sign in sign up
<<
Home , Insulin detemir, Insulin glulisine, Pramlintide

Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Randomized Comparison of or Mealtime Added to Basal Insulin Treatment for Patients With Type 2

1 2 MATTHEW RIDDLE, MD KAREN LUTZ, PHD limit postmeal hyperglycemia. 2 2 RICHARD PENCEK, PHD KEN WILHELM, MD deficiency accelerates gastric emptying, 2 2 SUPOAT CHARENKAVANICH, PHD LISA PORTER, MD increases secretion, and alters satiety mechanisms (10,11). Pramlintide, an injectable synthetic OBJECTIVE — To compare the efficacy and safety of adding mealtime pramlintide or rapid- analog of amylin, slows gastric emptying, acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 attenuates postprandial glucagon secre- diabetes. tion, enhances satiety, and reduces food intake (12–14). Pramlintide is approved RESEARCH DESIGN AND METHODS — In a 24-week open-label, multicenter study, ␮ as adjunctive treatment for patients with 113 patients were randomly assigned 1:1 to addition of mealtime pramlintide (120 g) or a diabetes who use mealtime insulin with or titrated RAIA to basal insulin and prior oral antihyperglycemic drugs (OADs). At screening, patients were insulin naive or had been receiving Ͻ50 units/day basal insulin for Ͻ6 months. without oral antihyperglycemic drugs The basal insulin dosage was titrated from day 1, seeking fasting plasma (FPG) Ն70– (OADs) and have not achieved desired Ͻ100 mg/dl. Pramlintide and an RAIA were initiated on day 1 and week 4, respectively. The glucose control. Recently, a 16-week, proportion of patients achieving A1C Յ7.0% without weight gain or severe at double-blind, placebo-controlled study week 24 was the primary end point. of patients with showed that pramlintide reduces A1C and weight RESULTS — More pramlintide- than RAIA-treated patients achieved the primary end point without increasing insulin-induced hypo- (30 vs. 11%, P ϭ 0.018) with a similar dose of basal insulin. Pramlintide and an RAIA yielded glycemia when added to basal insulin Ϯ similar mean Ϯ SEM values for FPG and A1C at 24 weeks (122 Ϯ 7 vs. 123 Ϯ 5 mg/dl and 7.2 Ϯ Ϯ OADs without mealtime insulin (15). 0.2 vs. 7.0 0.1%, respectively) and similar least squares mean reductions from baseline to end Pramlintide may offer an additional point (Ϫ31 Ϯ 6 vs. Ϫ34 Ϯ 6 mg/dl and Ϫ1.1 Ϯ 0.2 vs. Ϫ1.3 Ϯ 0.2%, respectively). RAIAs but not pramlintide caused weight gain (ϩ4.7 Ϯ 0.7 vs. ϩ0.0 Ϯ 0.7 kg, P Ͻ 0.0001). Fewer patients therapeutic option for mealtime use by reported mild to moderate hypoglycemia with pramlintide than with the RAIA (55 vs. 82%), but patients with type 2 diabetes already us- more patients reported nausea (21 vs. 0%). No severe hypoglycemia occurred in either group. ing basal insulin. Rapid-acting insulin an- alogs (RAIAs) and pramlintide have CONCLUSIONS — In patients taking basal insulin and OADs, premeal fixed-dose pram- different mechanisms of action and differ- lintide improved glycemic control as effectively as titrated RAIAs. The pramlintide regimen ent patterns of desired and unwanted ef- sometimes caused nausea but no weight gain and less hypoglycemia. fects. Although both can limit after-meal hyperglycemia, RAIAs often cause weight Diabetes Care 32:1577–1582, 2009 gain and hypoglycemia (6), whereas pramlintide is associated with weight loss dding basal insulin therapy to oral Previous studies have shown that de- and nausea (15,16). This study was de- agents improves glycemic control fects in addition to insulin deficiency con- signed to compare the efficacy and side A for many patients with type 2 dia- tribute to after-meal hyperglycemia. Both effects of pramlintide versus RAIAs when betes, but up to 50% of patients continue insulin and amylin are secreted by ␤-cells, added to basal insulin to intensify treat- to have A1C values Ͼ7% (1–5). Persistent and, in individuals with abnormal ␤-cell ment of type 2 diabetes. after-meal hyperglycemia is generally ob- function, glucose- and mixed meal– served in such patients (6). The usual next stimulated secretion of both is RESEARCH DESIGN AND step in treatment is addition of mealtime delayed and reduced (7–9). Insulin defi- METHODS — Patients enrolled were insulin injections, but this approach in- ciency impairs suppression of hepatic aged 18–75 years, had a clinical diagnosis creases risks of weight gain and hypogly- glucose production