, Dr. Finkelstein and Dr. Brown wrote an editorial

 in response to our study on the return on investment (ROI) to bariatric surgery.

 We thank Drs. Finkelstein and Brown for their thoughtful comments and outline below our responses to their critiques. 

First, and perhaps most importantly, we agree with Drs. Finkelstein and Brown that, in an ideal setting, the decision to cover bariatric surgery should be based on the health benefits associated with the surgery rather than the speed of cost recovery. As they correctly point out, the standard we apply to bariatric surgery (full ROI) is not applied to heart disease, cancer, or diabetes treatments. Instead, the costs of treatment, whether pharmacologic or surgical, are evaluated against the benefits to patients. Our stricter standard does not consider benefits to the patients in calculating the ROI; instead, we focused exclusively on the economic return to the payer. The reality is that such ROI calculations are employed by third-party payers to determine coverage, and that pointing out the positive ROI might help focus third-party payers on the clinical benefits of the intervention, which Drs. Finkelstein and Brown correctly point to as the appropriate standard to apply in coverage decisions. 

The editorial raises 3 methodological critiques. First, it questions the robustness of our findings because of limited long-term postoperative data, especially for laparoscopic patients. Second, the editorial observed that the cost savings could be the result of the worsening health of the control group rather than the improved health of the surgery patients. Finally, the editorial argues that a few patients with catastrophic outcomes could overturn our results. 

We are fully confident that the results reported in our study are robust. We have tested the robustness of our findings by estimating alternative forms of models, including a 2-part model, alternative controls for comorbidities, additional and alternative time-related controls, alternative statistical corrections for standard errors, and multivariate analyses that omit matching but control for all 18 comorbidities and baseline costs directly in the model. All these robustness analyses yield results that fall within the range of ROIs reported in our analysis. In addition, since the publication of our article, we have received a significant update to our claims database, resulting in an additional 1200 surgery patients and an additional year (2006) of study data. This extends our postoperative data to 2.5 years for laparoscopic procedures and 7 years for open procedures. The resulting ROI was 29 months for  laparoscopic surgery and 44 months for open surgery, well within the range of values reported in our paper. Based on these supplementary analyses, we believe that our results are robust.

Our data were limited to a few years even though patients may live 30 years postsurgery. Therefore, our study did not address the long-run uncertainty (beyond 7 years) of surgery cost savings. Of course, this is equally true for the control population. As was pointed out by Drs. Finkelstein and Brown, the morbidly obese control population is getting sicker and more expensive to treat relative to the surgery population as time elapses. These trends are likely to endure beyond the observed period as well.

Drs. Finkelstein and Brown comment that cost savings result from an increase in costs among the control group rather than a cost decrease among surgery patients. Although part of the cost gap between the surgery group and the control group resulted from increased costs for nonsurgery patients, costs for surgery patients do fall relative to presurgery costs. This finding demonstrates that bariatric surgery improves patient conditions and lowers costs both relative to presurgery conditions and to the morbidly obese control population. 

Finally, we do not believe that a few patients with catastrophic outcomes could overturn the results. Our analysis included all medical costs, including any costs associated with complications or catastrophic outcomes on both sides. Furthermore, our sample size was large. Our published analysis is based on a sample of more than 3600 surgery patients and their controls, and our updated sample includes more than 4800 surgery patients and their controls. No single patient or single set of catastrophic outcomes for a patient will significantly affect our results given the size of the sample.

2. CrÃ©mieux PY, Buchwald H, Shikora SA, Ghosh A, Yang HE, Buessing M

. A study on the economic effects of bariatric surgery. 

Articles

LETTERS TO THE EDITORS

Return on Investment for Bariatric Surgery

 To examine the cost-effectiveness of analogs versus human insulins, citing primarily studies conducted in the United States.

 The use of insulin analogs in type 1 and type 2 diabetes mellitus provides a better balance between glycemic control and hypoglycemia compared with human insulins, with the resultant potential to reduce the costs of treatment of hospitalization and chronic complications. The lower incidence of hypoglycemia seen with analogs versus human insulins may help to overcome barriers to insulin acceptance among patients with type 2 diabetes mellitus. In type 2 diabetes mellitus, prompt initiation or intensification of insulin therapy could save costs by delaying the development of complications. 

