Exploring the Substitution of Exenatide for Insulin in Patients with Type 2 Diabetes Treated with Insulin in Combination with Oral Antidiabetes Agents

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Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Exploring the Substitution of Exenatide for Insulin in Patients With Type 2 Diabetes Treated With Insulin in Combination With Oral Antidiabetes Agents

1 2 STEPHEN N. DAVIS, MD HANGTAO XU, MS barriers to improvement of glycemic con- 2 2 DON JOHNS, PHD JUSTIN H. NORTHRUP, MPT trol (9,10). 3 2 DAVID MAGGS, MD ROBERT G. BRODOWS, MD Exenatide is a first-in-class incretin mimetic indicated for use with metformin and/or a sulfonylurea but is not approved as OBJECTIVE — This 16-week study explored the safety of substituting exenatide for insulin in a substitute for insulin in insulin-requiring patients with type 2 diabetes using insulin in combination with oral antidiabetes agents. patients. The mechanism whereby exenatide improves glycemic control is quite RESEARCH DESIGN AND METHODS — Successful maintenance of glycemic control different from that of exogenous insulin. was predefined as an A1C increase of Ͻ0.5%. A total of 49 patients (aged 53 Ϯ 8 years, with BMI Ϯ 2 Ϯ Ϯ Exenatide stimulates endogenous insulin 34 4 kg/m , A1C 8.1 1.1%, and duration of diabetes 11 7 years) were randomized to secretion in a glucose-dependent manner, either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed Ն8 weeks of study or discontinued because of loss of glycemic control were suppresses glucagon, slows gastric empty- included in primary efficacy analysis. ing, and reduces food intake (11,12). Non- inferiority studies (13,14) of patients failing RESULTS — A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic to maintain glycemic control on oral an- control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide- tidiabetes agents have shown that it is feasi- treated patients who did not maintain control, 5 discontinued before week 16 because of loss of ble to attain similar A1C improvement with glucose control. The overall safety profile was generally consistent with previous exenatide trials. exenatide and insulin. Exenatide also low- The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide ers postprandial and fasting glucose but, and insulin reference groups, respectively. unlike insulin, is associated with a reduction in body weight. However, there are few CONCLUSIONS — This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predic- data supporting the potential substitution tors of outcome given the size and exploratory nature of the study, the data suggest that patients of insulin with exenatide in patients with with longer disease duration, who are taking higher doses of insulin and have less endogenous type 2 diabetes (15–17). Therefore, the pri- ␤-cell function, may experience deterioration in glucose control if exenatide is substituted for mary objective of this study was to explore insulin therapy. the safety of substituting exenatide for insulin in patients with type 2 diabetes who Diabetes Care 30:2767–2772, 2007 were using insulin in combination with oral antidiabetes medications. rogressive loss of ␤-cell function (1) trol. Initiation of therapy can include and mass (2) makes it difficult for once-daily intermediate or long-acting in- RESEARCH DESIGN AND P patients to maintain glycemic con- sulin or a formulation containing both METHODS — This exploratory, mul- trol (3–5). Historically, insulin therapy is basal and rapid-acting components (6– ticenter, two-arm, parallel-design, open- considered the treatment of choice when 8). However, intensification of insulin label trial was conducted over 16 weeks at diet, exercise, and oral antidiabetes agents therapy is often accompanied by weight five centers in the U.S. Patients random- fail to maintain adequate glycemic con- gain and hypoglycemia, well-recognized ized to the exenatide group used a multi- use pen to subcutaneously inject a fixed ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● dose of 5 ␮g b.i.d. for 4 weeks and 10 ␮g From 