Clinical Care/Education/Nutrition ORIGINAL ARTICLE Does Treatment With Duloxetine for Neuropathic Pain Impact Glycemic Control? 1 1 THOMAS HARDY, MD, PHD MARY ARMBRUSTER, MSN, CDE betic peripheral neuropathic pain (DPNP) 2 3,4 RICHARD SACHSON, MD ANDREW J.M. BOULTON, MD, FRCP vary from 3% to Ͼ20% (4). 1 SHUYI SHEN, PHD For many agents, the data supporting effectiveness is limited. In addition, nearly all treatments are associated with OBJECTIVE — We examined changes in metabolic parameters in clinical trials of duloxetine safety or tolerability issues. One category for diabetic peripheral neuropathic pain (DPNP). of side effects common to a number of the antidepressant and anticonvulsant drugs RESEARCH DESIGN AND METHODS — Data were pooled from three similarly de- is related to metabolic changes. Weight signed clinical trials. Adults with diabetes and DPNP (n ϭ 1,024) were randomized to 60 mg ϭ gain is seen with tricyclic antidepressants duloxetine q.d., 60 mg b.i.d., or placebo for 12 weeks. Subjects (n 867) were re-randomized (TCAs) (5) and anticonvulsants (e.g., val- to 60 mg duloxetine b.i.d. or routine care for an additional 52 weeks. Mean changes in plasma glucose, lipids, and weight were evaluated. Regression and subgroup analyses were used to proate, gabapentin, pregabalin) (6). identify relationships between metabolic measures and demographic, clinical, and electrophys- Changes in plasma glucose have also been iological parameters. reported with TCAs (7,8) and phenytoin (9), and dyslipidemia can be seen with RESULTS — Duloxetine treatment resulted in modest increases in fasting plasma glucose carbamazepine (10). in short- and long-term studies (0.50 and 0.67 mmol/l, respectively). A1C did not increase in Duloxetine has demonstrated efficacy placebo-controlled studies; however, a greater increase was seen relative to routine care in in several large clinical trials of DPNP long-term studies (0.52 vs. 0.19%). Short-term duloxetine treatment resulted in mean weight (11–13) and is one of only two drugs to Ϫ Ͻ loss ( 1.03 kg; P 0.001 vs. placebo), whereas slight, nonsignificant weight gain was seen in have received regulatory approval for the both duloxetine and routine care groups with longer treatment. Between-group differences were treatment of this condition. As a selective seen for some lipid parameters, but these changes were generally small. Metabolic changes did not appear to impact improvement in pain severity seen with duloxetine, and nerve conduction reuptake inhibitor of both norepineph- was also not significantly impacted by treatment. rine and serotonin, it shares some features with secondary amine TCAs such as nor- CONCLUSIONS — Duloxetine treatment was associated with modest changes in glycemia triptyline. However, it differs from TCAs in patients with DPNP. Other metabolic changes were limited and of uncertain significance. in some aspects, including the lack of in- These changes did not impact the significant improvement in pain observed with duloxetine teraction with acetylcholine receptors in treatment. vitro. In clinical trials of major depressive disorder, duloxetine was not associated Diabetes Care 30:21–26, 2007 with weight gain; however, other meta- bolic parameters, such as fasting glucose europathy is the most common di- risk factor for diabetic foot complications and lipids, were not tested (14). abetic microvascular complication, and nontraumatic amputations. Though The clinical trials of duloxetine for N affecting up to 50% of all individu- these late complications frequently occur DPNP provide a large database to evaluate als with diabetes (1). Substantial morbid- in the insensate foot, symptomatic DPN potential metabolic effects of duloxetine ity is associated with diabetic peripheral also significantly impacts quality of life in patients with diabetes. The current neuropathy (DPN), which is the leading (2,3). Estimates of the prevalence of dia- study examined pooled data from both ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● short- and long-term studies to assess From 1Eli Lilly, Indianapolis, Indiana; the 2Department of Internal Medicine, Southwestern Medical Center, changes in weight, glycemia, and plasma University of Texas, Dallas, Texas; the 3Division of Endocrinology, Metabolism, and Diabetes, University of lipids and to test for relationships be- Miami School of Medicine, Miami, Florida; and the 4University Department of Medicine, Manchester Royal tween metabolic changes and baseline Infirmary, Manchester, U.K. clinical factors, as well as the analgesic Address correspondence and reprint requests to Thomas Hardy, MD, PhD, Eli Lilly, Lilly Corporate Center DC 2138, Indianapolis, IN 46285. E-mail: [email protected]. response to duloxetine treatment. Received for publication 10 May 2006 and accepted