A comparison of the risk of hypoglycemia between users of human and animal insulins. 1. Experience in the United Kingdom

In a case-control study of 121 young insulin-dependent diabetics diagnosed as having an episode of hypoglycemia, the relative risk estimate comparing human with animal insulins was 0.8 (95% confidence interval 0.4, 1.6) controlling for age, general practice, and calendar time. We conclude that in this study population derived from general practices in the United Kingdom, the risk of hypoglycemia was no higher in users of human insulin than it was in users of animal insulins.     

不同胰岛素注射液在糖尿病治疗中的应用研究

目的探讨不同胰岛素注射液在糖尿病患者的治疗中的使用和治疗效果。方法回顾性分析2009年1月—2011年6月我院收治的600例糖尿病患者的临床资料,根据采用治疗的胰岛素的不同将患者分为3组,每组各200例。其中A组采用甘精胰岛素治疗,B组使用精蛋白锌重组人胰岛素混合注射液治疗,C组采用动物源胰岛素治疗。观察三组患者的血糖水平、血糖达标时间、胰岛素日用量及低血糖发生率。结果治疗后3组患者空腹血糖、餐后2h血糖、血糖达标时间、胰岛素日用量及低血糖发生率比较,差异均有统计学意义(P<0.05)。结论使用甘精胰岛素能够起到较好的血糖控制作用,胰岛素用量少,减少低血糖的发生率,有效改善B细胞功能,是治疗糖尿病的良好方法。     

Outcomes and healthcare resource utilization associated with medically attended hypoglycemia in older patients with type 2 diabetes initiating basal insulin in a US managed care setting

Objective: To assess health outcomes and the economic burden of hypoglycemia in older patients with type 2 diabetes initiating basal insulin (BI).

Research design and methods: Medicare Advantage claims data were extracted for patients with type 2 diabetes initiating BI and patients were stratified into two groups: those with medically attended hypoglycemia during the first year of BI treatment (HG group) and those without (non-HG group). Main outcome measures were hospitalization, mortality, healthcare utilization and costs 1 year before and 1 year after BI initiation.

Results: Of 31,035 patients included (mean age 72 years [SD 9.2]), 3066 (9.9%; HG group) experienced hypoglycemia during 1 year post-BI initiation. After adjustment for demographic, comorbidity and medication history, hypoglycemia was associated with risk of hospitalization (HR 1.59; 95% CI: 1.53–1.65) and death (HR 1.50; 95% CI: 1.40–1.60). Healthcare utilization was higher pre-index and showed greater increases post-BI initiation in the HG vs. the non-HG group. Per-patient healthcare costs were substantially higher for the HG group than the non-HG group, both pre-index ($54,057 vs. $30,249, respectively) and post-BI initiation ($75,398 vs. $27,753, respectively).

Conclusions: Based on available claims data, hypoglycemia during the first year of BI treatment is associated with risk of hospitalization or death in older people, increasing healthcare utilization and costs. Due to the observational nature of this study, causality cannot be attributed, and further prospective studies into the effect of hypoglycemia on health outcomes in this population are warranted.     

Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice

This article reviews pharmacokinetic (PK) and pharmacodynamic (PD) concepts relating to the pharmacology of basal insulin analogs. Understanding the pharmacology of currently available long-acting basal insulins and the techniques used to assess PK and PD parameters (e.g. the euglycemic clamp method) is important when considering the efficacy and safety of these agents, and can help in understanding the rationale for specific dosing strategies when tailoring therapy for a specific patient. Basal insulins such as insulin glargine 100 units (U)/mL and insulin detemir show improved PK/PD characteristics compared with the intermediate-acting NPH insulin, with a longer duration of action, a more consistent glucose-lowering effect and less prominent concentration peaks. However, more recently developed basal insulins (insulin glargine 300?U/mL, and insulin degludec 100?U/mL and 200?U/mL) have PK/PD profiles closer to the physiologic profile of endogenous basal insulin owing to a more evenly distributed, predictable and prolonged time–action profile that exceeds 24?hours and improved within-patient variability in glucose-lowering effect. The clinical implications and relevance of these PK/PD profiles is explored, including the potential effect of PK/PD parameters on glycemic control and hypoglycemia, and the timing of dosing. The improved PK/PD properties of newer longer-acting basal insulins may translate into clinical benefits for patients with type 1 and type 2 diabetes, such as more consistent insulin levels in the blood over 24?hours, lower intra-patient variability, a reduced risk of nocturnal hypoglycemia, and more flexibility in dosing time, all of which are important to consider when choosing a basal insulin regimen.     