1Endocrinology and Metabolism, Vanderbilt University, Nashville, Tennessee; 2Eli Lilly, Indianapolis, b.i.d. for the remaining 12 weeks of the 3 Indiana; and Amylin Pharmaceuticals, San Diego, California. study (before morning and evening meals). Address correspondence and reprint requests to Dr. Stephen N. Davis, Endocrinology and Metabolism, Vanderbilt University, 715 PRB, 2220 Pierce Ave., Nashville, TN 37232-6303. E-mail: steve.davis@ Patients in the reference group remained on vanderbilt.edu. their insulin regimens throughout the 16- Received for publication 14 December 2006 and accepted in revised form 19 June 2007. week study. No specific glycemic goals Published ahead of print at http://care.diabetesjournals.org on 26 June 2007. DOI: 10.2337/dc06-2532. were set for insulin patients during the Clinical trial reg. no. NCT00099333, clinicaltrials.gov. trial. Patients in both treatment arms con- Additional information for this article can be viewed in an online appendix at http://dx.doi.org/10.2337/ dc06-2532. tinued their oral antidiabetes medications Abbreviations: SMBG, self-monitored blood glucose. and were instructed to continue their cur- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion rent diet and exercise regimens. As per factors for many substances. protocol instructions, the sulfonylurea © 2007 by the American Diabetes Association. ϳ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby dose was decreased by 50% in response marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. to one confirmed or two suspected See accompanying Editorial on p. 2972. (symptoms without confirmatory blood

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Table 1—Baseline demographic and metabolic characteristics Statistical analysis The primary hypothesis was that Ͼ60% Exenatide Exenatide of the patients who stopped insulin ther- Exenatide Insulin (maintained (lost apy and initiated exenatide twice daily Patient characteristics ITT ITT control) control) would maintain glycemic control. It was estimated that 30 patients, randomized in n 33 16 18 11 a 2:1 ratio (exenatide to insulin refer- Age (years) 54 Ϯ 852Ϯ 854Ϯ 854Ϯ 10 ence), would be sufficient to verify the Sex (% women) 54 50 61 36 probability of observing Ͼ60% success in Body weight (kg) 95 Ϯ 17 102 Ϯ 19 93 Ϯ 19 98 Ϯ 18 the exenatide group. The function of the BMI (kg/m2) 33 Ϯ 435Ϯ 433Ϯ 532Ϯ 4 reference group was to provide additional Fasting serum glucose (mmol/l) 8.8 Ϯ 2.6 8.6 Ϯ 2.7 8.6 Ϯ 2.4 8.4 Ϯ 2.6 confidence in the validity of changes in A1C (%) 8.0 Ϯ 1.2 8.3 Ϯ 0.9 8.1 Ϯ 1.1 8.0 Ϯ 1.3 A1C observed in those using exenatide. Diabetes duration (years) 10.4 Ϯ 6.2 11.9 Ϯ 7.4 9.9 Ϯ 7.1 11.7 Ϯ 5.4 SAS (version 8.2; SAS Institute, Cary, NC) Insulin treatment duration (years) 2.9 Ϯ 3.1 3.0 Ϯ 3.2 2.5 Ϯ 2.9 3.8 Ϯ 3.3 was used to conduct all statistical analy- Insulin dose (unit/day) 41 Ϯ 24 54 Ϯ 38 37 Ϯ 25 52 Ϯ 25 ses. Tests of within-group change (last ob- C-peptide (nmol/l) 1.0 Ϯ 0.5 0.9 Ϯ 0.5 1.2 Ϯ 0.5 0.8 Ϯ 0.5 servation carried forward) were based on Background therapy the Wilcoxon’s signed-rank test (with a Metformin only 13 8 4 8 two-sided significance level of 0.05). Stu- Sulfonylurea only 4 0 2 0 dent’s t tests (with a two-sided signifi- Metformin and sulfonylurea 16 8 12 3 cance level of 0.05) and Fisher’s exact Glargine 8 2 4 4 tests were used for between-group com- NPH insulin 0 1 0 0 parisons. We conducted a post hoc anal- Ultralente 1 0 0 1 ysis of hypoglycemia based on events Mixtures 6 4 3 1 confirmed by glucose measurement. The Multiple insulin therapies 4 3 1 3 overall exposure rate (total confirmed Data are means Ϯ SD or n unless otherwise indicated. ITT, intent to treat. events divided by total exposure) was cal- culated using two criteria: 1) the Ameri- can Diabetes Association criteria glucose Ͻ3.4 mmol/l) hypoglycemic were recruited according to local prac- (confirmed blood glucose Ͻ3.9 mmol/l) events. tices, and all participants gave written in- and 2) the a priori study design criteria Eligible patients were between 30 and formed consent before participation. A1C (confirmed blood glucose Ͻ3.4 mmol/l). 