Pramlintide Reduces Postprandial Glucose Excursions When Added to Regular Insulin Or Insulin Lispro in Subjects with Type 1 Diabetes a Dose-Timing Study

Emerging Treatments and Technologies ORIGINAL ARTICLE

Pramlintide Reduces Postprandial Glucose Excursions When Added to Regular Insulin or Insulin Lispro in Subjects With Type 1 Diabetes A dose-timing study

1 3 CHRISTIAN WEYER, MD MARIA GUTIERREZ, MD espite important advances in the 1 1 ALAN GOTTLIEB, PA YAN WANG, PHD delivery and pharmacology of insu- 1 1 DENNIS D. KIM, MD JAMES A. RUGGLES, PHD 1 1 lin (1,2), most patients with type 1 AREN UTZ PHD RVILLE OLTERMAN MD D K L , O G. K , 2 1 diabetes are still unable to achieve glyce- SHERWYN SCHWARTZ, MD DAVID G. MAGGS, MD mic targets with insulin therapy alone (3,4). The limitations of current insulin replacement therapy are especially evi- dent during the postprandial period, when rapid and profound changes in glu- OBJECTIVE — To assess the postprandial glucose-lowering effect of the human amylin analog pramlintide when given with either regular insulin or insulin lispro in subjects with type 1 cose flux are required to accommodate diabetes, with an emphasis on the optimal dose timing relative to meals. the sudden appearance of meal-derived glucose into the circulation (5–7). RESEARCH DESIGN AND METHODS — In this randomized, single-blind, placebo- In healthy individuals, meal ingestion controlled, five-way crossover study, 19 subjects with type 1 diabetes using regular insulin and leads to the rapid release of two gluco- 21 subjects with type 1 diabetes using insulin lispro underwent five consecutive mixed meal regulatory ␤-cell hormones, insulin and tests. In randomized order, subjects received subcutaneous injections of placebo at Ϫ15 min or amylin (8). These hormones act in con- 60 ␮g pramlintide at Ϫ15, 0, ϩ15, or ϩ30 min relative to the meal after an overnight fast. cert to limit the postprandial glucose ex- Ϫ Regular insulin or insulin lispro was injected at 30 and 0 min, respectively, at doses that were cursion, with amylin reducing the rate of adjusted appropriately for both the content of the standardized meal and the anticipated effects glucose appearance into the circulation of pramlintide. Plasma glucose concentrations were measured before and during the 4-h post- meal period. and insulin stimulating the rate of glucose disappearance from the circulation (5–7). RESULTS — In both the regular insulin and insulin lispro groups, pramlintide injections at all In addition, the secretion of glucagon, the four time points lowered the postprandial glucose excursion (36 to Ͼ100% reduction in incre- main hormonal stimulus for hepatic glu- mental area under the concentration time curve from 0 to 4 h (AUC0–4 h) compared with cose production, is normally suppressed placebo. However, only preprandial injections of pramlintide (Ϫ15 and 0 min) were able to in response to a carbohydrate meal (9). prevent the initial postprandial surge in glucose. The optimal time for pramlintide injection was In people with type 1 diabetes, post- 0 min, which reduced the postprandial glucose excursion by Ͼ100% compared with regular prandial insulin and amylin responses are Ϫ Ϯ Ϯ Ϫ1 Ϫ1 Ͻ insulin plus placebo (incremental AUC0–4 h: 0.6 2.5 vs. 11.0 2.9 mmol h l , P Ϯ completely absent (5–8), and glucagon se- 0.0007) and by 75% compared with insulin lispro plus placebo (incremental AUC0–4 h: 2.5 Ϫ Ϫ cretion is abnormally increased, leading to 2.1 vs. 10.0 Ϯ 2.5 mmol h 1 l 1, P Ͻ 0.0098). No serious adverse events were reported. excessive postprandial glucose excursions CONCLUSIONS — Pramlintide, given at or just before a meal, reduces the postprandial (9–11). Mealtime insulin replacement re- glucose excursion in subjects with type 1 diabetes, regardless of whether added to regular insulin duces postprandial hyperglycemia (12). or a rapid-acting insulin analog. However, even with the use of rapid-acting insulin analogs, it is still not possible to rep- Diabetes Care 26:3074–3079, 2003 licate the rapid release of endogenous insulin into the portal vein or to correct the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● abnormal postprandial rise in glucagon of- From the 1Amylin Pharmaceuticals, Inc., San Diego, California; the 2Diabetes and Glandular Disease Re- ten seen in patients with type 1 diabetes search Associates, San Antonio, Texas; and the 3Clinical Studies, Ltd., Fort Lauderdale, Florida. (6,7). Both of these abnormalities contrib- Address correspondence and reprint requests to Christian Weyer, MD, Amylin Pharmaceuticals, Inc., ute to the lack of appropriate suppression of 9360 Towne Centre Dr., San Diego, CA 92121. E-mail: [email protected]. Received for publication 2 April 2003 and accepted in revised form 24 July 2003. hepatic glucose production and, hence, to C.W., A.G., D.D.K., K.L., S.S., Y.W., J.A.R., O.G.K., and D.G.M. are employed by and hold stock in excessive postprandial glucose excursions Amylin Pharmaceuticals, Inc. S.S. is a member of an advisory panel for Amylin Pharmaceuticals, Inc. J.A.R. (9–11). also holds stock in Bristol-Myers Squibb and Schering Plough. Pramlintide is a synthetic analog of Abbreviations: AUC, area under the curve. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion human amylin that is under development factors for many substances. as an adjunct to insulin therapy in people © 2003 by the American Diabetes Association. with types 1 and 2 diabetes (5–7,13).