Intermediate and long-acting insulins: a review of NPH insulin,insulin glargine and insulin detemir

ABSTRACT

Objective: To review intermediate- and long-acting insulins with specific emphasis on the newer insulin analogs.

Methods: A MEDLINE search, in English, was conducted with a cut-off of June 30, 2006, using the terms ‘NPH insulin’, ‘insulin analogs’, ‘insulin glargine’, ‘insulin detemir’ and ‘long-acting insulins’. All clinical trials from within the search period were included.

Results: The insulin analogs, insulin glargine and insulin detemir, were introduced in an attempt to improve glycemic control among patients with diabetes, without increasing the risk of hypoglycemia. This review indicates that both insulin analogs demonstrate better glycemic control than NPH insulin, based on measurements of HbA_1c, fasting glucose and intra-subject variability in blood glucose. This was accomplished with similar or reduced risk of hypoglycemia. Also, insulin detemir appears to be associated with less body weight increase than NPH insulin or insulin glargine.

Conclusion: The newer long-acting insulin analogs, insulin detemir and glargine, appear to provide better glycemic control than NPH insulin without increasing the risk of hypoglycemia.     

Risk of hypoglycemia associated with thyroid agents is increased in patients with liver impairment

OBJECTIVE: To determine the risk of developing hypoglycemia from drugs that affect glucose homeostasis and evaluate the elevation of that risk by liver impairment as judged by a decrease of liver reserve or the severity of abnormal values in liver function tests. METHODS: A hospital-based case-control study was carried out. The base population consisted of all patients aged 20 years and older attending a university hospital in Japan from 2002 - 2004 who had received drugs and serum glucose measurements. Cases were defined as having had at least one episode of hypoglycemia as determined by a serum glucose concentration below 70 mg/dl. Up to 5 controls for each case were matched for the year of serum glucose measurement, out- or inpatient status, clinical departments visited, and age difference within 5 years, taken randomly from the base population without hypoglycemia. The odds ratio for developing hypoglycemia was estimated using conditional logistic regression analysis. RESULTS: From a base population of 10,011, 245 cases and 1,194 controls were enrolled. Of the drugs investigated, levothyroxine use was associated with an increased risk of hypoglycemia in patients with liver impairment (adjusted odds ratio; non-use with normal liver (reference), non-use with liver impairment 0.91 (95% CI 0.62, 1.33), use with normal liver 4.50 (0.58, 34.76), use with liver impairment 14.68 (1.57, 137.4), p for trend 0.007). The risk elevation likely depended on the lowering of liver reserve. CONCLUSION: Clinicians and pharmacists should carefully monitor serum glucose concentrations in levothyroxine users with liver impairment, especially those with lower liver reserve.     

Estimates on the incidence of antidiabetic drug-induced severe hypoglycaemia in Hong Kong

In order to estimate the incidence of severe hypoglycaemia (defined as episodes severe enough to require hospitalization in general medical wards) among known diabetics in Hong Kong in 1990, both the total number of such admissions to the Prince of Wales Hospital and the age and sex distribution and number of known diabetics among its catchment population were defined. The latter was derived from the 1991 census and two studies or the prevalence of diabetes mellitus in Chinese subjects in the New Territories East region in 1987 and 1990. The incidence of severe hypoglycaemia was generally higher in women than in men and in older than in younger subjects. The incidence was 15-19 times higher in subjects aged >or=60 years than in those aged 相似文献   

Insulin analog preparations and their use in children and adolescents with type 1 diabetes mellitus