 The cost-effectiveness of analogs was analyzed through a literature review. Searches were conducted in PubMed to identify articles in the past 5 years with the name of any insulin analog plus the word cost or economic in the title or abstract. American Diabetes Association abstracts for 2005 to 2007 were also searched. 

 Pharmacoeconomic modeling studies have consistently shown that insulin analogs provide gains in quality-adjusted life-years at costs well below accepted cost-effectiveness limits. In these studies, increased prescription costs were offset by reductions in complications. Retrospective analyses of healthcare databases have also shown cost-effectiveness for analogs versus human insulins, primarily because of lower inpatient care costs.

 Treatment with insulin analogs has been demonstrated to be cost-effective versus other options over time and is an appropriate investment of healthcare dollars.

Treatment of type 1 and type 2 diabetes mellitus with insulin analogs is cost-effective versus other options over time.

Insulin analogs versus conventional human insulins improve the balance between glycemic control and hypoglycemia.

In type 2 diabetes mellitus, the use of analogs can help to overcome some of the barriers to insulin use. Prompt initiation or intensification of insulin therapy and adherence to an insulin regimen will delay or prevent the development of diabetes complications.

Pharmacoeconomic models and retrospective analyses of healthcare databases have demonstrated the cost-effectiveness of analogs.

It is well known that the costs of diabetes mellitus (DM) are high. The American Diabetes Association (ADA)

 estimated that in the United States the 2007 costs for DM were $174 billion, composed of $116 billion in direct medical expenditure and $58 billion attributed to lost productivity. The ADA also estimated that healthcare costs are more than doubled when DM is present.

Much of this increased expenditure is accounted for by the complications of DM.

 Landmark clinical trials such as the Diabetes Complications and Control Trial and follow-up studies and the United Kingdom Prospective Diabetes Study have shown that improving glycemic control reduces microvascular and macrovascular complications.

 For example, it is estimated that every 1% decrease in glycosylated hemoglobin (A1C) level is associated with a 37% reduction in microvascular events and a 21% reduction in DM-related mortality (

 These are epidemiological associations and not causality studies; nevertheless, on the basis of these and similar studies, leading entities such as the ADA

 and the American Association of Clinical Endocrinologists

 have recommended target maximum levels for A1C. However, surveys have shown that in the United States many patients fail to achieve these targets.

The costs of DM include direct and indirect costs. Among the direct costs, the cost of the drugs alone is estimated to account for only 10% to 20%, with a much larger proportion of the direct costs being contributed by the costs of healthcare services directly related to DM or associated with complications of DM. For example, a breakdown of DM costs in the United States in 2007 assigned amounts as follows: $27.7 million for outpatient medication and supplies, $65.8 million for institutional care, and $22.7 million for outpatient care.

Indirect costs of DM cover aspects such as lost productivity. Drug treatment that improves glycemic control can reduce the costs of DM, primarily by delaying or preventing the complications of the disease and the associated morbidity and mortality. This was illustrated by a study

 in which the authors reviewed cost-benefit analyses for 17 DM interventions, with reduction of A1C level shown to be cost-effective. In that study, Klonoff and Schwartz

 noted that intensive insulin therapy (&#8805;3 insulin injections/d, with dose adjustments based on frequent glucose monitoring) was cost-effective versus conventional therapy (1-2 insulin injections/d, with less stringent glucose goals), based on the results of interventional studies

that used human insulins (analogs were unavailable at the time).

Many patients with type 2 DM will eventually need insulin as their disease progresses and as they become unable to maintain glycemic control using oral antidiabetic drugs (OADs). However, patient acceptance of insulin use is still low, due in part to injection phobias and concerns related to adverse effects such as hypoglycemia or weight gain.

In recent decades, insulin analogs have been developed with the aim of overcoming some of the disadvantages of conventional human insulins. Analog molecules resemble human insulins except for small changes in amino acid sequence or the addition of a fatty acid chain, which results in different pharmacokinetic and pharmacodynamic profiles. The analogs can be used in regimens that mimic the action of endogenous insulin more closely and provide a less variable and more consistent effect than conventional human insulins. The available insulin analogs are listed in 

In this article, evidence is reviewed about the cost-effectiveness of insulin analogs compared with human insulins, primarily using pharmacoeconomic studies conducted in US settings. Despite the well-established acceptance of insulin analogs by clinicians and patients, such studies are important because the higher initial cost of analogs versus conventional insulins means that their value has to be demonstrated to payers and to authorities. This review presents a brief description of the clinical benefits of insulin analogs and how these may help to overcome barriers to insulin acceptance, followed by an overview of pharmacoeconomic studies that were available as of 2007.