75 years of age, had been diagnosed with levels were measured at weeks Ϫ2, 0 (ran- The intention-to-treat sample in- type 2 diabetes for Ն2 years, and had domization and study initiation), and 16 cluded all randomized patients with type been treated with one of the following for (or at early discontinuation). Blood chem- 2 diabetes who received at least one dose Ն3 months to 12 years: once- or twice- istries and fasting serum lipids were as- of the study drug. Patients were consid- daily NPH insulin, once-daily insulin sessed at weeks Ϫ2 and 16 (or at early ered to have maintained glycemic control glargine, once- or twice-daily ultralente discontinuation). Fasting serum glucose if they did not experience a clinically rel- Ն insulin, or an insulin mixture. All patients and fasting C-peptide were assessed at evant rise in A1C (an increase of 0.5%) were on oral antidiabetes regimens con- weeks Ϫ2, 2, 4, and 8. Weight, vital signs, at end point. Patients were also consid- sisting of an immediate- or extended- concomitant medications, and drug doses ered to have maintained glycemic control release metformin and/or a sulfonylurea were collected at week 0 and at each if they maintained their A1C levels below for at least 3 months before screening or a subsequent visit. Patients performed the prespecified limit but discontinued fixed-dose sulfonylurea/metformin com- from the study after week 8 for reasons 5-point self-monitored blood glucose bination therapy. Additional inclusion other than loss of glucose control. Patients (SMBG) profiles at study weeks 2, 4, 8, criteria included, at the time of screening, were considered to have lost glycemic and 16. an A1C level Յ10.5%, BMI Ͼ27 and Ͻ40 control if they experienced a clinically rel- kg/m2, and a history of stable body Adverse events were assessed at each evant rise in A1C or if they discontinued weight. Patients were excluded if they had visit and were reported as preferred terms from the study at any time because of loss more than three episodes of severe hypo- from the Medical Dictionary for Regula- of glycemic control (as determined by the glycemia within 6 months before screen- tory Activities. A clinical trial adverse investigator). A stepwise logistic regres- ing, had used any prescription drug to event was defined as any untoward med- sion procedure was used to identify vari- promote weight loss within 3 months, or ical occurrence, without regard to the ables associated with maintenance of had previously received exenatide or glu- possibility of a causal relationship. A hy- glycemic control in the exenatide group. cagon-like peptide 1 analogs. poglycemic episode was defined as any time a patient felt that he or she was RESULTS Study measurements experiencing a sign or symptom of hy- A common clinical protocol was ap- poglycemia or noted a blood glucose Patient disposition and clinical proved by an institutional review board at level Ͻ3.4 mmol/l (60 mg/dl) during characteristics each site and was conducted in accor- self-monitoring, regardless of whether A total of 51 patients with type 2 diabetes dance with the principles described in the this level was associated with signs, symp- were randomized (2:1) to exenatide or in- Declaration of Helsinki (18). Patients toms, or treatment. sulin reference therapy (online appendix

2768 DIABETES CARE, VOLUME 30, NUMBER 11, NOVEMBER 2007 Davis and Associates

Fig. 1 [available at http://dx.doi.org/ 10.2337/dc06-2532]). A total of 45 patients (29 in the exenatide and 16 in the insulin reference groups) had sufﬁcient data for the primary efﬁcacy analysis; 4 discontinued before their true glycemic control outcome could be determined. Table 1 presents baseline demographics, clinical characteristics, and background therapy. Exenatide-treated patients who successfully maintained glycemic control (n ϭ 18) had (on average) shorter disease duration, higher pretreatment fasting C- peptide levels, were taking comparatively less insulin, and were observed to have been receiving insulin therapy for a shorter period of time.