and enhancement of of type 2 diabetes, and had A1C Ͼ7% and cemia (4,6). glucose uptake by tissues that normally Յ10% with or without use of any combi- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● nation of , , From the 1Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Medicine, Oregon or OADs. Study participants 2 Health & Science University, Portland, Oregon; and , San Diego, California. were pramlintide naive and either insulin Corresponding author: Ken Wilhelm, [email protected]. naive or had used Ͻ50 units/day of basal Received 2 March 2009 and accepted 23 May 2009. Ͻ Published ahead of print at http://care.diabetesjournals.org on 5 June 2009. DOI: 10.2337/dc09-0395. insulin for 6 months. Inclusion criteria Clinical trial reg. no. NCT00467649, clinicaltrials.gov. included BMI Ն25 and Յ50 kg/m2. Fe- © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly male patients were neither pregnant nor lac- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. tating and were postmenopausal or using org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby birth control. Candidates were excluded if marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. they adhered poorly to diabetes manage-

DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 1577 Pramlintide versus mealtime insulin ment recommendations, had recurrent nificant nausea. Patients randomly as- signed patients receiving at least one dose severe hypoglycemia within the last 6 signed to an RAIA received only titrated of study . Missing individual months, or had a history of hypoglycemia basal insulin therapy for 4 weeks to avoid data were imputed from the last sched- unawareness. Patients with gastroparesis the hypoglycemia risk associated with titrat- uled visit (last observation carried for- or those who required to al- ing basal insulin and an RAIA simulta- ward). Insulin dose was analyzed in the ter gastric motility were excluded, as were neously. After 4 weeks, RAIA-randomized ITT observed population. Measured val- patients using or , patients started RAIA therapy with 5 units ues for insulin dose, A1C, FPG, and any antiobesity agents, systemic glu- of lispro, aspart, or glulisine before each glucose increments are presented as arith- cocorticoid agents, or investigational meal. Mealtime insulin doses were ad- metic mean Ϯ SEM. medications. Patients with eating disor- justed with investigator guidance by 1–2 Fisher’s exact test was used to com- ders, a history of bariatric surgery, or plans units every 3–7 days with the aim of pare the proportion of patients achieving to lose weight were excluded, as were pa- maintaining glucose concentrations at the primary end point. The Cochran- tients with any significant medical condi- Ն70 and Ͻ100 mg/dl before the subse- Mantel-Haenszel test that controlled for tions or advanced diabetes complications. quent meal or (for the dinnertime dose) at A1C at screening was used as a confirma- bedtime. Patients self-monitored tory test. Intergroup comparisons of con- Ethical considerations glucose daily according to individualized tinuous changes from baseline were The study protocol was approved by ap- advice from site investigators. A seven- assessed with ANOVA models including plicable institutional review boards and point glucose profile consisting of mea- treatment group, A1C at screening conducted in accordance with the Decla- surements taken 15 min before and 1.5–2 (Յ9.0% or Ͼ9.0%), insulin treatment be- ration of Helsinki. All patients provided h after the start of each of the three meals fore screening, and baseline value (for pa- written informed consent before study and at bedtime was completed during the rameters other than A1C). Data were initiation. week before each visit. At each visit, reported as least squares mean change Ϯ weight, body circumference, and vital SEM. Study design and interventions signs were measured and blood glucose This was a randomized, open-label, par- values were reviewed. Participants were RESULTS allel-group, multicenter 24-week study counseled on adjustment of basal and conducted at 29 centers throughout the mealtime insulin dosage (RAIA group) at Patient disposition, baseline U.S. between April 2007 and May 2008 (a each visit. A1C was measured at all study demographics, and therapies complete list of the participating investi- visits, and FPG was measured at