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OBSERVATIONS Changes in Weight and Glucose Tolerance During Treatment With Mirtazapine
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eight gain is a serious problem with numerous psychotropic drugs (1), and drug-induced weight gain may be associated with health risks typically linked to obesity such as type 2 diabetes. Some second generation antipsychotics are known to lead to weight gain and to impair glucose tolerance (2), but little is known about the influence of weight gain–inducing novel antidepressants such as mirtazapine on glucose tolerance. In a naturalistic study, we assessed weight, glucose tolerance, and plasma levels of insulin and cortisol, which are major players regarding glucose metabolism (3), in 11 inpatients (7 males and 4 females; age [mean ⫾ SD]: 46.7 ⫾ 20.5 years; weight: 73.3 ⫾ 5.5 kg) with major depression according to the ICD-10 and Diagnostic and Statistical Manual of Mental Disorders Fourth Edition receiving mirtazapine during psychiatric hospital treatment of 2– 6 weeks. After the initial baseline examination, mirtazapine treatment was started and the dosage adjusted according to clinical needs. At baseline and at the end of treatment, patients were weighed and underwent an oral glucose tolerance test (OGTT) over 4 h. During treatment with mirtazapine, subjects gained on average 2.17 ⫾ 1.97 kg (t ⫽ 3.65, df ⫽ 10, P ⫽ 0.004). However, basal serum glucose (102 ⫾ 14 vs. 96 ⫾ 6 mg/dl; t ⫽ 2.23, df ⫽ 10, P ⫽ 0.05) and glucose tolerance as measured by 120-min glucose (150 ⫾ 83 vs. 128 ⫾ 83 mg/dl; t ⫽ 2.25, df ⫽ 10, P ⫽ 0.048) and glucose area under the curve during OGTT (df ⫽ 10, P ⫽ 0.028) improved in parallel. Also, 120-min insulin levels decreased during treatment (from 51 ⫾ 27 to 37 ⫾ 34 U/ml; t ⫽ 2.33, df ⫽ 10, P ⫽ 0.042). Indexes of insulin sensitivity (4) showed no statistically significant changes during the treatment period (homeostasis model assessment: from 4.91 ⫾ 1.44 to 5.01 ⫾ 1.19; t ⫽ ⫺0.22, df ⫽ 10, P ⫽ 0.827; Matsuda and DeFronzo index: from 4.42 ⫾ 1.71 to 4.89 ⫾ 2.12, t ⫽
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⫺1.00, df ⫽ 10, P ⫽ 0.339). Cortisol levels did not decrease significantly from baseline to the end of therapy but did between baseline and treatment week 2 (from 195.11 ⫾ 58.29 to 162.98 ⫾ 34.54 g/l; t ⫽ 2.28, df ⫽ 9, P ⫽ 0.049). The present study confirms that treatment with mirtazapine is likely to be associated with weight gain. Although weight gain is expected to impair glucose tolerance, mirtazapine had the opposite effect in the present study. Improved glucose tolerance during treatment with mirtazapine may, at least in part, be mediated by a reduction of cortisol secretion, because cortisol plasma levels are reported to be elevated in depressed patients (5), and it was found that they can be lowered by antidepressant treatment with mirtazapine (6). Usually, depression goes along with a decrease in physical activity, appetite, and food intake but a relative excess of carbohydrates and a preference for sweets (7). Recovery from depression might therefore lead to favorable changes in nutritional preferences and physical activity. Additionally, mirtazapine unfolds ␣-adrenergic antagonism effects by blocking ␣2-receptors (8). It is possible that this ␣-adrenergic antagonism is responsible for the drop in glucose, similar to the effect of the ␣-adrenergic antagonist doxazosin, which has been reported to lead to a decrease in plasma glucose during OGTT without changing the plasma insulin response (9). Depression has been significantly linked with the development of type 2 diabetes (10), making it highly desirable to gain further knowledge on the effect of antidepressants on glucose metabolism. HUBERTUS HIMMERICH, MD1 STEPHANY FULDA, MSC1 LUDWIG SCHAAF, MD1 PIERRE A. BEITINGER, MD1 ANDREAS SCHULD, MD1,2 THOMAS POLLMA¨ CHER, MD1,2 From the 1Max Planck Institute of Psychiatry, Munich, Germany; and the 2Center of Mental Health, Klinikum Ingolstadt, Ingolstadt, Germany. Address correspondence to Prof. Th. Pollma¨cher, MD, Center of Mental Health, Klinikum Ingolstadt, Krumenauer Str. 25, 85049 Ingolstadt, Germany. E-mail:
[email protected]. © 2006 by the American Diabetes Association.
Acknowledgments — The authors thank Irene Gunst and Gabriele Kohl for excellent technical assistance and Dorothea Skottke for help in preparing the manuscript.
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References 1. Zimmermann U, Kraus T, Himmerich H, Schuld A, Pollma¨cher T: Epidemiology, implications and mechanisms underlying drug-induced weight gain in psychiatric patients. J Psychiatr Res 3:193–220, 2003 2. Newcomer JW: Abnormalities of glucose metabolism associated with atypical antipsychotic drugs. J Clin Psychiatry 65 (Suppl. 18):36 – 46, 2004 3. Andrews RC, Walker BR: Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond) 96:513–523, 1999 4. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22: 1462–1470, 1999 5. Holsboer F: The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477–501, 2000 6. Laakmann G, Hennig J, Baghai T, Schule C: Mirtazapine acutely inhibits salivary cortisol concentrations in depressed patients. Ann N Y Acad Sci 1032:279 –282, 2004 7. Kazes M, Danion JM:, Grange D, Pradignac A, Simon C, Burrus-Mehl F, Schlienger JL, Singer L: Eating behaviour and depression before and after antidepressant treatment: a prospective, naturalistic study. J Affect Disord 30:193–207, 1994 8. Gorman JM: Mirtazapine: clinical overview (Review). J Clin Psychiatry 60 (Suppl. 1):9 –13, 1999 9. Giordano M, Matsuda M, Sanders L, Canessa ML, DeFronzo RA: Effects of angiotensin-converting enzyme inhibitors, Ca2⫹ channel antagonists, and ␣-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension. Diabetes 44:665– 671, 1995 10. Musselman DL, Betan E, Larsen H, Phillips LS: Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry 54: 317–329, 2003
Retrospective Review of Metformin in Inpatients and Outpatients at the University of Michigan
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etformin is a hypoglycemic agent that is used in the treatment of type 2 diabetes. It is considered the drug of choice in patients who are overweight with no contraindications to
DIABETES CARE, VOLUME 29, NUMBER 1, JANUARY 2006
Letters its use (1). Metformin has been associated with lactic acidosis. Although metforminassociated lactic acidosis (MALA) is rare, it is fatal in approximately half of all cases. MALA is precipitated by clinical conditions that cause substantial tissue hypoperfusion and hypoxia and thus are identified as precautions and contraindications to its use in package labeling (1,2). Four studies have previously found that metformin is commonly prescribed, despite risk factors, with a range of 24.5– 54% in outpatients and 64 –73% in inpatients (3,5–7). The purpose of our study was to determine the frequency of inappropriate prescribing of metformin to patients with precautions or contraindications at an academic health center and secondarily to compare the findings with previously published studies. This retrospective study was approved by the institutional review board of the University of Michigan. We performed a chart review where 100 inpatients and 103 outpatients were randomly selected from 300 patients who received metformin between January and June of 2003. Patients’ medical records were used to collect demographic data, clinical characteristics, laboratory parameters, and information about contraindications and precautionary conditions. Risk factors for MALA were identified through ICD-9 codes in the clinical data repository, laboratory tests, and medical notes. A power analysis estimated that a sample size of 78 patients in each group was sufficient to detect a 20% difference in the frequency of inappropriate prescribing compared with the frequency (73%) reported by Holstein et al. (␣ ⫽ 0.05,  ⫽ 0.8) (3). A sample size of 100 patients per group was selected for simplicity. Frequencies of inappropriate prescribing were compared with literaturereported rates using Fisher’s exact test (4). Inpatient results were compared with those of Calabrese et al. (5). Outpatient results were compared with those of Emslie-Smith et al. (6). Of 103 outpatients, 3 (2.9%) had contraindications to metformin use. This is significantly lower than the 24.5% incidence of contraindications reported by Emslie-Smith et al. (P ⫽ 0.0001) (6). The contraindication present in all three of these patients was congestive heart failure requiring drug therapy. Of 100 inpatients, 68 (68%) had contraindications or precautionary conditions to metformin use. This incidence of inappropriate prescribing is not signifiDIABETES CARE, VOLUME 29, NUMBER 1, JANUARY 2006