Primary efficacy results: glycemic control The overall mean A1C change in the exenatide group (n ϭ 29) was ϩ0.3 Ϯ 1.5% (within-group change, P ϭ NS). The overall mean A1C change in the insulin Figure 1— Mean Ϯ SE body weight change over time in the insulin and exenatide patient groups. group (n ϭ 16) was Ϫ0.1 Ϯ 0.7% (with- Œ, insulin group; f, exenatide group that maintained glycemic control; E, exenatide group that in-group change, P ϭ NS). The mean lost glycemic control. changes in A1C were not significantly different between groups at end point. Of the patients who substituted exenatide for increased through week 8 (ϩ5.2 Ϯ 3.3 change, P ϭ NS). We conducted a post insulin, Ͼ60% (18 of 29, mean A1C mmol/l, P ϭ 0.008). However, neither an hoc analysis to determine the degree of change Ϫ0.5 Ϯ 0.7%, P ϭ 0.003) suc- end point rise in fasting glucose nor an correlation between change in A1C and cessfully maintained glycemic control as earlier rise in week 2 fasting glucose was change in body weight. The Pearson cor- defined a priori, supporting the primary significantly associated with treatment relation coefficients were Ϫ0.29 and hypothesis of the study. Of the 16 patients failure in logistic regression analyses. Of Ϫ0.25 for the exenatide and insulin ref- in the insulin reference group, 13 (81%) the characteristics described in Table 1, erence groups, respectively. maintained glycemic control. Individual pretreatment C-peptide (maximum like- As observed in the SMBG profiles (Ta- changes in A1C and fasting serum glucose lihood estimate 2.96, P ϭ 0.024) and ble 2), patients in the insulin reference are shown in online appendix Fig. 2. The baseline body weight (maximum likeli- group demonstrated consistently better majority of exenatide-treated patients hood estimate Ϫ0.07, P ϭ 0.088) were prebreakfast blood glucose control (P Ͻ who maintained control also completed identified as the best predictors of suc- 0.05) at all study follow-up visits (weeks the 16-week study (14 of 18) and had cessful glycemic control. 2, 4, 8, and 16) compared with that in reductions in A1C from baseline (12 of exenatide-treated patients. Conversely, 18). Four patients were observed to have Secondary efficacy results: body exenatide-treated patients demonstrated successfully maintained glycemic control weight and SMBG profiles better postprandial glucose control after at week 8 but discontinued before week Most of the exenatide-treated patients (27 breakfast (P Ͻ 0.05) at study weeks 2, 8, 16 for reasons other than loss of glycemic of 29, 93%) lost weight during the study. and 16, with less consistent improvement control (nausea [one patient] or patient Less than one-half of the patients (6 of 16, demonstrated following the evening decision [three patients]). 38%) in the insulin reference group lost meals (i.e., better postprandial control Of the 11 exenatide-treated patients weight. Exenatide patients experienced a compared with insulin only at week 8, who did not maintain glycemic control steady decline (Fig. 1) in mean body P Ͻ 0.05). (mean A1C change ϩ1.6 Ϯ 1.5%, P ϭ weight (end-point change Ϫ4.2 Ϯ 3.0 kg; 0.001), 5 discontinued the study before within-group change, P Ͻ 0.001), while Safety findings week 16 because of loss of glycemic con- the mean body weight with insulin was In the exenatide group, 26 of 33 (79%) trol (as determined by the investigator) not substantially changed (end-point patients reported a treatment-emergent and 6 lost glycemic control as evidenced change ϩ0.5 Ϯ 1.7 kg, P ϭ NS). The adverse event compared with 9 of 16 by exceeding the predefined A1C crite- between-group comparison of mean (56%) in the insulin reference group. rion. Within-group analyses demon- changes in body weight at end point was Most of the adverse events reported in this strated that the subset of exenatide- statistically significant (P Ͻ 0.001). The study were mild to moderate in intensity. treated patients unable to maintain mean changes in body weight observed in Adverse events considered possibly re- glycemic control had a significant in- the two exenatide groups (those who lated to exenatide treatment were pre- crease in fasting glucose by week 2 maintained vs. those who lost glycemic dominantly gastrointestinal in nature (ϩ3.9 Ϯ 2.7 mmol/l, P ϭ 0.005), which control) were similar (between-group (e.g., nausea, diarrhea, vomiting, abdom-