screen- Of 113 patients randomly assigned, 48 gators can be found in the APPENDIX). After ing, baseline, and weeks 4, 12, and 24. No (84%) pramlintide-treated and 50 (89%) the screening visit, eligible patients visited specific lifestyle modification was ad- RAIA-treated patients completed the the study center on day 1 (baseline) and at vised; patients were asked to maintain study (Table 1). One patient in the pram- weeks 4, 8, 12, 18, and 24. Scheduled usual diet and exercise patterns. lintide group withdrew consent before in- telephone visits to review self-monitored jecting study medication, resulting in an glucose measurements and direct insulin Study end points ITT population of 56 patients per treat- adjustment occurred between visits. Ran- The primary end point was the propor- ment group. Baseline characteristics were dom assignment 1:1 to pramlintide (Amy- tion of patients achieving the following well matched between groups (Table 1). lin Pharmaceuticals, San Diego, CA) or to prespecified criteria at week 24: 1) A1C Before the study, 46% of patients used an RAIA (, , or Յ7.0%, 2) no weight gain from baseline, insulin and 91% of patients used at least ) occurred at baseline and and 3) no severe hypoglycemia. Severe one OAD. was centrally generated and stratified ac- hypoglycemia was defined as an event re- Basal insulin dosage increased cording to A1C screening values (Յ9.0% quiring assistance of another individual steadily throughout the study, resulting or Ͼ9.0%) and insulin use (insulin naive and/or administration of glucagon injec- in similar mean doses at week 24: 52 Ϯ 4 Ϫ or receiving basal insulin at screening). tion or intravenous glucose. Secondary units/day (0.48 Ϯ 0.04 unit kg 1 Ϫ All patients received end points included the individual com- day 1) for pramlintide-treated patients or detemir throughout the study, once or ponents of the composite end point, insu- and 57 Ϯ 4 units/day (0.52 Ϯ 0.04 units Ϫ Ϫ twice daily. Basal insulin was titrated at lin dose, A1C, change in A1C, proportion kg 1 day 1) for patients in the RAIA arm the investigator’s direction weekly or of patients reaching A1C Յ6.5%, FPG, (Fig. 1A). After 24 weeks, RAIA-treated twice weekly to achieve a fasting plasma postprandial glucose increments, changes patients administered a mean daily dose Ϫ glucose (FPG) concentration of Ն70– in weight, changes in waist circumfer- of 37 Ϯ 3 units (0.34 Ϯ 0.03 unit kg 1 Ϫ Ͻ100 mg/dl, as in the Treat-To-Target ence, and adverse events including the in- day 1) of insulin lispro, aspart, or glu- Study (1). Study medication (pramlintide cidence, severity, and time courses of lisine. Numbers of patients initiating ther- or an RAIA) was self-administered subcu- hypoglycemia and nausea. apy with insulin lispro, aspart, or glulisine taneously before major meals. Patients in were 16 (29%), 31 (55%), and 9 (16%), the pramlintide treatment group received Statistical analyses respectively. To achieve glycemic results 120 ␮g s.c. before major meals beginning A sample size of 45 patients per group was similar to those of the pramlintide group, on day 1 because a prior study demon- predicted to provide 90% power to detect patients in the RAIA group used an aver- strated no increased risk of hypoglycemia a 27% difference in the proportion of pa- age of 80% more insulin (basal ϩ rapid- when fixed-dose pramlintide was added tients achieving the primary end point acting) at week 24 (94 vs. 52 units, to basal insulin (15). Dose reduction to 60 (␣ϭ0.05). Analyses were performed on respectively). ␮g pramlintide per meal was permitted patients within the intent-to-treat (ITT) Forty-six participants (82%) contin- for patients with persistent clinically sig- population including all randomly as- ued to take 120 ␮g pramlintide before

1578 DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 Riddle and Associates