3074 DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 Weyer and Associates

Short-term clinical studies in patients and all subjects provided written in- reduction to avoid postprandial hypogly- with type 1 diabetes have shown that formed consent before participation. This cemia if the premeal glucose was near- mealtime amylin replacement via pre- study was conducted in accordance with normal) but not for the purpose of prandial injections of pramlintide, in ad- principles described in the Declaration of glycemic control (dose increase to im- dition to regular insulin injections, Helsinki (1964), including all amend- prove postprandial hyperglycemia). The corrects postprandial hyperglucagonemia ments up to and including the South Af- basal insulin regimens, which were com- (14) and slows the rate of gastric empty- rica revision (1996). prised of continuous subcutaneous insu- ing (15,16). As a result, the appearance of lin infusion (n ϭ 8) or subcutaneous both endogenous (liver-derived) and ex- Study design injections of intermediate- or long-acting ogenous (meal-derived) glucose into the Within 14 days after screening, consenting insulin (n ϭ 32), were held constant circulation is controlled to better match subjects were admitted to the clinical re- throughout the study. the rate of insulin-mediated glucose dis- search center for at least 6 days. Between appearance, leading to a substantial re- screening and admission, subjects were Statistical analyses duction of postprandial glucose asked to record their daily food intake, in- Main pharmacodynamic parameters in- excursions (17–19). Long-term clinical sulin regimen, and self-monitored blood cluded the incremental plasma glucose studies have shown that the postprandial glucose results in a diary. Upon admission, area under the concentration time curve glucose lowering effect of pramlintide each subject underwent a mixed meal test (AUC) from 0 to 2 h (AUC0–2h), incre- translates into a clinically meaningful and on 5 consecutive days in a randomized, sin- mental AUC0–4h, and the incremental statistically significant reduction in A1C gle-blind, placebo-controlled, five-way plasma glucose concentrations at specific in patients with types 1 and 2 diabetes crossover design. The meal was a standard- sampling times. The mean Ϯ SEM incre- (20–23). ized breakfast, consisting of a bagel with mental plasma glucose concentration The objective of the present study was margarine and jam, cheese, yogurt, milk, profiles were calculated and plotted by to further characterize the effect of pram- and orange juice. The size of the meal was treatment and by study group. For each lintide on postprandial glucose concen- calculated individually to provide 30% of a study group, the pharmacodynamic pa- trations when used as an adjunct to either subject’s total daily caloric requirements rameter data were summarized descrip- regular insulin or insulin lispro, with an with a macronutrient composition accord- tively and were analyzed using mixed emphasis on the optimal dose timing rel- ing to the American Diabetes Association effect models. The mixed effect models ative to meals. nutritional recommendations (55%/15%/ included treatment, treatment sequence, 30% of kcal from carbohydrate/protein/fat, and period as fixed effects and subject- RESEARCH DESIGN AND respectively). The size of the standardized within-sequence as random effects. METHODS breakfast meal was the same on each study The P values for comparisons among day for each individual, and the meal was the least square means of the incremental Study population always consumed within 15 min. AUC0–2h, incremental AUC0–4h, and in- A total of 21 subjects with type 1 diabetes On each day, subjects received one of cremental glucose concentrations at vari- using insulin lispro and 19 subjects with five treatments (a subcutaneous injection of ous time points between dose timings type 1 diabetes using regular insulin un- placebo at Ϫ15minor60␮g pramlintide were provided. Because the study was not derwent a standardized mixed meal test [0.6 mg/ml, Amylin Pharmaceuticals, Inc., powered to perform multiple compari- on 5 consecutive days. Subjects were San Diego, CA] at Ϫ15, 0, ϩ15, or ϩ30 sons, the P values were not adjusted for 18–65 years of age and had the following min relative to the standardized breakfast) multiple comparisons. characteristics: a history of type 1 diabetes according to a randomized sequence, after Safety evaluations were based on re- for at least 1 year, a baseline A1C value of an overnight fast. Pramlintide or placebo ports of treatment-emergent adverse 7–11%, free from symptoms of severe hy- was injected into the subcutaneous tissue of events in response to nondirected ques- poglycemia or severe hyperglycemia (de- the anterior abdominal wall, on the oppo- tioning, clinical laboratory evaluations fined according to Diabetes Control and site side from the insulin injection. (hematology, serum chemistry, urinaly- Complications Trial criteria [24]) for 2 Subjects’ short-acting insulin dose sis), vital signs (blood pressure and pulse months, stable weight for 2 months, sta- was adjusted appropriately for both the rate), electrocardiograms, and physical ble daily insulin dose (within Ϯ 10%), content of the standardized meal and the examinations in all subjects. and no change in type of insulin used for anticipated effects of pramlintide based 2 months before the study. Women who upon the individual subject’s history of RESULTS were not surgically sterile or postmeno- their usual dietary intake and insulin use. pausal were to practice appropriate con- Regular insulin was injected at Ϫ30 min Subject disposition and baseline traception. Subjects were excluded if they and insulin lispro at 0 min relative to the demographics had clinically significant comorbid condi- standardized meal, which was consistent Of the 40 subjects who were randomized, tions or received concomitant treatment with the respective package insert direc- 38 were included in the evaluation popu- with drugs known to affect gastrointesti- tions. Efforts were made to keep the lation. Two subjects (one from the regular nal motility, including but not limited to short-acting insulin dose constant at the insulin and one from the insulin lispro erythromycin, metoclopramide, cisa- time of each of the standardized breakfast group) were excluded from the evaluation pride, cholestyramine, or colestipol. meal challenges. Deviations from the pre- population because they received only The Institutional Review Board of determined short-acting insulin dose four of the five possible treatments. The each study site approved the protocol, were allowed only for safety reasons (dose regular insulin and the insulin lispro

DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 3075 Pramlintide in type 1 diabetes

Table 1—Demographic characteristics at baseline, intent-to-treat population lintide injections at Ϫ15 or 0 min, plasma glucose concentrations decreased slightly Characteristic Regular insulin Insulin lispro from baseline during the first hour, followed by a slight rise during the next 2 h n 19 21 before reaching a plateau (Fig. 1A). Com- Sex (M/F) 14/5 13/8 paratively, in subjects using insulin lispro Race (Caucasian/Black/Hispanic) 11/1/7 13/1/7 and having pramlintide injections at Ϫ15 Ϯ Ϯ Age (years) 37 16 41 12 or 0 min, the decrease in plasma glucose Ϯ Ϯ Weight (kg) 80.4 12.1 77.7 16.9 concentrations was more pronounced 2 Ϯ Ϯ BMI (kg/m ) 26.8 3.8 25.7 4.8 during the first hour followed by a more Diabetes duration (years) 22 Ϯ 12 20 Ϯ 12 Ϯ Ϯ pronounced rise during the subsequent A1C (%) 9.3 1.7 8.3 1.2 3 h (Fig. 1B). Data are n or means Ϯ SD. AUC0–2h. As shown in Table 2, in both the regular insulin and insulin lispro groups, the AUC0 –2hfor all four pram- groups had similar demographic charac- points lowered the postprandial glucose ex- lintide dose timings was significantly reduced compared with the placebo teristics with regard to sex, race, age, BMI, cursion compared with placebo (Table 2). Ͻ Ͻ and diabetes duration; however, the base- Postprandial glucose profiles. As illus- group (P 0.0001 and P 0.0026, line A1C was somewhat lower in the in- trated in Fig. 1 and Table 2, pramlintide respectively). In the regular insulin sulin lispro compared with the regular injections at Ϫ15 and 0 min prevented group, administration of pramlintide at Ͻ insulin group (Table 1). the initial rise in plasma glucose (signifi- 0 min elicited a significantly (P cant difference in incremental plasma glu- 0.0001) greater reduction in AUC0 –2h Glucose pharmacodynamics cose at 30 and 45 min) compared with the than the ϩ15-min dose timing (Table The mean premeal glucose concentra- ϩ15 and ϩ30 min pramlintide injections 2). In the insulin lispro group, admin- tions were comparable across all 5 study in both the regular insulin and insulin lis- istration of pramlintide at Ϫ15 min elic- days in both the regular insulin and insu- pro groups. The type of insulin used had ited a significantly greater reduction in AUC than the ϩ30-min dose timing, lin lispro groups (Table 2). In both the aneffectontheresultingglucosepharmaco- 0 –2h regular insulin and insulin lispro groups, dynamic profile (Fig. 1). Thus, in subjects and administration of pramlintide at 0 pramlintide injections at all four time using regular insulin and having pram- min elicited a significantly greater re-