cantly different (P ⫽ 0.2524) from the results of Calabrese et al., who found a similar incidence of 62% of inpatients receiving metformin. In our inpatient sample, the most commonly seen precautions were concomitant cationic drug use and failure to measure serum creatinine before restarting metformin after a surgical procedure. No cases of metabolic acidosis were documented. Approximately 25% of inpatients had more than one precautionary or contraindicating condition; however, there were no patients with more than three risk factors. We have demonstrated that in our health system, prescribing patterns do not conform to the guidelines established by the manufacturer and the Food and Drug Administration. While the incidence of inappropriate prescribing for outpatients is lower than that reported in the literature, inappropriate use of metformin among inpatients is frequent and occurs at a rate similar to that reported in the literature. Frequent metformin use in patients with risk factors was not accompanied by lactic acidosis in our population. Reexamination of these precautionary and contraindicating conditions in light of extensive worldwide experience with metformin could be helpful in more precisely identifying patients who are likely to develop MALA. This would minimize unnecessary avoidance of the drug in patients with type 2 diabetes who could benefit from treatment. HANADY M. SHARABASH, PHARMD1,2 TAMI L. REMINGTON, PHARMD2 PETER MAR, PHARMD2 RALPH WINSTON, PHARMD2 PAUL C. WALKER, PHARMD2 From the 1Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois; and the 2Department of Pharmacy, University of Michigan Hospitals and Health Centers, College of Pharmacy, Department of Clinical Sciences, University of Michigan, Ann Arbor, Michigan. Address correspondence to Hanady Sharabash, 1812 S. Clark St. #13, Chicago, IL 60616. E-mail:
[email protected]. © 2006 by the American Diabetes Association. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
References 1. Glucophage package insert. Princeton, NJ, Bristol-Myers Squibb, 2001 2. Bailey CJ, Turner RC: Drug therapy: metformin. N Engl J Med 334:574 –579, 1996 3. Holstein A, Nahrwold D, Hinze S, Egberts EH: Contraindications to metformin therapy are largely disregarded. Diabet Med 16:692– 696, 1999 4. Chap TL: Introductory Biostatistics. Hobo-
ken, NJ, John Wiley & Sons, 2003 5. Calabrese AT, Coley KC, Dapos SV, Swanson D, Rao HR: Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med 162:434 – 437, 2002 6. Emslie-Smith AM, Boyle DR, Evans JM, Sullivan F, Morris AD: Contraindications to metformin therapy in patients with type-2 diabetes a population based study of adherence to prescribing guidelines. Diabet Med 18:483– 488, 2001 7. Sulkin TV, Bosman D, Krentz AJ: Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 20: 925–928, 1997
The Peroxisome Proliferator– Activated Receptor␥2 P12A Polymorphism and Type 2 Diabetes in an Arab Population
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he association of type 2 diabetes with the P12A polymorphism of the peroxisome proliferator–activated receptor gene (PPAR-␥2) has been established in several populations (1). However, no studies have thus far been reported for Arab populations. While many variants have been identified in this gene, the most prevalent and best studied is the P12A polymorphism. There is considerable interpopulation variance in the incidence of the risk allele (P12). This ranges in frequency from a high of 0.96 – 0.98 in populations including the Japanese, Chinese, and African Americans to 0.91 in Pima Indians and a low of 0.81 in the Finnish population (2). We utilized a case-control study to test association of the PPAR-␥ P12A variant with type 2 diabetes in an Arab (Saudi) population for the first time. Genotyping was performed using a molecular beacon– based real-time PCR assay developed in our laboratory and validated in ⬎100 samples by direct sequencing. The study population consisted of 1,137 individuals of Saudi ancestry with type 2 diabetes as defined by World Health Organization criteria and ranging in age from 20 to 85 years. The control group consisted of 219 individuals of Saudi ancestry ⬎60 years old (range 60 –92 years) having a fasting blood glucose ⬍7 mmol/l. The control 171