Table 1—Patient disposition and demographic and clinical characteristics at baseline were ϩ0.0 Ϯ 0.7 kg (pramlintide) versus ϩ4.7 Ϯ 0.7 kg (RAIA) (P Ͻ 0.0001). Pramlintide RAIA Differences in waist measurements were consistent with weight differences. Disposition Waist circumferences at week 24 were Randomized 57 56 115 Ϯ 2 and 120 Ϯ 2 cm for the pram- Withdrew before treatment 1 0 lintide and RAIA groups, respectively. Completed 48 50 Least squares mean changes in waist cir- Withdrew between treatment and week 24 8 6 cumference from baseline were Ϫ0.6 Ϯ Reason for withdrawal 0.9 and ϩ2.2 Ϯ 0.9 cm, respectively (P ϭ Withdrawal of consent 4 2 0.016). Adverse event 2 0 FPG. Similar basal insulin titration in Investigator decision 1 0 both treatment arms resulted in similar Protocol violation 0 0 mean FPG concentrations at week 24: Lost to follow-up 2 4 Ϯ Ϯ Baseline demographics 122 7 mg/dl (pramlintide) and 123 5 ITT population 56 56 mg/day (RAIA) (Fig. 1D). The least Sex (male/female) 34/22 37/19 squares mean change of FPG from base- Ϫ Ϯ Race (Caucasian/other) 48/8 43/13 line was 31 6 mg/dl (pramlintide) Ϫ Ϯ ϭ Age (years) 55 Ϯ 11 54 Ϯ 10 and 34 6 mg/dl (RAIA) (P 0.65). Ͻ Weight (kg) 108 Ϯ 22 103 Ϯ 18 An FPG concentration 100 mg/dl was BMI (kg/m2) 36 Ϯ 636Ϯ 6 achieved at week 24 by 17 of 56 (30%) of Diabetes duration (years) 10 Ϯ 79Ϯ 6 pramlintide-treated and 15 of 56 (27%) of A1C (%) 8.2 Ϯ 0.8 8.3 Ϯ 0.8 RAIA-treated patients (P ϭ 0.83). FPG (mg/dl) 155 Ϯ 40 164 Ϯ 50 Postprandial glucose increments. Post- OAD use at randomization 50 52 prandial glucose increments were similar Average number of oral medications per patient 1.9 1.7 between treatment groups at week 24 Sulfonylurea 34 29 (Fig. 2A). No significant difference in the Metformin 36 38 least squares mean change in postpran- 16 15 dial increment from baseline to week 24 Combined drug formulations 5 2 was found between treatment groups Insulin use before randomization 27 24 (Ϫ17 Ϯ 5 mg/dl [pramlintide] vs. Ϫ27 Ϯ Daily basal insulin dose at baseline (units/day) 20 Ϯ 10 24 Ϯ 12 5 mg/dl [RAIA], P ϭ 0.17). Type of basal insulin initiated after randomization Adverse events. The most common ad- Insulin glargine q.d. 37 45 verse events were hypoglycemia and nau- Insulin glargine b.i.d. 1 0 sea (Fig. 2B). Although no episodes of q.d. 18 11 severe hypoglycemia were observed, mild Insulin detemir b.i.d. 0 0 or moderate hypoglycemia occurred Data are n or means Ϯ SD. more frequently than nausea in both treatment groups and was observed in meals throughout the study. Two partici- Secondary end points more patients treated with RAIAs (82%) ␮ Ϯ pants reduced the dosage to 60 g be- A1C. Mean A1C at 24 weeks was 7.2 than with pramlintide (55%). Hypoglyce- cause of nausea. 0.2% with addition of pramlintide and mic events occurred more frequently in Ϯ 7.0 0.1% with addition of an RAIA (Fig. the pramlintide treatment group in the Primary end point 1B). The least squares mean reduction of first 4 weeks but were more common in The primary composite end point com- Ϫ Ϯ A1C from baseline was 1.1 0.2 for the RAIA treatment group from 18 to 24 prised several highly desirable goals as- Ϫ Ϯ pramlintide and 1.3 0.2 for RAIA weeks (Fig. 2C). Nausea was reported sessed after 24 weeks of treatment: A1C ϭ Յ Յ (P 0.46 between groups). A1C 6.5% only in the pramlintide group (12 of 56 7.0%, no weight gain from baseline, at 24 weeks was achieved by 16 of 56 and no severe hypoglycemia (Table 2). [21%]), most often early in treatment (10 (29%) of patients treated with pramlin- of 56 patients in the first 4 weeks), and Significantly more pramlintide-treated tide and by 19 of 56 (34%) of patients than RAIA-treated patients achieved this declined over time (Fig. 2D). Two pa- treated with an RAIA (P ϭ 0.68 between end point (30 vs. 11%, P ϭ 0.018). tients (4%) withdrew from pramlintide groups). A1C values were stable after Among the components of the composite, therapy and the study because of nausea. only the percentage of patients without week 12 (Fig. 1B). Eight serious adverse events were re- weight gain at week 24 differed signifi- Weight and waist circumference. A sig- ported in six patients during the study: cantly between pramlintide- and RAIA- nificant between-group difference in one patient in the pramlintide group (cor- treated patients (59 vs. 16%, P Ͻ 0.0001). weight was observed throughout the onary artery disease) and five patients in No significant differences in the fre- study (Fig. 1C). At week 24, mean the RAIA group (coronary artery disease, quency of achieving A1C Յ7.0% or in the weights were 106 Ϯ 3 kg (pramlintide) congestive heart failure, ischemic cerebral incidence of severe hypoglycemia were versus 109 Ϯ 3 kg (RAIA). Least squares infarction, syncope, noncardiac chest observed between groups. mean changes in weight from baseline pain, cellulitis, and biliary dyskinesia).

DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 1579 Pramlintide versus mealtime insulin

Figure 1—A: Mean changes in insulin dosage over the course of the trial. Solid squares, unbroken line ϭ basal insulin in the pramlintide group. Open triangles, unbroken line ϭ basal insulin in the RAIA group. Open circles, broken line ϭ total insulin (basal plus mealtime) in the RAIA group. B: Mean A1C at each visit. Solid squares ϭ pramlintide; open circles ϭ RAIA. C: Least squares mean weight changes over time with the last observation carried forward. Solid squares ϭ pramlintide; open circles ϭ RAIA. ***P Ͻ 0.001; **P Ͻ 0.01. D: Mean fasting plasma glucose over time. Solid squares ϭ pramlintide; open circles ϭ RAIA. LOCF, last observation carried forward; LS, least squares.

CONCLUSIONS — This head-to- tive assessment (the between-treatment greater with an RAIA plus basal insulin than head comparison demonstrated that pre- difference of change from baseline in all with pramlintide plus basal insulin (82 vs. meal pramlintide and RAIA have similar patients receiving study medication, last 55%). Nausea occurred more frequently glycemic effects when either agent is observation carried forward), RAIA treat- with pramlintide, and two patients (4%) added to titrated basal insulin with or ment contributed to a 4.7 kg (10.3 lb) withdrew from the study. However, as in without an OAD. On average, pramlin- gain compared with pramlintide treat- other clinical studies, reports of nausea as- tide reduced A1C from 8.2 to 7.2%, and ment over 24 weeks. With similar glyce- sociated with pramlintide declined steadily an RAIA reduced A1C from 8.3 to 7.0% mic effects and no severe hypoglycemic during continued treatment. after 24 weeks of treatment. Reductions in events with either treatment, the compos- This study builds on findings of a 16- A1C, FPG, and postmeal glycemic incre- ite primary end point favored pramlintide week study that compared administration ments were not statistically different over an RAIA because of the difference in of pramlintide versus placebo during titra- between treatment groups. However, weight gain. tion of basal insulin with continuation of an changes in body weight accompanying Other clinical differences between OAD, in which glycemic control improved improved glycemic control differed be- these therapies are related to unwanted ef- more with pramlintide than with placebo tween treatments. By the most conserva- fects. The incidence of hypoglycemia was and no severe hypoglycemia was reported (15). Weight declined a mean of 1.6 kg with Table 2—Primary end point pramlintide but increased 0.7 kg with pla- cebo. The larger absolute body weight dif- ference between groups in this study is Fisher’s exact probably due to RAIA-associated weight Pramlintide RAIA test P value gain. n 56 56 The potential clinical importance of Patients achieving composite end point* 17 (30) 6 (11) 0.018 weight gain associated with treatment for Individual end points hyperglycemia has been studied for many Patients achieving A1C Յ7.0% at week 24 27 (48) 34 (61) 0.25 years and remains controversial. An unfa- Patients with no weight gain at week 24 33 (59) 9 (16) Ͻ0.0001 vorable relationship between adiposity Incidence of severe hypoglycemia 0 (0) 0 (0) NS and a variety of medical outcomes, in- Data are n (%). *Composite end point: A1C Յ7.0% at week 24 with no weight gain and no severe hypo- cluding cardiovascular disease, is well glycemia. NS, not significant. established (17,18). Recently, an obser-

1580 DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 Riddle and Associates