Table 2—Glucose pharmacodynamics and preprandial insulin dose adjustments, evaluable population

Regular insulin ϩ Placebo ϩ 60 ␮g Pramlintide Parameter Ϫ15 min* Ϫ15 min† 0 min‡ ϩ15 min§ 30 min Preprandial (Ϫ5 min) plasma glucose (mmol/l) 9.7 Ϯ 0.9 9.8 Ϯ 0.8 9.5 Ϯ 0.9 9.2 Ϯ 0.9 9.8 Ϯ 0.8 Preprandial short-acting insulin dose (units)¶ 7.5 Ϯ 1.0 7.9 Ϯ 1.0 7.2 Ϯ 0.9 7.1 Ϯ 1.0 8.1 Ϯ 0.9 Ϯ Ϫ Ϯ Ϫ Ϯ Ϯ Ϯ Incremental plasma glucose C30 min (mmol/l) 2.1 7.4 0.2 7.1*§ 0.4 3.7*§ 1.8 6.6†‡ 1.5 7.7†‡ Ϯ Ϫ Ϯ Ϫ Ϯ Ϯ Ϯ Incremental plasma glucose C45 min (mmol/l) 3.5 8.7 0.5 8.9*§ 1.0 6.0*§ 1.4 7.8*†‡ 2.2 8.8*†‡ Ϯ Ϯ Ϫ Ϯ Ϯ Ϯ Postprandial incremental AUC0–2h(mmol/l h) 6.7 1.1 0.3 1.0* 1.2 0.7*§ 1.3 0.9*‡ 1.3 1.1* Ͼ Percent reduction in incremental AUC0–2h‡ 96 100 81 81 Ϯ Ϯ Ϫ Ϯ Ϯ Ϯ Postprandial incremental AUC0–4h(mmol/l h) 11.0 2.9 3.8 2.5* 0.6 2.5* 3.0 2.4* 0.1 3.0*† Ͼ Percent reduction in incremental AUC0–4h# 65 100 73 99

Insulin lispro ϩ Placebo ϩ 60 ␮g Pramlintide Parameter Ϫ15 min* Ϫ15 min† 0 min‡ ϩ15 min§ ϩ30 min Preprandial (Ϫ5 min) plasma glucose (mmol/l) 9.2 Ϯ 0.6 8.7 Ϯ 0.4 8.9 Ϯ 0.5 8.9 Ϯ 0.5 8.4 Ϯ 0.7 Preprandial short-acting insulin dose (units)¶ 6.3 Ϯ 1.1 6.3 Ϯ 1.1 6.2 Ϯ 1.0 6.2 Ϯ 0.9 6.0 Ϯ 1.0 Ϯ Ϫ Ϯ Ϫ Ϯ Ϯ Ϯ Incremental plasma glucose C30 min (mmol/l) 2.9 7.7 0.5 3.9*§ 0.5 6.4*§ 2.3 7.1†‡ 3.1 7.3†‡ Ϯ Ϫ Ϯ Ϫ Ϯ Ϯ Ϯ Incremental plasma glucose C45 min (mmol/l) 4.4 8.7 1.0 6.6*§ 1.3 8.3*§ 1.3 7.8†‡ 3.9 9.0†‡ Ϯ Ϫ Ϯ Ϫ Ϯ Ϯ Ϯ Postprandial incremental AUC0–2h(mmol/l h) 7.1 1.0 0.3 0.9* 1.6 0.9*§ 0.8 1.0*‡ 3.1 0.9*†‡ Ͼ Ͼ Percent reduction in incremental AUC0–2h# 100 100 89 56 Ϯ Ϯ Ϯ Ϯ Ϯ Postprandial incremental AUC0–4h(mmol/l h) 10.0 2.5 6.4 2.3 2.5 2.1*# 4.5 2.7 6.1 2.0 Percent reduction in incremental AUC0–4h# 36 75 54 39 Data are means Ϯ SE, and percent reductions were calculated using mean values. Statistically signiﬁcant (P Ͻ 0.05) pairwise comparison of least-square means denoted by *treatment vs. placebo; †treatment vs. Ϫ15 min; ‡treatment vs. 0 min; §treatment vs. ϩ15 min; treatment vs. ϩ30 min; ¶day Ϫ1 insulin dose: 10.8 units and 8.6 units for the regular insulin and insulin lispro groups, respectively; #relative to the placebo control.

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Figure 1—Postprandial glucose proﬁles in subjects with type 1 diabetes following injections of regular insulin (A) or insulin lispro (B) plus either placebo or 60 ␮g pramlintide at different time points relative to a standardized breakfast (evaluation population).

ϩ duction in AUC0 –2hthan the 15- or reduced compared with the placebo acting insulin dose administered at each ϩ30-min dose timings (Table 2). group (Table 2). of the five meal challenge tests was ϳ30% AUC0–4h. In the regular insulin group, reduced (Table 2). the AUC0–4hfor all four pramlintide dose Preprandial insulin dose timings was significantly (P Ͻ 0.03) re- The mean preprandial doses of regular in- Safety duced compared with the placebo group sulin and insulin lispro administered with There were no severe hypoglycemic epi- (Table 2). In the insulin lispro group, only the standardized test meal were compara- sodes, no serious adverse events, and no the AUC0–4hfor the 0-min pramlintide ble on each of the five meal test days (Ta- clinically relevant changes in laboratory injection was significantly (P Ͻ 0.0098) ble 2). Compared with day Ϫ1, the short- tests, vital signs, electrocardiograms, or