Insulin analogs have consistently been shown to improve the balance between glycemic control and tolerability (in terms of hypoglycemia) in type 1 and type 2 DM compared with human insulins. A detailed overview was published by Gough.16 Some representative studies

comparing insulin analogs with human insulins are summarized in 

. These trial durations ranged from 12 to 26 weeks. 

In type 1 DM, lower A1C and postprandial glucose levels were achieved with rapid-acting analogs versus human insulins, and hypoglycemia risk was reduced. With basal analogs, A1C levels were generally similar to those achieved with conventional insulins, as the studies were treat-to-target trials in which insulin doses were titrated upward to reach prespecified target glycemic values. However, hypoglycemia risk was reduced by treatment with analogs.

In type 2 DM, studies were generally treat-to-target trials, and A1C levels were similar for analogs versus conventional insulins, but hypoglycemia was lower with analogs. Therefore, cost-savings can result if the incidence of hypoglycemia requiring treatment is reduced (discussed herein in the &#8220;Retrospective Analyses of Databases&#8221; section) and, in the longer term, if preventing complications of DM is obtained through better glycemic control.

In type 2 DM, patients may be unwilling to initiate or intensify insulin therapy, exhibiting so-called psychological insulin resistance. This reluctance to use insulin is based on factors that include a perception of failing in their disease control efforts, fear of hypoglycemia and weight gain, and needle anxiety.

 However, prompt initiation or intensification of insulin therapy is vital to delay or reduce the development of complications. Analogs may have a role in overcoming psychological insulin resistance, as discussed herein.

The reputed potential for hypoglycemia is widely believed to be a major barrier to insulin acceptance by patients.

For example, 41% of respondents in a study

 agreed that possible hypoglycemia might explain the reluctance to begin insulin therapy. However, analogs are associated with less frequent and less severe hypoglycemia,

which may encourage patients to accept and adhere to insulin therapy from an earlier stage. In terms of weight gain, the insulin analog insulin detemir has been associated with slightly less weight gain than conventional insulins. In studies

of patients with type 2 DM, weight gain was slightly but significantly less with detemir than with neutral protamine Hagedorn (NPH) insulin.

Observational studies of insulin analogs reveal an important aspect of treatment outcomes not fully illuminated by controlled clinical trials, namely, adherence to therapy. Adherence to DM therapy has been shown to be cost-saving: a 10% increase in adherence is estimated to be associated with up to a 29% decrease in annual healthcare costs, primarily because better adherence is associated with fewer hospital visits.

Compact, prefilled, disposable pen devices are available for use with all insulin analogs. Human insulins are available in prefilled and refillable pens. These pen devices can help to overcome needle anxiety because they are easier to use, are more discreet than needles and syringes, are typically not painful, and are preferred by patients compared with standard needles.

 in the United States found that adherence improved and rates of hypoglycemia and total annual costs per patient decreased after patients switched from vial and syringe to an insulin analog pen device. Total annual cost-savings were $1590 per patient, of which $788 were hypoglycemia-related cost-savings and $600 were other DM-related cost-savings (

 <.01 for all compared with the use of vials and syringes before the switchover).

Insulin analogs have also been shown to improve patients&#8217; health-related quality of life (QOL) relative to human insulins.

Because QOL is an important determinant of adherence, 43 this is another factor that may result in improved adherence to analog use and may lower expenses related to poor compliance with or delayed adoption of insulin therapy. Finally, the rapid-acting insulin analogs are suitable for pump therapy, which allows patients to achieve similar or better glycemic control relative to human insulins.

Insulin analogs are more expensive to the payer than human insulins. Although the cost of medication may be higher, there may be reductions in more expensive long-term expenditures such as the costs related to treatment of hypoglycemia or chronic complications of DM.