Figure 2—A: Postprandial glucose increments from before to after meals at 24 weeks. Black bars ϭ pramlintide; white bars ϭ RAIA. B: Incidence and severity of hypoglycemia and nausea in patients treated with pramlintide or RAIA in addition to basal insulin. White bar ϭ mild; striped bar ϭ mild or moderate; cross-hatched bar ϭ moderate; black bar ϭ severe. C: The rate of hypoglycemia (events/week) over the course of the study with RAIA and pramlintide treatment. Black bars ϭ pramlintide; white bars ϭ RAIA. D: Number of patients reporting nausea over time during treatment with pramlintide. vational study of ϳ4,900 patients with not associated with weight gain or hypo- in the timing of RAIA initiation, the po- type 2 diabetes showed a 13% increase in glycemia, reduced the incidences of myo- tential for weight gain in the RAIA group risk for fatal or nonfatal coronary heart cardial infarction and all-cause mortality may be underestimated at week 24, but disease with each 1-unit increase of BMI (23). Similar trends were shown in an- glycemic outcomes at week 24 did not over ϳ6 years (19). Furthermore, evi- other study with , an antihyper- seem to be affected, as insulin doses, A1C, dence suggests that intended weight re- glycemic agent that also does not cause and FPG in both treatment groups stabi- duction reduces cardiovascular risk weight gain or hypoglycemia (24). In con- lized after 12 weeks, well before the factors (20) and mortality (21). However, trast, the Action to Control Cardiovascu- study’s end. The incidence of nausea ac- direct evidence that weight gain associ- lar Risk in Diabetes (ACCORD) trial, companying initiation of pramlintide ated with insulin treatment is harmful is which compared intensive versus standard (ϳ20%) was confirmed as a leading draw- lacking. Notably, at the end of 10 years of glycemic control strategies associated with back of starting treatment at 120 ␮g. Both randomized treatment, the U.K. Prospec- weight gain and hypoglycemia, was nausea associated with pramlintide and hy- tive Diabetes Study (UKPDS) showed a stopped early because of higher all-cause poglycemia/weight gain associated with an marginally significant reduction of myo- mortality in the intensive arm, despite a RAIA might have been mitigated by more cardial infarction (16%, P ϭ 0.052) with 1.1% lower A1C in this group (25). Poten- gradual titration. The small imbalance in insulin or sulfonylurea treatment com- tial underlying mechanisms include the use of detemir as the basal insulin (18 with pared with dietary treatment, despite doubled occurrence of weight gain Ͼ10 kg pramlintide and 11 with an RAIA) is of un- greater weight gain. Follow-up after ces- with intensive treatment, the threefold in- certain significance. Differences in overall sation of randomized treatment showed crease of severe hypoglycemia, or both. costs between the pramlintide and RAIA persistence of the difference over time, This study had several limitations. It regimens might exist but are not addressed and the advantage of insulin or sulfonyl- was a small study, powered to address the in this study of efficacy and safety. urea became statistically significant with composite primary outcome but not sep- Overall, these findings support the more events (15%, P Ͻ 0.01) (22,23). arate clinical outcomes, and the open- role of mealtime pramlintide as a poten- Other findings indirectly suggest that label design allows the possibility of tial alternative to RAIAs for patients using avoiding weight gain and hypoglycemia unintended bias. The 4-week delay in ini- basal insulin treatment with or without while improving glycemic control may tiating an RAIA to avoid insulin-induced OADs who are not achieving glycemic provide cardiovascular benefit. In a study hypoglycemia from simultaneous initia- goals. Longer-term studies to evaluate embedded in the UKPDS, treatment of tion of basal and rapid-acting insulin was cardiovascular and microvascular out- obese patients with metformin, which is also a limitation. Because of the difference comes of controlling after-meal hyper-

DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 1581 Pramlintide versus mealtime insulin glycemia without weight gain and lowering drugs in insulin-naïve people 14. Chapman I, Parker B, Doran S, Feinle-Bis- hypoglycemia would be helpful to inform with type 2 diabetes. Diabetes Care 2006; set C, Wishart J, Strobel S, Wang Y, Burns C, clinical treatment decisions for patients 29:1269–1274 Lush C, Weyer C, Horowitz M. Effect of with type 2 diabetes. 3. Rosenstock J, Davies M, Home PD, Larsen pramlintide on satiety and food intake in J, Koenen C, Schernthaner G. A random- obese subjects and subjects with type 2 di- ized, 52-week, treat-to-target trial com- abetes. Diabetologia 2005;48:838–848 Acknowledgments— Funding for this study paring insulin detemir with insulin 15. Riddle M, Frias J, Zhang B, Maier H, was provided by Amylin Pharmaceuticals. glargine when administered as add-on to Brown C, Lutz K, Kolterman O. Pramlin- M.R. has received grant or research support glucose-lowering drugs in insulin-naïve tide improved glycemic control and re- from Amylin Pharmaceuticals, Eli Lilly, and people with type 2 diabetes. Diabetologia duced weight in patients with type 2 sanofi-aventis; has served as a consultant for 2008;51:408–416 diabetes using basal insulin. Diabetes Amylin Pharmaceuticals, Eli Lilly, Novo Nor- 4. Bretzel RG, Nuber U, Landgraf W, Owens Care 2007;30:2794–2799 disk, and sanofi-aventis; and has received lec- DR, Bradley C, Linn TL. Once-daily basal 16. Hollander PA, Levy P, Fineman MS, ture honoraria from Amylin Pharmaceuticals, insulin glargine versus thrice-daily pran- Maggs DG, Shen LZ, Strobel SA, Weyer C, Eli Lilly, and sanofi-aventis. dial insulin lispro in people with type 2 Kolterman OG. Pramlintide as an adjunct No other potential conflicts of interest rele- diabetes on oral hypoglycemia agents to insulin therapy improves long-term vant to this article were reported. (APOLLO): an open randomised con- glycemic and weight control in patients Parts of this study were presented in ab- trolled trial. Lancet 2008;371:1073–1084 with type 2 diabetes. Diabetes Care 2003; stract form at the 68th Scientific Sessions of 5. Janka HU, Plewe G, Riddle MC, Kliebe- 26:784–790 the American Diabetes Association, San Fran- Frisch C, Schweitzer MA, Yki-Jarvinen H. 17. Must A, Spadano J, Coakley EH, Field AE, cisco, California, 6–10 June 2008, and at the Comparison of basal insulin added to oral Colditz G, Dietz WH. The disease burden 44th Annual Meeting of the European Associ- agents versus twice-daily premixed insu- associated with overweight and obesity. ation for the Study of Diabetes, Rome, Italy, lin as initial insulin therapy for type 2 di- JAMA 1999;282:1523–1529 7–11 September 2008. abetes. Diabetes Care 2005;28:254–259 18. Prospective Studies Collaboration. Body We thank Gayle Lorenzi for careful review 6. Holman RR, Thorne KI, Farmer AJ, Da- mass index and cause-specific mortality of the manuscript and Mary Beth DeYoung for vies MJ, Deenan JF, Paul S, Levy JC, 4-T in 900,000 adults: collaborative analyses editorial assistance. Treatment Group. Addition of biphasic, of 57 prospective studies. Lancet 2009; prandial, or basal insulin to oral therapy 373:1083–1096 in type 2 diabetes. N Engl J Med 2007; 19. Eeg-Olofsson K, Cederholm J, Nilsson APPENDIX 357:1716–1730 PM, Zethelius B, Nunez L, Gudbjornsdot- Participating investigators are as follows: 7. Hartter E, Svoboda T, Ludvik B, Schuller tir, Eliasson B. Risk of cardiovascular dis- R. Bhushan, Baton Rouge, LA; T. Blevins, M, Lell B, Kuenburg E, Brunnbauer M, ease and mortality in overweight and Austin, TX; N. Fishman, Chesterfield, Woloszczuk W, Prager R. Basal and stim- obese patients with type 2 diabetes: an MO; K. Furlong, Philadelphia, PA; R. ulated plasma levels of pancreatic amylin observational study in 13,087 patients. Guthrie, Wichita, KS; S. Hippler, Peoria, indicate its co-secretion with insulin in Diabetologia 2008;52:65–73 IL; P. Hollander, Dallas, TX; D. Karl, Port- humans. Diabetologia 1991;34:52–54 20. Poirier P, Giles TD, Bray GA, Hong Y, 8. Koda JE, Fineman M, Rink TJ, Dailey GE, Stern JS, Pi-Sunyer FX, Eckel RH. Obesity land, OR; D. Karounos, Lexington, KY; K. Muchmore DD, Linarelli LG. Amylin con- and cardiovascular disease: pathophysiol- Klatt, Portland, OR; E. Klein, Olympia, centrations and glucose control. Lancet ogy, evaluation and effect of weight loss. WA; K. Latif, Bartlett, TN; P. Levy, Phoe- 1992;339:1179–1180 Circulation 2006;113:898–918 nix, AZ; M.E. May, Nashville, TN; J. 9. Knowles NG, Landchild MA, Fujimoto 21. Bray, GA. The missing link—lose weight, Mersey, Baltimore, MD; T. Moretto, Indi- WY, Kahn SE. Insulin and amylin release live longer. N Engl J Med 2007;357:818– anapolis, IN; L. Myers, Lexington, KY; C. are both diminished in first-degree rela- 820 Pacheco, Maitland, FL; J. Pollock, Planta- tives of subjects with type 2 diabetes. Di- 22. UK Prospective Diabetes Study (UKPDS) tion, FL; J. Pullman, Butte, MT; J. Reed, abetes Care 2002;25:292–297 Group. Intensive blood glucose control Roswell, GA; S. Rizvi, Hamilton, NJ; J. 10. Gedulin BR, Jodka CM, Herrmann K, with sulphonylureas or insulin compared Rothman, Staten Island, NY; T. Abraham, Young AA. Role of endogenous amylin in with conventional treatment and risk of glucagon secretion and gastric emptying complications in patients with type 2 di- Detroit, MI; J. Snyder, Las Vegas, NV; S. in rats demonstrated with the selective an- abetes (UKPDS 33). Lancet 1998;352: Varma, Bridgeville, PA; R.B. Vaughters tagonist, AC187. Regul Pept 2006;137: 837–853 III, Aiken, SC; D. Weiss, Mentor, OH; and 121–127 23. Holman RR, Paul SK, Bethel MA, Mat- C. Wysham, Spokane, WA. 11. Lutz TA. Pancreatic amylin as a centrally thews DR, Neil HAW. 10-year follow-up acting satiating . Curr Drug Tar- of intensive glucose control in type 2 dia- gets 2005;6:181–189 betes. N Engl J Med 2008;359:1577– References 12. Fineman MS, Koda JE, Shen LZ, Strobel 1589 1. Riddle MC, Rosenstock J, Gerich J. The SA, Maggs DG, Weyer C, Kolterman OG. 24. Chiasson JL, Josse RG, Gomis R, Hanefeld Treat-to-Target Trial: randomized addi- The human amylin analogue, pramlin- M, Karasik A, Laakso M, STOP-NIDDDM tion of glargine or human NPH to oral tide, corrects postprandial hyperglu- Trial Research Group. Acarbose and the therapy of type 2 diabetic patients. Diabe- cagonemia in patients with type 1 risk of cardiovascular disease and hyper- tes Care 2003;26:3080–3086 diabetes. Metabolism 2002;51:636–641 tension in patients with impaired glucose 2. Hermansen K, Davies M, Derezinski T, 13. Vella A, Lee JS, Camilleri M, Szarka A, tolerance: the STOP-NIDDM trial. JAMA Ravn GM, Clauson P, Home P, Levemir Burton DD, Zinsmeister AR, Rizza RA, 2003;290:486–494 Treat-to-Target Study Group. A 26-week, Klein PD. Effects of pramlintide, an amy- 25. Action to Control Cardiovascular Risk in randomized, parallel, treat-to-target trial lin analogue, on gastric emptying in type Diabetes Study Group. Effects of intensive comparing insulin detemir with NPH in- 1 and 2 diabetes mellitus. Neurogastroen- glucose lowering in type 2 diabetes. sulin as add-on therapy to oral glucose- terol Motil 2002;14:123–131 N Engl J Med 2008;358:2545–2559

1582 DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009