DIABETES CARE, VOLUME 26, NUMBER 11, NOVEMBER 2003 3077 Pramlintide in type 1 diabetes abnormal findings upon physical fact that rapid-acting insulin analogs limit ϳ30%. For the purpose of the present examinations. the postprandial glucose excursion in part study, it was important to keep both the The overall incidence of treatment- by facilitating a more rapid uptake of glu- dosing and the timing of insulin injec- emergent adverse events was similar cose from the circulation into peripheral tions comparable across the five dose tim- among the regular insulin and insulin lis- tissues. In contrast, pramlintide reduces ings. However, it would be interesting in pro groups with mild to moderate hypo- the postprandial glucose excursion by future studies to examine the postpran- glycemia and mild nausea being the most tempering the appearance of both endog- dial glucose lowering effect of pramlintide frequent treatment-emergent adverse enous (liver-derived) and exogenous in the context of various insulin dosing events. In the regular insulin group, the (meal-derived) glucose into the circula- and timing regimens, such as in conjunc- incidence of hypoglycemia was 15.8, tion (5–7). tion with postprandial insulin dosing, or 26.3, 27.8, 21.1, and 21.1% and the inci- A comparison between the regular in- in comparison with an increased prepran- dence of nausea was 10.5, 21.1, 16.7, sulin and insulin lispro groups showed dial insulin dose. 10.5, and 26.3% in the placebo, Ϫ15-, 0-, that while pramlintide reduced the post- Although the study was not con- ϩ15-, and ϩ30-min pramlintide dose prandial glucose excursion with both ducted in a clinical use setting and did not arms, respectively. In the insulin lispro types of insulin, the profile of the post- formally test different insulin dose adjust- group, the incidence of hypoglycemia was prandial glucose concentrations was in- ment regimens, it provides important in- 28.6, 28.6, 33.3, 28.6, and 20.0% and the fluenced by, and in fact reflective of, the formation that may help guide incidence of nausea was 0, 4.8, 9.5, 14.3, onset and duration of action of the con- appropriate insulin dose management and 5.0% in the placebo, Ϫ15-, 0-, ϩ15-, comitantly injected insulin. Thus, follow- when initiating pramlintide treatment in and ϩ30-min pramlintide dose arms, re- ing mealtime injection of pramlintide as patients with type 1 diabetes. Subcutane- spectively. The vast majority of postpran- an adjunct to insulin lispro, the mean glu- ous administration of pramlintide 15 min dial hypoglycemic events in the cose concentration initially fell slightly before or immediately before meal inges- pramlintide dosing groups occurred (with a nadir at ϳ60 min that coincided tion is optimal for reducing postprandial when the fasting plasma glucose concen- with the time at which insulin lispro glucose excursions, with differences in tration was Ͻ7.0 mmol/l (9 of 10 epi- reaches its peak action [26]), and then glucose excursion dependent on the du- sodes in the regular insulin group and 11 gradually rose as the action of insulin lis- ration of effect of the short- or rapid- of 14 episodes in the insulin lispro pro tapered off. In contrast, following acting insulin used. A reduction of the group). mealtime administration of pramlintide preprandial insulin dose (ϳ30–50%) is as an adjunct to regular insulin, the glu- advised when initiating pramlintide treat- CONCLUSIONS — Several previous cose concentration remained within a ment unless subjects persistently have placebo-controlled studies in subjects narrower range, consistent with the preprandial blood glucose concentrations with type 1 diabetes have consistently slower onset and longer duration of ac- Ͼ14 mmol/l, in which case smaller reduc- shown that preprandial administration of tion of regular insulin. tions (or no reduction) may be appropri- pramlintide reduced the early postpran- The systematic evaluation of different ate. The finding that the majority of dial rise and overall postprandial excur- dose-timing regimens showed that pram- nonsevere hypoglycemic episodes during sion of plasma glucose when used in lintide administrations at either Ϫ15 min the postprandial period occurred when conjunction with regular insulin (17–19). or immediately before a meal both pre- fasting glucose concentrations were Ͻ7 However, these previous studies have not vented the early postprandial surge in mmol/l indicates that even larger reduc- assessed the effects of pramlintide when plasma glucose that occurred with admin- tions in preprandial short-acting insulin given at various injection times or when istration of regular insulin or insulin lis- doses may be required when the prepran- given with a rapid-acting insulin analog. pro alone (placebo). Administration of dial glucose concentration is in or near the In this respect, the present study revealed pramlintide at ϩ15 or ϩ30 min relative normal range. In addition, increases in several novel, clinically important to the meal did not prevent the initial rise basal insulin coverage may be appropri- findings. in plasma glucose but nevertheless still ate, particularly in subjects using rapid- The results from the insulin lispro reduced the overall postprandial glucose acting insulin analogs, such as insulin group indicate that pramlintide also re- excursion compared with administration lispro, for whom the importance of basal duces the postprandial glucose excursion of regular insulin or insulin lispro alone. insulin adjustments has long been recog- when used as an adjunct to a rapid-acting This latter observation is entirely consis- nized (28). When used with appropriate insulin analog. This is a clinically impor- tent with the mechanism of action of adjustments to both basal and bolus insu- tant finding, given that rapid-acting insu- pramlintide: as the rate of glucose appear- lin regimens, adjunctive treatment with lin analogs have themselves been shown ance is reduced to better match the rate of pramlintide may lead to a reduction of to improve postprandial glucose excur- insulin-mediated glucose disappearance, excessive glucose fluctuations throughout sion compared with regular insulin in pa- even after the ingestion of the meal, the the day, as recently documented by con- tients with type 1 diabetes (25–27). In glycemic surge is curbed and plasma glu- tinuous glucose monitoring in subjects these previous studies (25–27), rapid- cose concentrations revert toward lower with type 1 diabetes treated intensively acting insulin analogs reduced the overall levels. with insulin pumps (29). postprandial glucose excursion, but the The potent postprandial glucose low- initial rise in postprandial glucose was ering effect of pramlintide occurred de- typically unaffected, compared with reg- spite a concomitant lowering of the mean Acknowledgments— We wish to thank ular insulin. This may be explained by the preprandial short-acting insulin dose by Mark Fineman, Jonathan Kornstein, Terrie

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