Standard or 'traditional' human insulin preparations such as regular soluble insulin and neutral protamine Hagedorn (NPH) insulin have shortcomings in terms of their pharmacokinetic and pharmacodynamic properties that limit their clinical efficacy. Structurally modified insulin molecules or insulin 'analogs' have been developed with the aim of delivering insulin replacement therapy in a more physiological manner. In the last 10 years, five insulin analog preparations have become commercially available for clinical use in patients with type 1 diabetes mellitus: three 'rapid' or fast-acting analogs (insulin lispro, aspart, and glulisine) and two long-acting analogs (insulin glargine and detemir). This review highlights the specific pharmacokinetic properties of these new insulin analog preparations and focuses on their potential clinical advantages and disadvantages when used in children and adolescents with type 1 diabetes mellitus. The fast-acting analogs specifically facilitate more flexible insulin injection timing with regard to meals and activities, whereas the long-acting analogs have a more predictable profile of action and lack a peak effect. To date, clinical trials in children and adolescents have been few in number, but the evidence available from these and from other studies carried out in adults with type 1 diabetes suggest that they offer significant benefits in terms of reduced frequency of nocturnal hypoglycemia, better postprandial blood glucose control, and improved quality of life when compared with traditional insulins. In addition, insulin detemir therapy is unique in that patients may benefit from reduced risk of excessive weight, particularly during adolescence. Evidence for sustained long-term improvements in glycosylated hemoglobin, on the other hand, is modest. Furthermore, alterations to insulin/insulin-like growth factor I receptor binding characteristics have also raised theoretical concerns that insulin analogs may have an increased mitogenic potential and risk of tumor development, although evidence from both in vitro and in vivo animal studies do not support this assertion. Long-term surveillance has been recommended and further carefully designed prospective studies are needed to evaluate the overall benefits and clinical efficacy of insulin analog therapy in children and adolescents with type 1 diabetes.     

Insulin therapy in diabetes mellitus: how can the currently available injectable insulins be most prudently and efficaciously utilised?

The era of animal source insulins has passed and human recombinant DNA insulins are gradually being replaced because of the superior efficacy of insulin analogues. Analogue insulins are available in both rapid- and long-acting preparations. Currently available rapid-acting insulins are lispro, aspart and glulisine, and the currently available long-acting analogue basal insulins are detemir and glargine. The rapid-acting insulin analogues are also available in combination with protamine in fixed-dose pre-mixed insulins to provide a more sustained action. The chemical structure, subcutaneous behaviour, time of onset, maximal effect and duration of action of both analogue and human insulins, and how these actions can be best utilised in the diabetic patient are discussed in this review. In addition, strategies where efficacy of the available analogue insulins can be maximally utilised in both type 1 and type 2 diabetes mellitus are described. Maximal utilisation of analogue insulins will result not only in better glycaemic control, but will also minimise the frequency and severity of hypoglycaemic episodes. In addition, maximisation of glycaemic control will result in prevention, delay of onset or amelioration of both the microvascular and perhaps the macrovascular complications of diabetes.     

Cost-effectiveness of switching to insulin degludec from other basal insulins: evidence from Swedish real-world data

Objectives: Health economic analysis from a healthcare and societal point of view was conducted to assess the cost-effectiveness of insulin degludec (IDeg) after switching from other basal insulins in people with type 1 diabetes.

Material and methods: This was a prospective, open-label, single arm, observational follow-up from August 2013 to October 2015 of 476 consecutive patients at Danderyd Hospital (Stockholm, Sweden) who switched to IDeg from other basal insulins (99% basal insulin analogs). The IMS CORE Diabetes Model (CDM) was used to predict the cost-effectiveness of life-long treatment with IDeg vs. other basal insulins, based on a Swedish setting.

Results: Mean (SD) duration of follow-up was 21.7 (6.0) weeks. Mean HbA_1c decreased by 2.7?mmol/mol, mean basal insulin dose decreased by 13.1% (p?p?p?=?.0127) and 53% (p?p?=?.0225). The CDM predicted a gain in life expectancy of 0.33 years, a discounted gain in quality-adjusted life-years (QALYs) of 0.54, and lower estimated direct lifetime healthcare costs of SEK 22,757 for patients switching to IDeg. The incremental cost-effectiveness ratio (ICER) showed IDeg as dominant (i.e. higher effectiveness with a lower cost). Sensitivity analyses confirmed the results.

Conclusion: Based on this prospective, real-world, follow-up and using the CDM, it was estimated that switching to IDeg from other basal insulins translated into QALY gains including improved life expectancy and health-related quality of life, as well as dominant ICER, meaning cost-savings for the healthcare system. However, the study is limited by its observational design. Extrapolation into the future is only estimated since the actual treatment effect cannot be projected with certainty.     

Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs

BACKGROUND: Non-steroidal anti-inflammatory drugs have been implicated in reports of liver injury. However, the precise risk of non-steroidal anti-inflammatory drugs for this rare complication is unknown. AIM: To review systematically the published literature of population-based epidemiological studies reporting the incidence or comparative risk of non-steroidal anti-inflammatory drugs for liver injury resulting in clinically significant events, defined as hospitalization or death. DATA EXTRACTION: Duplicate extraction of the methodological quality, design, source, population, years studied, particular non-steroidal anti-inflammatory drugs studied, definitions, patient counts and follow-up, and the adjustment for confounders. RESULTS: Seven articles met inclusion criteria. The comparative risk of liver injury resulting in hospitalization for current non-steroidal anti-inflammatory drug users compared with past non-steroidal anti-inflammatory drug users ranged from 1.2 to 1.7, but none was statistically significant. The incidence of liver injury resulting in hospitalization ranged from 3.1 to 23.4/100,000 patient-years of current use of non-steroidal anti-inflammatory drugs, with an excess risk compared with past non-steroidal anti-inflammatory drugs users of 4.8-8.6/100,000 patient-years of exposure. There were zero deaths from liver injury associated with non-steroidal anti-inflammatory drugs use in over 396,392 patient-years of cumulative exposure. CONCLUSION: These findings allow for the possibility of a small increase in the risk of clinically relevant hepatotoxicity with non-steroidal anti-inflammatory drugs use, but do not document that such a risk occurs.     

Risk of hospitalization for acute pancreatitis associated with conventional and atypical antipsychotics: a population-based case-control study

STUDY OBJECTIVE: To examine the association of atypical and conventional antipsychotics with the risk of hospitalization for acute pancreatitis. DESIGN: Population-based, case-control study. DATA SOURCE: Health care databases of Northern Denmark. PATIENTS: A total of 3083 adults hospitalized with acute pancreatitis (case patients) and 30,830 control subjects. MEASUREMENTS AND MAIN RESULTS: Controls were selected from the general population by using risk-set sampling and were matched to case patients by age and sex. The date of the case patients' admission for acute pancreatitis was used as the index date for the matched control subjects. Conditional logistic regression analysis was used to estimate rate ratios (RRs) for hospitalization due to acute pancreatitis in current users (0-90 days before admission or index date) and former users (> 90 days before admission or index date) of atypical and conventional antipsychotics compared with nonusers of the respective antipsychotics, while controlling for covariates and stratifying by age. Fifteen case patients (0.5%) were current users of atypical antipsychotics, and 128 case patients (4.2%) were current users of conventional antipsychotics. Adjusted RRs for current use and former use of atypical antipsychotics were 0.6 (95% confidence interval [CI] 0.3-1.1) and 0.3 (95% CI 0.1-0.9), respectively. A trend was noted for increasing risk of hospitalization due to acute pancreatitis with decreasing potency of conventional antipsychotics, with adjusted RRs of 1.2 (95% CI 0.7-2.0) for high-potency, 1.5 (95% CI 1.0-2.2) for intermediate-potency, and 2.8 (95% CI 2.0-3.8) for low-potency conventional antipsychotics, which was largely age-modified with an adjusted RR of 5.2 (95% CI 3.2-8.5) in patients younger than 60 years, compared with an adjusted RR of 1.5 (95% CI 0.9-2.5) in older users. Former use of conventional antipsychotics of any kind was associated with an adjusted RR of 1.6 (95% CI 1.4-1.9). CONCLUSIONS: Current use of low-potency conventional, but not atypical, antipsychotics was associated with an increased risk of hospitalization for acute pancreatitis.     

老年糖尿病人群低血糖风险和抗高血压药物应用的队列研究

目的 了解抗高血压药物应用与服用抗糖尿病(DM)药物治疗的老年DM人群低血糖风险的方法。方法 根据老年DM人群药物使用调查问卷，从我们建立的上海市社区老年DM人群用药监测系统中选取2001年6月至2002年6月服用抗DM药物的老年DM合并高血压者进行回顾性队列研究；以经过医院明确诊断的低血糖事件为观察终点；抗高血压药物相关的低血糖风险用经过校正的相对危险度(RR)表示；采用多个协变量的Poisson回归模型，在控制可能的混杂因素作用的基础上，对RR值进行估计。结果 观察期1a内确诊发生低血糖34例，同时服用抗高血压药物者低血糖发生率(2．76％)高于未服用抗高血压药物者(1．51％)，但经可能的混杂因素校正后，两者差异无显著性[RR=1．98，95％可信区间(CI)0．59～ 6．59]；复方降压片与其他抗高血压药物联合应用可显著增加同时服用磺酰脲类抗DM药物的老年患者低血糖的危险性(RR=6．87；95％ CI，1．01～47．21)；钙拮抗剂、利尿剂、选择性β受体阻滞剂、ACE抑制剂并不增加老年DM患者低血糖风险(P＞0．05)；但其中ACE抑制剂单一用药在抗高血压药物中低血糖发生率最高(4．91％)，对老年DM患者应慎用。结论在老年DM合并高血压的人群中，传统制剂复方降压片可以增加服用磺酰脲降糖药的老年患者的低血糖风险；对于老年DM患者抗高血压药物的选择极为重要，除考虑降压药物本身的疗效外，还应注意降压药对老年DM代谢控制的影响。     