Unlike clinical end points, cost-effectiveness cannot readily be measured using clinical trials because the required time span is too long and there are too many confounding variables that cannot be controlled. Therefore, pharmacoeconomic models are frequently used to compare the effect of 2 or more strategies (eg, drug A vs drug B or drug A vs no intervention) on long-term clinical and cost outcomes. The models may assess direct costs, indirect costs, or both and may calculate costs from different perspectives such as that of the payer (patient, managed care organization, healthcare authority, etc) or of society. The results of models may show that an intervention (drug A) is cost-saving when its use actually results in lower costs than the use of an alternative (drug B or no intervention). Alternatively, the results may suggest that drug A is cost-effective versus drug B or no intervention when its use results in higher costs but in an improved outcome for patients. In the latter case, the number of life-years gained by an intervention is adjusted to allow for QOL and is expressed as quality-adjusted lifeyears (QALYs). Cost-effectiveness is then expressed as an incremental cost-effectiveness ratio (ICER) (ie, the cost per QALY gained with drug A).

ICERs are relative values and can only be quoted for the intervention of interest (drug A) and not for the reference standard (drug B or no intervention) against which it is being measured. The lower the cost per QALY, the more cost-effective the treatment. In the United States, an ICER of $50,000 to $100,000 per QALY is typically deemed as acceptable, although these limits are not fixed and can vary according to many factors such as disease burden and societal expectations. For example, payers may decide that it is acceptable to provide a drug that costs more than $100,000 per QALY if it is effective in a rare disease that affects young patients. For an intervention that will be widely required by older patients, a more stringent ICER cutoff such as $30,000 per QALY may be applied.

Pharmacoeconomic models have several disadvantages. There may be a lack of good-quality clinical data, requiring the use of results from small trials or expert opinion. The observational data used may be biased. Assumptions have to be made, and these may be (intentionally or not) too conservative or too optimistic. Finally, it may be difficult to extrapolate data from one patient population to another. A good model must be transparent (ie, users must have access to how it works and the data sources used, and any assumptions made must be clearly explained). It should also be externally validated (ie, shown to predict accurate results in scenarios in which the real outcomes are known). The uncertainty arising from the need to make assumptions must be explored through sensitivity analyses in which the effect of varying the assumptions is explored.

Many of the modeling studies that were identified for the present analysis examined the cost-effectiveness of different strategies in type 1 and type 2 DM using the CORE Diabetes Model,

 an interactive Internet-based computer model that allows the calculation of long-term outcomes in different patient populations in realistic clinical settings. Users of the model are able to enter data about the baseline characteristics, history, and future management of the population under study. Development of complications, life expectancy,  QALYs, and total costs are then calculated by the model. The key treatment effects included in the model are clinically relevant results seen in trials, primarily reductions in A1C levels and hypoglycemia rates. The CORE Diabetes Model was validated by comparing results from model simulations with observed outcomes from published epidemiological and clinical studies in type 1 and type 2 DM.

It is important to note that model results cannot always be directly extended to other countries because of differences in healthcare systems and costs. Despite these limitations, strong similarities in trends are often mirrored across different countries, as would be expected if one intervention provides real clinical advantages versus another. The results of the pharmacoeconomic modeling studies analyzed in the present review follow.

. Three pharmacoeconomic modeling studies (1 study

of type 2 DM) were identified that compared analogs with human insulins in a US context (Table 3). Representative studies from other countries are also given in Table 3. The data reported for US studies and for non-US studies demonstrate that analog treatment regimens were associated with ICER values that indicate cost-effectiveness.

In type 1 DM, detemir was shown to be cost-effective versus NPH insulin and glargine when considered during a 35-year horizon in the United States.

 The cost per QALY gained with detemir relative to NPH insulin was $14,974 when direct costs were considered.

In type 2 DM, it was calculated that detemir would reduce costs by $2020 versus NPH insulin during 10 years in a US context, largely through anticipated reductions in complications, notably nephropathy and retinopathy.

 Projected during a 35-year period, an ICER of $6269 per QALY was calculated for patients switching to detemir (with or without OADs) from NPH insulin (with or without OADs).

 In these studies, the treatment effects of detemir were based on results from the German cohort of the Predictable Results and Experience in Diabetes Through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE) study,

 a large real-life observational trial that included more than 1800 patients with type 2 DM.

of insulin analogs in type 1 or type 2 DM conducted in Canada, the United Kingdom, or 7 European countries show ICER values associated with cost-effectiveness at levels comparable to those measured in the US studies (Table 3). Because healthcare delivery in those countries is not similar to the US system, the collective pharmacoeconomic modeling data strengthen the point that insulin analogs are costeffective.

Analogs Versus OADs. The cost-effectiveness of insulin analogs used to replace or enhance OAD regimens in type 2 DM has been examined using pharmacoeconomic modeling in a US context (

An ICER of $657 per QALY was calculated for patients switching to detemir from OADs during a 10-year period.

 During a 35-year period, a cost of $7412 per QALY was calculated for patients switching to detemir (with or without OADs) from OADs alone. Similar to the comparisons versus NPH insulin, these models used results from the German arm of the PREDICTIVE observational study,

 and the low ICERs resulted largely from reductions in DM complications.

considered the use of biphasic insulin aspart 70/30. Regimens of biphasic insulin aspart 70/30 plus an OAD were compared with OAD regimens over a lifetime perspective. In the first study,

 total lifetime direct costs were higher with biphasic insulin aspart 70/30 plus metformin than with an optimized OAD regimen. However, the use of biphasic insulin aspart 70/30 was projected to result in reduced complications, particularly nephropathy (one of the costliest DM-related complications); this resulted in an ICER of $8487 per QALY gained for biphasic insulin aspart 70/30 plus metformin versus the optimized OAD regimen.

When a regimen of biphasic insulin aspart 70/30 plus a thiazolidinedione was compared with a sulfonylurea plus a thiazolidinedione, the cost per QALY was $25,400.60 In another study,58 the addition of biphasic insulin aspart 70/30 to metformin plus pioglitazone hydrochloride was cost-effective versus metformin plus pioglitazone hydrochloride during a 35-year period, with a projected cost per QALY of $22,209.

In all of these studies versus OADs, the use of an insulin analog resulted in increased prescription costs, but these were offset by reductions in complications. This finding underlines the importance of achieving effective glycemic control as early as possible.

compared an analog with OADs in type 2 DM using a different approach. Direct drug costs were calculated based on the mean daily doses of the different drugs at the end of a clinical trial.

 evaluating the efficacy and safety of add-on glargine versus rosiglitazone maleate in insulin-naive patients with type 2 DM inadequately controlled on therapy with a sulfonylurea plus metformin. The improvements in A1C level from baseline were similar in both groups, but there was less weight gain with glargine (

 = .02). The mean cost of all antihyperglycemic medications and resources during the 24 weeks was $1368 with glargine and $1603 with rosiglitazone; therefore, the mean cost of glycemic control was $235 lower with glargine.

In the second study,70 costs were estimated based on drug dosages at the end of a 16-week clinical trial of patients receiving biphasic insulin aspart 70/30 plus metformin versus patients receiving 1 or more OADs titrated by their clinicians to optimize glycemic control.

 Direct pharmacy costs were higher for the biphasic insulin aspart 70/30 group. With the biphasic insulin aspart 70/30 regimen, significantly more patients achieved an A1C level of 7.0% or less (

 <.02). These patients were considered successfully treated; the mean annual cost for each successfully treated patient was $896 lower with biphasic insulin aspart 70/30.

. Lifetime costs of complications resulting from type 2 diabetes in the US. 

4. Writing Team for the DCCT/EDIC Research Group

. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. 

. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. 

8. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force

. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. 

10. Greisinger AJ, Balkrishnan R, Shenolikar RA, Wehmanen OA, Muhammad S, Champion PK

. Diabetes care management participation in a primary care setting and subsequent hospitalization risk. 

12. Diabetes Control and Complications Trial Research Group

. Lifetime benefits and costs of intensive therapy as practiced in the Diabetes Control and Complications Trial [published correction appears in 

14. Mollema ED, Snoek FJ, Pouwer F, Heine RJ, van der Ploeg HM

. Diabetes Fear of Injecting and Self-Testing Questionnaire: a psychometric evaluation. 

. A review of human and analogue insulin trials. 

18. Home PD, Lindholm A, Riis A; European Insulin Aspart Study Group

. Insulin aspart vs. human insulin in the management of longterm blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. 

20. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA; U.S. Study Group of Insulin Glargine in Type 1 Diabetes

. Less hypoglycaemia with insulin glargine in intensive insulin therapy for type 1 diabetes. 

22. Hermansen K, Fontaine P, Kukolja K, Peterkova V, Leth G, Gall MA

. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. 

24. Riddle M, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators

. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. 

26. Anderson JH Jr, Brunelle RL, Keohane P, et al; Multicenter Insulin Lispro Study Group

. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with nonâ€“insulin-dependent diabetes mellitus. 

28. Boehm BO, Home PD, Behrend C, Kamp NM, Lindholm A

. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in type 1 and type 2 diabetic patients [published correction appears in 

. When oral agents fail: practical barriers to starting insulin. 

33. Polonsky WH, Fisher L, Guzman S, Villa-Caballero L, Edelman SV

. Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem. 

35. Horvath K, Jeitler K, Berghold A, et al

. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. 

. Does insulin detemir have a role in reducing risk of insulin-associated weight gain? 

39. Korytkowski M, Bell D, Jacobsen C, Suwannasari R; FlexPen Study Team

. A multicenter, randomized, open-label, comparative, twoperiod crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial/syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. 

41. Bott U, Ebrahim S, Hirschberger S, Skovlund SE

. Effect of the insulin analogue insulin aspart on quality-of-life and treatment satisfaction in type 1 diabetic patients. 

. Quality of life, perceived difficulties in adherence to a diabetes regimen, and blood glucose control. 

45. Raskin P, Holcombe JH, Tamborlane WV, et al

. A comparison of insulin lispro and buffered regular human insulin administered via continuous subcutaneous insulin infusion pump. 

. Modelling cost effectiveness of insulin glargine for the treatment of type 1 and 2 diabetes in Canada. 

49. Palmer AJ, Roze S, Valentine WJ, Smith I, Wittrup-Jensen KU

. Costeffectiveness of detemir-based basal/bolus therapy versus NPH-based basal/bolus therapy for type 1 diabetes in a UK setting: an economic analysis based on meta-analysis results of four clinical trials. 

. Projecting the economic and health outcome effects of basal insulin among type 2 patients in clinical practice settings [abstract]. 

53. McEwan P, Poole CD, Tetlow T, Holmes P, Currie CJ

. Evaluation of the cost-effectiveness of insulin glargine versus NPH insulin for the treatment of type 2 diabetes in the UK. 

55. Palmer AJ, Roze S, Valentine WJ, et al

. The CORE Diabetes Model: projecting long-term clinical outcomes, costs and cost-effectiveness of interventions in diabetes mellitus (types 1 and 2) to support clinical and reimbursement decision-making. 

57. Meneghini CF, Rosenberg KH, Koenen C, Merilainen MJ, Lilddeke HJ

. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. 

. Estimating the long-term cost-effectiveness of biphasic insulin aspart plus metformin versus optimization of oral hypoglycemic agents in insulin-naive patients with type 2 diabetes in a US cost setting [poster]. 

61. Bullano MF, Al-Zakwani IS, Fisher MD, Menditto L, Willey VJ

. Differences in hypoglycemia event rates and associated cost-consequence in patients initiated on long-acting and intermediate-acting insulin products. 

. Incremental cost savings 6 months following initiation of insulin glargine in a Medicaid fee-for-service sample. 

65. Miller DM, Gardner J, Hendricks A, Fincke G, Zhang Q

. Changes in health care utilization and expenditures associated with insulin glargine use [abstract]. 

. Cost and utilization comparisons among propensity scoreâ€“matched insulin lispro and regular insulin users. 

69. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak E, Dailey G

. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients. 

71. Ushakova O, Sokolovskaya V, Morozova A, et al

. Biphasic insulin aspart 30 (NovoLog Mix 70/30), a premix analogue, is an effective and well tolerated starter insulin in type 2 diabetes [abstract]. 

REVIEW ARTICLE

This review shows that insulin analogs are cost-effective versus human insulins based on pharmacoeconomic models and retrospective database analyses.

Cost-Effectiveness of Insulin Analogs

 To review literature on the impact of bipolar disorder on the workplace, with respect to costs to employers, workplace productivity and functioning, and any employer-initiated programs implemented with the aim of improving work attendance and performance.

 Original studies relating to bipolar disorder in the workplace were identified from PubMed and EMBASE using a reproducible, systematic search strategy in July 2007. There were no constraints on publication dates. Results were first evaluated by title and/or abstract. Full manuscripts of potentially relevant papers then were obtained and assessed for inclusion. Productivity data were extracted in terms of absenteeism, short-term disability, presenteeism, and any associated cost burden to US employers. 

 Seventeen studies met search criteria and were included in this review. The data indicate that bipolar disorder imposes a significant financial burden on employers, costing more than twice as much as depression per affected employee. A large proportion of the total cost of bipolar disorder is attributable to indirect costs from lost productivity, arising from absenteeism and presenteeism. The presence of comorbid conditions and stigma in the workplace may lead to delays in accurate diagnosis and effective management of bipolar disorder.

 Bipolar disorder among the working population can have a significant, negative effect on work relationships, attendance, and functioning, which can lead to substantial costs to US employers arising from lost productivity. There is a need for workplace initiatives to address the health and cost consequences of bipolar disorder within an employed population.

Bipolar disorder has a considerable impact on the workplace and imposes a substantial financial burden on employers.

Indirect costs from lost productivity are a significant driver of the costs associated with bipolar disorder because of the increased rates of absenteeism and reduced productivity among employees with the condition.

Misdiagnosis and delays in seeking professional help are common and contribute to this burden.

There is a need for employer-initiated programs that may reduce indirect costs by ensuring early, accurate diagnosis and effective management, reducing stigma in the workplace, and encouraging better occupational relationships.

Bipolar disorder (BPD; also known as manic-depressive disorder) is a chronic mental illness characterized by recurrent, dramatic mood changes.

 Individuals with BPD cycle between a range of emotions that disrupt phases of near-normal behavior, often alternating between intense feelings of exhilaration (manic episodes) and sadness (depressive episodes).

Manic episodes are characterized by a euphoric state of mind and are associated with feelings of elation, grandiosity, impulsiveness, hyperactivity, distractibility, irritability, and excessive libido.

 Conversely, depressive episodes are associated with feelings of despair, hopelessness, lethargy, guilt, anxiety, violence, and suicidal ideation and activity.

 Some people with BPD experience mixed episodes, with both manic and depressive features.

Bipolar disorder, especially the depressive phase, is associated with high levels of morbidity, disability, and premature mortality.

 In 2000, the World Health Organization estimated that BPD was the fifth leading cause of disability worldwide among young adults (ie, 15-44 years of age).

 In the United States, the lifetime prevalence of BPD is estimated at 3.7%.

Bipolar disorder has a substantial effect on many aspects of a patient&#8217;s life and is a source of significant economic burden.

 The achievement of academic and occupational ambitions is impeded from an early age because the onset of BPD generally occurs during adolescence or early adulthood and the illness continues for the remainder of a patient&#8217;s working life.

Impaired functioning may remain for many patients even after BPD symptoms subside during a remission.

The objective of this review was to identify the impact of BPD on the workplace, with respect to costs to employers, workplace productivity and functioning, and any employer-initiated programs or management strategies implemented to improve work attendance and performance.

Systematic searches of PubMed and EMBASE were performed to identify studies addressing the impact of BPD in an employed population. This search was conducted as part of a wider review into the impact of mental illness in an employed population. Publications were retrieved in July 2007 using a reproducible search strategy, which included search terms such as absenteeism, bipolar disorder, disability, employee, employer-initiated programs, household earnings, presenteeism, and productivity. There were no constraints on publication dates.

References were imported into a database (EndNote, version X1, Thomson ResearchSoft, Carlsbad, CA), and duplicates were deleted. The results were then evaluated by title and/or abstract with the aim of rejecting any not written in English and selecting those specific to working adults and relevant to workplace productivity. Full manuscripts of potentially relevant papers were obtained and assessed for inclusion. Articles were included if they quantifiably measured productivity outcomes or provided examples of  employer-initiated programs to improve workplace performance. US papers were extracted and included in this publication.

. Lost productivity due to BPD imposes a significant economic burden on employers. A study analyzing data from 6 large US corporations found BPD to be the most expensive mental health condition in terms of medical care and lost productivity.

 The study utilized the MEDSTAT MarketScan Health and Productivity Management Database containing person-level information on nearly 375,000 individuals employed by the corporations between 1997 and 1999 and found that the cost of chronic maintenance of BPD (US $64.10 per eligible employee) was 2.5-fold greater than the cost of the next most expensive mental health condition, depression ($24.02).

 Indirect costs due to work absences and short-term disability losses accounted for 51% and 50%, respectively, of each of these costs.

 Treatment of severe depressive and manic episodes of BPD also ranked third ($22.70) and eighth ($2.71), respectively, in the top-10 list; 58% and 50% of each cost was attributed to work absences and short-term disability losses, respectively.

In 1991, the National Institute of Mental Health estimated the annual cost of BPD to the United States as $45 billion, of which only $7 billion was estimated to be direct treatment costs.

 The remaining $38 billion of indirect costs included lost productivity of wage earners ($18 billion), homemakers ($3 billion), institutionalized patients ($3 billion), individuals who committed suicide ($8 billion), and caregivers of BPD family members ($6 billion).

Individuals with BPD also incur a substantial burden of general medical comorbidity. A retrospective analysis of data extracted from the Human Capital Management Services Research Reference Database between 2001 and 2002 revealed that BPD is associated with multiple, costly, comorbid conditions, both mental (eg, affective disorders, schizophrenia, dissociative/ personality disorders) and physical (eg, endocrine, metabolic, immunity, and circulatory disorders).

 Bipolar disorder also was associated with significantly greater costs in the poisoning/medical/drugs category, which the study accounted for by the fact that the depressive phase of BPD often is linked with suicidal ideation, with 25%-50% of BPD patients attempting suicide at least once.

A related study reported that US employees with BPD had about 2 to 3 times higher costs than employees without BPD in several physical health condition categories, including headaches and migraines, intervertebral disc disorders, hyperlipidemia, and other nontraumatic joint disorders.

. A diagnosis of BPD is associated with an increased likelihood of missing work because of illness.

A retrospective analysis of data from the Human Capital Management Services Research Reference Database relating to health benefit costs and healthrelated absences during 2001-2002 reported that employees with BPD had significantly more health-related absences from work than employees without the disorder.

Individuals with BPD missed an average of 18.9 workdays each year, significantly more (

 &#8804;.05) than employees without BPD, who missed an average of 7.4 workdays annually.

The majority of this lost time (58%) occurred under the short-term disability benefit.

Total costs associated with this absenteeism were approximately 2.5-fold higher for employees with BPD than for those without BPD ($1995 vs $777; 

 &#8804;.05).4,5 A breakdown revealed that employees with BPD were consistently more costly than employees without BPD across all types of absences, including sick leave ($489 vs $353; 

 &#8804;.05), shortterm disability ($975 vs $255; 

 &#8804;.05), long-term disability ($118 vs $6; 

 &#8804;.05), and workers&#8217; compensation ($413 vs $163; 

The same study reported that when present at work, the average hourly productivity of employees with BPD was similar to that of employees without BPD.

However, because of their high rates of absenteeism, on an annual basis, the overall productivity loss was significantly different, with an annual output 20% lower than that of employees without BPD (

In terms of total healthcare benefit costs, employees with BPD were $6836 more expensive per year than employees without the disorder ($9983 vs $3147; 

 <.05).4,14 Total costs also were 59% greater than those for employees with other mental disorders ($9983 vs $6268; 

A retrospective analysis of the MEDSTAT MarketScan Health and Productivity Management Database of 320,000 employees from 6 large US employers in 2000 concluded that BPD has a substantial impact on work time lost.

 Employees with BPD were absent significantly more hours per year (55 h vs 21 h; 

 = .009) than employees without BPD, while short-term disability payments were significantly larger for employees with BPD than for both employees without BPD ($1231 vs $131; 

 <.001) and employees with depression ($1231 vs $741; 

A regression analysis of BPD and major depressive disorder indicated that productivity loss due to BPD was twice that associated with depression.

 Using data from 3378 workers who responded to the National Comorbidity Survey Replication conducted in 2001-2003, it was estimated that employees with BPD had 65.5 lost workdays per year due to absenteeism and presenteeism, significantly more than those with major depressive disorder, who missed 27.2 workdays per year (

 The study attributed the higher rate of work loss associated with BPD to the more severe and persistent depressive episodes experienced; these lasted 134-164 days, whereas those for major depression lasted, on average, 98 days (

This systematic review examines the impact of bipolar disorder on employee attendance and functioning at work, along with the associated economic burden to US employers.

November 2008

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