in revised form 29 September 2006. R.S. has received research grants from and has been a speaker for Eli Lilly. A.J.M.B. serves on an advisory RESEARCH DESIGN AND panel for Eli Lilly. Data from this study were previously published in abstract form in 2004, specifically as “The safety of METHODS — Three randomized tri- duloxetine in the long-term treatment of diabetic neuropathic pain” at the 20th Annual Meeting of the als (each with a 12-week, double-blind, American Academy of Pain Medicine in Orlando, Florida, and as “Duloxetine at doses of 60 mg QD and 60 placebo-controlled acute phase and a 52- mg BID is effective treatment of diabetic neuropathic pain” at the 56th Annual Meeting of the American week, open-label extension phase) were Academy of Neurology in San Francisco, California. Abbreviations: BPI, brief pain inventory; DPN, diabetic peripheral neuropathy; DPNP, DPN pain; FPG, included in these analyses. Entry criteria fasting plasma glucose; TCA, tricyclic antidepressant. and study designs were nearly identical A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion for these large, phase-three clinical trials, factors for many substances. and details of these studies have been pre- DOI: 10.2337/dc06-0947. Clinical trial reg. no. NCT00058968, clinicaltrials.gov. viously published (11–13). Briefly, pa- © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby tients were adults with type 1 or type 2 marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. diabetes and with bilateral peripheral DIABETES CARE, VOLUME 30, NUMBER 1, JANUARY 2007 21 Metabolic parameters in duloxetine DPNP trials Table 1—Baseline characteristics of patients in pooled DPNP studies study. Raw values were used for the anal- ysis of fasting glucose, A1C, weight, and Acute studies Extension studies electrophysiology measures, and rank- transformed data were used for other lab- Duloxetine Placebo Duloxetine Routine care oratory analytes. The change from n 685 339 580 287 baseline to last observation carried for- Age (years) 59.7 60.1 59.4 59.2 ward in fasting glucose and A1C were also Male (%) 42.9 46.6 55.7 56.4 analyzed using subgroups based on base- line BMI (Ͻ30 and Ն30 kg/m2), A1C Caucasian (%) 85.4 85.8 86.0 83.3 Յ Ͼ Type 2 diabetes (%) 87.7 89.4 87.4 87.8 level ( 8 and 8%), and change in status Duration of DPN (years) 4.04 3.85 4.09 3.52 of peroneal F wave (same, better, and Smoking (%) 14.0 13.9 13.4 13.6 worse) using an ANCOVA model with FPG (mmol/l) 9.75 10.09 10.18 10.67 terms for treatment, subgroup, study, and A1C (%) 7.81 7.86 7.74 7.90 subgroup-by-treatment interaction, with Triglycerides (mmol/l) 2.70 2.28 2.44 2.46 baseline score as a covariate. Analysis of LDL cholesterol (mmol/l) 2.95 2.93 3.01 3.02 the primary efficacy variable (24-h aver- HDL cholesterol (mmol/l) 1.19 1.21 1.21 1.23 age pain severity) and one of the second- Total cholesterol (mmol/l) 5.24 5.14 5.26 5.34 ary efficacy variables (BPI interference) was performed using subgroups based on Weight (kg) 94.29 95.03 92.99 94.88 Յ Ͼ Pain severity (0–10 scale) 5.90 5.70 NA NA baseline A1C level ( 8 and 8%) and baseline peroneal F wave (presence or ab- sence), as well as the same ANCOVA neuropathic pain of at least moderate se- MedRA terms. A history of hypoglycemic model terms as previously listed. Categor- verity. Peripheral neuropathy was con- events was taken from patients at each ical data (categorical change in fasting firmed with the Michigan Neuropathy visit. Patients kept a daily diary of average glucose and A1C, diabetes-related ad- Screening Instrument (15). Entry A1C pain severity during the acute-phase stud- verse events, significant hypoglycemic Ͼ12% and major depressive disorders ies (0–10 scale), which was then averaged episode, and shift of status in electrophys- were among the exclusion criteria. on a weekly basis. Interference of pain iology measures) were assessed using the Patients analyzed for this study were with daily activities was measured using Cochran-Mantel-Haenszel test to adjust randomized to placebo or 60 mg dulox- the brief pain inventory (BPI) interference for study. Pearson’s correlation coeffi- etine q.d. or 60 mg b.i.d. during the acute scale (16). Nerve conduction studies were cients (r) were calculated to evaluate cor- phase of treatment. Patients completing performed in two of three studies at base- relations between the continuous 12 weeks of treatment were then re- line and at the conclusion of both the variables of pain severity score and meta- randomized (2:1) to 60 mg duloxetine acute and extension phases using the NC- bolic parameters. Data for all subjects b.i.d. or routine care. In one of the stud- stat automated nerve conduction testing were used for correlations between two ies, some patients were also randomized system (NeuroMetrix, Waltham, MA).