Brand-Name Antidepressants Outperform Their Generic Counterparts in Preventing Hospitalization for Depression: The Real-World Evidence from Taiwan

BackgroundGeneric antidepressants are approved on the market based on evidence of bioequivalence to their brand-name versions. We aimed to assess whether generic antidepressants exert equal effectiveness as their brand-name counterparts for treating patients with depressive disorders.MethodsIn a nationwide, population-based cohort in Taiwan from 1997 through 2013, patients with a diagnosis of a depressive disorder aged between 18 and 65 years who were new users of antidepressant drugs were classified into either the brand-name group or the generic group. All patients were followed up until medication discontinuation or the end of the study period. We assessed the risk for hospitalization as a primary outcome and augmentation therapy, daily dose, medication discontinuation, or switching to another antidepressant as secondary outcomes.ResultsA total of 277 651 brand-name users (35.8% male; mean age: 41.2 years) and 270 583 generic users (35.8% male; mean age: 41.0 years) were divided into 10 different antidepressant groups (fluoxetine, sertraline, paroxetine, escitalopram, citalopram, venlafaxine, mirtazapine, moclobemide, imipramine, and bupropion). We found that patients treated with the generic form of sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine, and bupropion demonstrated significantly higher risks of psychiatric hospitalization (adjusted hazard ratios ranged from 1.20–2.34), compared to their brand-name counterparts. The differences between brand-name antidepressants and their generic counterparts in secondary outcomes varied across different drugs.ConclusionsCompared to most generic antidepressants, brand-name drugs exhibited more protective effects on psychiatric hospitalization for depressive patients. These findings could serve as an important reference for clinicians when encountering patients with depressive disorder.     

Sensitive and fast identification of urinary human,synthetic and animal insulin by means of nano‐UPLC coupled with high‐resolution/high‐accuracy mass spectrometry

The double‐chain polypeptide insulin and its synthetic (Insulin Glulisine, Insulin Aspart, Insulin Glargine, or Insulin Lispro) or animal analogues (porcine insulin or bovine insulin) are potential performance‐enhancing agents in elite sports or potentially effective toxins in forensic science. The present study demonstrates an analytical method to purify the insulins simultaneously from urine specimens with an approach based on immunoaffinity isolation, using coated magnetic beads (anti‐mouse) and a primary anti‐insulin antibody (IgG, monoclonal). The extracts were purified sufficiently for separation by means of nano‐flow liquid chromatography coupled with nano‐scale high‐resolution, high‐accuracy ESI‐MS/MS. Elucidation of collision‐induced dissociations with product ion experiments using the fivefold protonated precursor ion of each target analyte enabled all synthetic and animal insulins to be differentiated from their human counterpart, which was particularly important for Lispro, possessing the same molecular mass as human insulin. The method was fully validated for specificity, limit of detection (LOD, 0.5 fmol/mL), precision (<20%), recovery (approximately 30%) and linearity (2–40 fmol/mL) for all target analytes. Copyright © 2009 John Wiley & Sons, Ltd.     

Efficacy of therapeutic drug monitoring in prevention of hypoglycemia caused by cibenzoline

