associates growing trend in the diabetes community served with other short-acting insulin an- evant) compared with RHI. Glulisine, toward reaching ever more normoglyce- alogs) (12). Certain aspects of the study therefore, may prove a valuable addition mic control (7,8). Consequently, the in- design may have contributed to the ob- to the armamentarium of therapeutic adequate glycemic control achieved served between-treatment difference in tools for the management of diabetes. historically by patients with type 2 diabe- baseline to end point change in HbA1c. tes is becoming increasingly unaccept- The open-label design could have intro- APPENDIX able. There is no doubt that the addition duced bias in favor of the newer study of basal insulin to ongoing OAD therapy, treatment; however, this type of open- The investigators of the HMR1964/ particularly in treat-to-target insulin titra- label design has been, and remains, a ne- 3002 Study Group tion regimens, significantly improves gly- cessity with any study comparing a rapid- U.S. D.A. Bell, S.O. Bookin, P. Boyle, P. cemic control in most patients; however, acting insulin analog with RHI because of Bressler, V. Broadstone, L. Chaykin, G. some patients may remain suboptimally the considerable differences in the timing Dailey, S. Davis, J. Desemone, A. Dwarka- controlled (9). It is through the control of of the administration of these two types of nathan, M. Farooqi, M. Feinglos, J. Felic- postprandial hyperglycemia using short- insulin. In this study, attempts were made etta, R. Fink, V. Fonseca, S. Garg, J. acting insulin at mealtimes that the best to reduce treatment bias through mea- Gilbert, G. Grunberger, R.A. Guthrie, M. levels of glycemic control will be achieved surement of HbA1c at a central laboratory Henderson, K. Hershon, L. Isley, R.K. in patients with type 2 diabetes. and blinding investigators to these cen- Jain, R. Juneja, R. Kaplan, H. Katzeff, D.S. In addition to the benefits of control- trally measured HbA1c levels until data- Kayne, L.J. Klaff, T. Knecht, P. Koenig, D. ling postprandial excursions, it is becom- bases were locked after the study end. The Kumar, R. Lang, P. Levy, D. Lorber, J. ing increasingly apparent that large sample size of the study may also Dostou, M. Magee, M. McClanahan, J. postprandial hyperglycemia may be an account, in part, for a determination of McGill, A. Mehta, M. Meredith, J. Mersey, important predictor of cardiovascular statistical significance for a difference that S. Miller, P. Peters, P. Raskin, M. Reeves, mortality from an epidemiologic stand- is of unclear clinical relevance at this time. P. Reith, M. Rendell, R. Reynolds, S. point (10). In addition, recent evidence Any between-treatment differences in Richardson, V. Roberts, J. Rosenstock, S. demonstrates that in patients with type 2 glycemic control were not a result of in- Schwartz, T. Sherradon, S. Rubens, N.G. diabetes on oral agents and on no insulin creased short-acting, basal, or total insu- Soler, B. Spinowitz, R. Tanenberg, S. treatment, the relative contribution of lin doses; OAD usage; or the number of Thomson, T. Wahl, R. Weinstock, S. postprandial glucose is more relevant in insulin injections per day. Published Werbel, K. Wietecha, J. Williams, C.H. the lowest quintiles of HbA1c (11). In light studies (13,14) with other rapid-acting Wysham, and D. Streja. of this evidence, it is important to maxi- insulin analogs in combination with NPH Canada. C. Abbot, M. Boctor, R. Aron- mize postprandial glycemic control and insulin in type 1 diabetes suggest that son, P. Chevalier, C. Garceau, G. Girard, evaluate any new short-acting insulin de- these analogs may require greater basal R. Goldenberg, P. Hierlihy, C. Kovacs, H. signed to do this in patients with type 2 insulin supplementation compared with Lochnan, S. Mann, L. Murphy, P. Perron, diabetes. RHI even to maintain equivalent levels of A. Telner, and H.D. Tildesley. The purpose of this study was to com- glycemic control. Australia. R. Arnott, M. Gerstman, J. pare the efficacy and safety of glulisine It is noteworthy that the patients in- Graham, J. Karrasch, A. Lang, R. Moses, with RHI in patients with type 2 diabetes. cluded in this study were considerably N. Petrovsky, P. Phillips, T. Roberts, and The study was designed to reflect real- overweight; the mean BMI was Ͼ34 K. Stanton. world clinical practice as much as possi- kg/m2 in both groups. Most published ble by allowing patients to continue with studies of the pharmacokinetics and prestudy OAD regimens. The study in- pharmacodynamics of rapid-acting insu- References cluded ϳ900 patients. There were no be- lin analogs have been in lean healthy sub- 1. UK Prospective Diabetes Study (UKPDS) tween-treatment differences in any jects or patients with type 1 diabetes. Group: Intensive blood-glucose control category of symptomatic hypoglycemia Thus, there are little published data on with sulphonylureas or insulin compared with glulisine versus RHI, despite the sta- the pharmacokinetics and pharmacody- with conventional treatment and risk of complications in patients with type 2 di- tistically significant improvement in gly- namics of these agents in type 2 diabetic abetes (UKPDS 33). Lancet 352:837–853, cemic control with glulisine relative to patients, the vast majority of whom are 1998 RHI. Weight gain was also comparable overweight. Studies are currently under- 2. Yki-Jarvinen H: Role of insulin resistance between treatment groups. way to evaluate the activity of glulisine in in the pathogenesis of NIDDM. Diabetolo- The greater baseline to end point re- obese individuals. gia 38:1378–1388, 1995 duction in HbA1c observed with glulisine In conclusion, this is the largest study 3. Expert Committee on the Diagnosis and versus RHI in this study was small and to date evaluating the use of a rapid-acting Classification of Diabetes Mellitus: Report statistically significant, although the clin- insulin analog in patients with type 2 di- of the Expert Committee on the Diagnosis ical relevance of such a difference remains abetes in a multiple insulin injection reg- and Classification of Diabetes Mellitus. to be established. Such a difference has imen. The results demonstrate that Diabetes Care 20:1183–1197, 1997 4. Heinemann L, Heise T, Jorgensen LN, not been observed previously in type 2 glulisine, which offers greater treatment Starke AA: Action profile of the rapid act- diabetic patients in studies with other convenience due to its time-action pro- ing insulin analogue: human insulin rapid-acting insulin analogs (although file, provides small and statistically signif- B28Asp. Diabet Med 10:535–539, 1993 significant reductions in the incidence of icant improvements in glycemic control 5. Overmann H, Heinemann L: Injection- hypoglycemia versus RHI have been ob- (which remain to be proven clinically rel- meal interval: recommendations of dia-

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