DIABETES CARE, VOLUME 30, NUMBER 11, NOVEMBER 2007 2769 Exploring substitution of exenatide for insulin

Table 2—Five-point self-monitored blood glucose proﬁles

Breakfast Dinner Prebreakfast excursion Predinner excursion Bedtime Week 2 Exenatide group 10.21 Ϯ 0.458 Ϫ0.84 Ϯ 0.578 8.94 Ϯ 0.587 0.34 Ϯ 0.632 9.51 (0.632) Insulin group 7.81 Ϯ 0.533 1.42 Ϯ 0.661 8.27 Ϯ 0.671 2.08 Ϯ 0.722 9.15 (0.717) Difference 2.403 Ϫ2.263 0.673 Ϫ1.736 0.363 P 0.0018 0.0155 0.4568 0.0812 0.7070 Week 4 Exenatide group 10.06 Ϯ 0.441 Ϫ0.06 Ϯ 0.653 9.34 Ϯ 0.532 Ϫ0.47 Ϯ 0.563 8.54 (0.543) Insulin group 7.03 Ϯ 0.497 1.72 Ϯ 0.735 8.08 Ϯ 0.620 0.71 Ϯ 0.638 7.99 (0.611) Difference 3.039 Ϫ1.784 1.261 Ϫ1.173 0.555 P Ͻ0.001 0.0791 0.1328 0.1782 0.5021 Week 8 Exenatide group 9.58 Ϯ 0.507 Ϫ0.86 Ϯ 0.653 9.12 Ϯ 0.681 Ϫ1.38 Ϯ 0.536 8.43 (0.733) Insulin group 7.54 Ϯ 0.571 1.74 Ϯ 0.735 8.54 Ϯ 0.766 1.15 Ϯ 0.587 9.21 (0.831) Difference 2.033 Ϫ2.607 0.579 Ϫ2.533 Ϫ0.775 P 0.0120 0.0123 0.5760 0.0033 (0.4895) Week 16 Exenatide group 9.35 Ϯ 0.485 Ϫ0.39 Ϯ 0.522 9.00 Ϯ 0.685 Ϫ0.70 Ϯ 0.635 8.23 (0.731) Insulin group 7.58 Ϯ 0.549 2.07 Ϯ 0.592 8.64 Ϯ 0.777 0.52 Ϯ 0.720 8.71 (0.829) Difference 1.744 Ϫ2.460 0.368 Ϫ1.213 Ϫ0.479 P 0.0217 0.0040 0.7253 0.2165 (0.6678) Data are means Ϯ SD unless otherwise indicated. The units for all glucose values and excursions are expressed in millimoles per liter. Between-group differences represent exenatide minus the insulin reference. Exenatide group, n ϭ 19; insulin group, n ϭ 15. inal pain, gastroesophageal reflux dis- and 0.97 events/patient-year for the ex- cemic control, a potential benefit for car- ease), with nausea the most common enatide and insulin reference groups, re- rying out such substitution of therapy was (48.5% incidence). Five exenatide-treated spectively. The rates were slightly higher the observed weight loss. Although A1C patients discontinued from the study be- in the subgroups that maintained glyce- was not increased at end point in the ma- cause of an adverse event (nausea [three pa- mic control (exenatide, 2.54 events/ jority (15 of 29, 52%) of the exenatide- tients], bronchitis, and hyperglycemia). patient-year; insulin, 1.18 events/patient- treated patients, A1C remained above Two serious adverse events (chest pain year). There were no episodes of serious target (Ͼ7.0%) in many (20 of 29, 69%). and excessive hyperglycemia) were re- hypoglycemia (i.e., requiring medical in- Most of the insulin-treated patients (9 of ported in the study, both occurring in the tervention). One patient treated with ex- 16, 56%) also did not experience an in- same exenatide-treated patient; this pa- enatide and sulfonylurea had three severe crease in A1C; however, all but 1 patient tient required hospitalization and discon- hypoglycemic episodes (i.e., episodes (15 of 16, 94%) remained above target tinued because of hyperglycemia before that required assistance of another person (A1C Ͼ 7%) at end point. The number of completing the week-16 study visit. and were associated with either a blood exenatide-treated patients who both im- There were no adverse events considered glucose level Ͻ50 mg/dl or prompt recov- proved glycemic control and lost weight possibly related to insulin treatment. ery after oral carbohydrate, intravenous (11 of 29) through this therapeutic sub- Headache was the most common adverse glucose, or glucagon injection), which stitution was relatively small. The adverse event (31.3% incidence) reported in the were treated with food or drink; this pa- event profile in patients who switched to insulin reference group, followed by nau- tient discontinued after week eight be- exenatide was consistent with the pre- sea (12.5%) and cough (12.5%) cause of nausea. dominance of gastrointestinal side effects The incidence of hypoglycemia was observed in prior phase III, placebo- 39% (13 of 33) and 38% (6 of 16) in the CONCLUSIONS — In this explor- controlled trials. The overall incidence of exenatide and insulin reference groups, atory study, substitution of exenatide for hypoglycemia was similar between the respectively. Most of the hypoglycemia insulin therapy resulted in no deteriora- exenatide and insulin reference groups, was reported to have occurred during the tion in glycemic control in ϳ62% of the and most of the patients in the exenatide daytime (exenatide, 11 of 13 patients; in- type 2 diabetic patients studied. The re- group who experienced hypoglycemia sulin, 4 of 6 patients). Of the 13 ex- maining 38% of patients did experience were taking concomitant sulfonylurea. It enatide-treated patients who reported deterioration in glycemic control. In is known from the phase III trials studies hypoglycemia, 10 were taking concomi- some, this deterioration manifested as a of exenatide that hypoglycemia occurs, tant sulfonylurea. A total of 12 hypogly- rise in A1C noted at study end (after 16 most commonly, when exenatide is used cemia events (8 in the exenatide and 4 in weeks), and in others the worsening of with sulfonylurea. the insulin groups) were confirmed by hyperglycemia occurred by 2–8 weeks af- Several factors should be considered glucose measurement (Ͻ3.4 mmol/l). ter insulin withdrawal. In those patients when interpreting our results. First, the The overall hypoglycemia rates were 1.72 where there was no deterioration in gly- glycemic control results may have been

2770 DIABETES CARE, VOLUME 30, NUMBER 11, NOVEMBER 2007 Davis and Associates better if we had added exenatide to the given the size and exploratory nature of References treatment of patients on insulin and de- the study. 1. U.K. Prospective Diabetes Study Group: creased insulin doses gradually rather The weight effect observed in this U.K. Prospective Diabetes Study 16: than replacing insulin with exenatide study is also of interest. Prior clinical trials Overview of 6 years’ therapy of type II abruptly. This choice may have also con- have shown that exenatide treatment re- diabetes: a progressive disease. Diabetes tributed to the relatively high dropout sults in weight loss as a monotherapy and 44:1249–1258, 1995 rate in the exenatide group. Secondly, this when added to a variety of background 2. Butler AE, Janson J, Bonner-Weir S, Ritzel ␤ study was not designed to compare insu- oral therapies including metformin, sul- R, Rizza RA, Butler PC: -cell deficit and increased ␤-cell apoptosis in humans lin treatment with exenatide; thus, there fonylureas, and thiazolidinediones (20– were no specific glycemic goals set for in- with type 2 diabetes. Diabetes 52:102– 23). Greater weight loss is seen in 110, 2003 sulin patients during the trial. The small exenatide-treated individuals with met- 3. UK Prospective Diabetes Study (UKPDS) number of patients in the trial also makes formin background therapy. Data from Group: Effect of intensive blood-glucose drawing conclusions from between- 2-year open-label extension trials have control with metformin on complications group statistical comparisons problem- demonstrated that the weight reduction in overweight patients with type 2 diabe- atic. Finally, given the small sample size associated with exenatide is progressive tes (UKPDS 34). Lancet 352:854–865, and exploratory nature of this study, it over time and is associated with improve- 1998 was not possible to adequately answer all 4. UK Prospective Diabetes Study (UKPDS) ments in a number of cardiovascular risk Group: Intensive blood-glucose control clinically relevant questions related to this factors (24). In the current study, early type of therapy substitution. For example, with sulphonylureas or insulin compared (week 2) weight reduction was observed with conventional treatment and risk of since only five patients treated with ex- Ͻ in the patients who maintained glycemic complications in patients with type 2 di- enatide had a baseline A1C 7%, it control after coming off insulin, suggest- abetes (UKPDS 33). Lancet 352:837–853, would be difficult to conclusively deter- ing that the weight effect may be associ- 1998 mine whether it is possible to sustain gly- ated with both exenatide treatment and 5. Turner RC, Cull CA, Frighi V, Holman cemic control below the target level. insulin withdrawal. The current study RR, the UK Prospective Diabetes Study It should be noted that while stable (UKPDS) Group: Glycemic control with demonstrates that a substantial number diet, sulfonylurea, metformin, or insulin glucose control was observed in a major- of patients treated with insulin will ex- ity of patients, deterioration in glycemic in patients with type 2 diabetes mellitus: perience deterioration in glucose con- control was observed in some patients, progressive requirement for multiple trol when exenatide is substituted. therapies (UKPDS 49). JAMA 281:2005– and many patients remained above target However, the study does not ascertain 2012, 1999 (A1C Ͼ7.0%). Exenatide elicits its glu- the mechanism by which weight loss 6. International Ddiabetes Federation Clini- cose-lowering effect in part by glucose- occurs. cal Guidelines Task Force: Global Guide- dependent stimulation of insulin release In conclusion, this exploratory study line for Type 2 Diabetes. Brussels, Inter- from pancreatic ␤-cells (11,19). It is not national Diabetes Federation, 2005 clear whether glucose-dependent stimu- gives some insight into the outcome of 7. Janka HU, Plewe G, Riddle MC, Kliebe- lation of insulin is the dominant glucose- substituting one injectable therapy (ex- Frisch C, Schweitzer MA, Yki-Jarvinen lowering mechanism compared with enatide) for another (insulin) in patients H: Comparison of basal insulin added to suppression of glucagon or slowing of with long-standing type 2 diabetes. The oral agents versus twice-daily premixed gastric emptying, for example, but it has majority of patients maintained glycemic insulin as initial insulin therapy for type control, although most did not fully opti- 2 diabetes. Diabetes Care 28:254–259, been observed to be an important action 2005 in the hierarchy of possible mechanisms. mize control. Several patients experienced deterioration in glycemic control, 8. Raskin P, Allen E, Hollander P, Lewin A, Given that type 2 diabetes is a progressive Gabbay RA, Hu P, Bode B, Garber A, the disease where ␤-cell function gradually indicating that therapy substitution is not INITIATE Study Group: Initiating insulin diminishes over time (1), it is possible feasible for all patients currently treated therapy in type 2 diabetes: a comparison that exenatide may have a diminished ca- with insulin. In this study, patients who of biphasic and basal insulin analogs. Di- pacity to exert a glucose-lowering effect in transitioned from insulin to exenatide abetes Care 28:260–265, 2005 patients with more advanced disease and needed to perform SMBG and were given 9. American Diabetes Association: Stan- minimal ␤-cell function. For example, pa- parameters as to when to contact their dards of medical care in diabetes–2006. Diabetes Care 29 (Suppl. 1):S4–S42, 2006 tients who require insulinization during physician. Although the exploratory nature of this study limits its predictive 10. Garber AJ: Premixed insulin analogues for the night may be more likely to experi- the treatment of diabetes mellitus. Drugs ence deterioration in glycemic control if power, the results suggest that patients 66:31–49, 2006 cessation of insulin is attempted. It is with longer disease duration who are tak- 11. Keating GM: Exenatide. Drugs 65:1681– therefore interesting to note that ex- ing higher doses of insulin and who have 1692, 2005 enatide-treated patients less likely to have less endogenous ␤-cell reserves are less 12. Nielsen LL, Young AA, Parkes DG: Phar- a favorable outcome in the current study likely to have a favorable outcome with macology of exenatide (synthetic ex- had (on average) longer disease duration, this therapy substitution. Further investi- endin-4): a potential therapeutic for lower pretreatment fasting C-peptide lev- gation is warranted. improved glycemic control of type 2 diabetes. Regul Pept 117:77–88, 2004 els, were taking comparatively more insu- 13. Heine RJ, Van Gaal LF, Johns D, Mihm lin, and were observed to have been MJ, Widel MH, Brodows RG, the GWAA receiving insulin therapy for a longer pe- Acknowledgments— We wish to thank the Study Group: Exenatide versus insulin riod of time. However, it is not possible to patients, investigators, and their staffs for par- glargine in patients with suboptimally characterize clear predictors of outcome ticipating in the study. controlled type 2 diabetes: a randomized

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