OBJECTIVE: The purpose of this study was to evaluate the efficacy of our therapeutic drug monitoring (TDM) services in cibenzoline therapy using the risk of hypoglycemia as an end point. METHODS: The TDM services of cibenzoline were introduced in March 1998. If the serum concentrations of cibenzoline deviated from the therapeutic range, adjustment of dosage was recommended. In addition, the physicians were recommended to pay attention to the hypoglycemia induced by cibenzoline. A series of case-control studies were performed before and after introduction of TDM services. After introduction of TDM services of cibenzoline, four case-control studies were performed every 6 months between March 1998 and February 2000 (stage 2 between March 1998 and August 1998; stage 3 between September 1998 and February 1999; stage 4 between March 1999 and August 1999; stage 5 between September 1999 and February 2000) using the same method as in the previous study which had been performed between September 1997 and February 1998 (stage 1). The TDM data of inpatients and outpatients between March 1998 and February 2000 were reviewed. RESULTS: A significantly increased risk of hypoglycemia was observed for users of cibenzoline during stage 1 [crude odds ratio (OR) 10.4; 95% confidence interval (CI) 2.7-40.3], stage 2 (crude OR 3.1; 95% CI 1.0-9.0), and stage 3 (crude OR 3.8; 95% CI 1.2-12.7). However, during stage 4 and stage 5, no significantly increased risk of hypoglycemia was observed. There was no significant difference between the mean doses during stage 1 and stage 5. However, there was a significant difference in the distributions of the trough levels among the four stages. During stage 4 and stage 5, the percentage of samples with a trough level of 200-400 ng/ml was higher than during stage 2 and stage 3. During stage 2, the percentage of samples with a trough level over 400 ng/ml was 42.9%. Furthermore, the risk of hypoglycemia associated with cibenzoline use decreased together with the increase in the percentage of outpatients whose serum concentrations of cibenzoline had been measured in the past. The risk of hypoglycemia associated with cibenzoline use decreased after introduction of TDM of cibenzoline. CONCLUSION: Dose adjustment based on TDM and the physicians' increased recognition of hypoglycemia associated with cibenzoline use were beneficial for those patients treated with cibenzoline in order to prevent hypoglycemia.     

An update on the use of insulin detemir,with a focus on type 2 diabetes (drug evaluation update)

Background: The efficacy and tolerability of insulin detemir (detemir), a long-acting basal insulin analog, is already well documented for type 1 diabetes. This article reviews new evidence, in particular on the weight-sparing effect of detemir and its use in type 2 diabetes. Methods: All clinical trials of detemir published since a 2006 drug evaluation and up to December 2007, including large real-life studies, are covered in this review. Earlier studies are cited when relevant. Results/conclusion: In type 2 diabetes, detemir used once or twice daily achieves equivalent glycemic control to other basal insulins in treat-to-target trials but tends to improve control in patients switched from other basal insulins in basal–oral regimens. The risk of hypoglycemia (nocturnal, overall, or both) is substantially and significantly reduced with detemir compared with NPH insulin. Body weight increase is consistently significantly lower with detemir than with NPH in type 1 and type 2 diabetes. The results of both glucose clamp studies and clinical trials support initiation of detemir at a once-daily dosing regimen.     

Gastrointestinal bleeding rates among managed care patients newly started on cox-2 inhibitors or nonselective NSAIDs

OBJECTIVE: While cyclooxygenase-2 (COX-2) inhibitors were introduced to the U.S. market with the promise of less gastrointestinal (GI) toxicity than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), additional research is needed to examine this outcome in the naturalistic setting. The objective of this study was to examine whether use of COX-2 inhibitors is associated with reduced risk of GI bleed in a managed care population. METHODS: Adult patients in a multistate managed care organization that were initiated on a nonselective NSAID between January 1999 and August 2002 were identified and matched using propensity scoring with patients in the same managed care organization that were initiated on a COX-2 inhibitor. Matching variables included age, gender, geographical state, comorbidity index, corticosteroid use, warfarin use, arthritis indication, and history of recent GI bleed. Patients were followed until they switched or discontinued their NSAID or COX-2 inhibitor, disenrolled from the health plan, developed a GI bleed, or reached the end of the 1-year follow-up period. A GI bleed was defined as an inpatient hospitalization for GI bleed or at least 2 medical claims with a primary diagnosis for GI bleed. The relative risk (RR) of GI bleed was calculated using proportional hazards regression. RESULTS: Overall, 35,007 pairs of COX-2 inhibitor and nonselective NSAID users were evaluated. Mean age was 63 years, and 65% were female. There were 375 cases of GI bleed among 19,201 follow-up years for COX-2 users (19.5 cases per 1,000 person-years) versus 228 cases of GI bleed among 12,680 follow-up years for NSAID users (18.0 cases per 1,000 person-years). The risk of GI bleed was not significantly different for COX-2 users compared with nonselective NSAID users (RR 1.07; 95% confidence interval [CI], 0.90-1.26). Even among high-risk patients, there was no reduction in the risk of a GI bleed among users of COX-2 inhibitors (RR 0.995; 95% CI, 0.84 -1.19). CONCLUSION: Overall, within this managed care population, COX-2 inhibitor users did not have a reduced risk of a GI bleed compared with patients with similar baseline characteristics using nonselective NSAIDs.     

Severe Hypoglycemia Caused by Lenalidomide

Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74‐year‐old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work‐up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26‐day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work‐up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patient's hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patient's development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide.