Obstacles and proposed solutions to effective antiretroviral therapy in resource-limited settings.

More than 3 million people were receiving antiretroviral therapy (ART) at the end of 2007, but this number represents only 31% of people clinically eligible for ART in resource-limited settings. The primary objective of this study is to summarize the key obstacles that impede the goal of universal access prevention, care, and treatment. We performed a systematic literature search to review studies that reported barriers to diagnosis and access to treatment of HIV/AIDS in resource-limited countries. Persons living with HIV/ AIDS commonly face economic, sociocultural, and behavioral obstacles to access treatment and care for HIV. A variety of programs to overcome these barriers have been implemented, including efforts to destigmatize HIV/AIDS, enhance treatment literacy, provide income-generation skills, decentralize HIV services, promote gender equality, and adopt a multisectoral approach to optimize limited resources. An understanding of these obstacles and suggested methods to overcome them must be addressed by global policy makers before universal ART access can be achieved.

Comparison of Markov model and discrete-event simulation techniques for HIV.

BACKGROUND: Markov models have been the standard framework for predicting long-term clinical and economic outcomes using the surrogate marker endpoints from clinical trials. However, they are complex, have intensive data requirements and are often difficult for decision makers to understand. Recent developments in modelling software have made it possible to use discrete-event simulation (DES) to model outcomes in HIV. Using published results from 48-week trial data as model inputs, Markov model and DES modelling approaches were compared in terms of clinical outcomes at 5 years and lifetime cost-effectiveness estimates. METHODS: A randomly selected cohort of 100 antiretroviral-naive patients with a mean baseline CD4+ T-cell count of 175 cells/mm3 treated with lopinavir/ritonavir was selected from Abbott study M97-720. Parameter estimates from this cohort were used to populate both a Markov and a DES model, and the long-term estimates for these cohorts were compared. The models were then modified using the relative risk of undetectable viral load as reported for atazanavir and lopinavir/ritonavir in the published BMS 008 study. This allowed us to compare the mean cost effectiveness of the models. The clinical outcomes included mean change in CD4+ T-cell count, and proportion of subjects with plasma HIV-1 RNA (viral load [VL]) <50 copies/mL, VL 50-400 copies/mL and VL >400 copies/mL. US wholesale acquisition costs (year 2007 values) were used in the mean cost-effectiveness analysis, and the cost and QALY data were discounted at 3%. RESULTS: The results show a slight predictive advantage of the DES model for clinical outcomes. The DES model could capture direct input of CD4+ T-cell count, and proportion of subjects with plasma HIV-1 RNA VL <50 copies/mL, VL 50-400 copies/mL and VL >400 copies/mL over a 48-week period, which the Markov model could not. The DES and Markov model estimates were similar to the actual clinical trial estimates for 1-year clinical results; however, the DES model predicted more detailed outcomes and had slightly better long-term (5-year) predictive validity than the Markov model. Similar cost estimates were derived from the Markov model and the DES. Both models predict cost savings at 5 and 10 years, and over a lifetime for the lopinavir/ritonavir treatment regimen as compared with an atazanavir regimen. CONCLUSION: The DES model predicts the course of a disease naturally, with few restrictions. This may give the model superior face validity with decision makers. Furthermore, this model automatically provides a probabilistic sensitivity analysis, which is cumbersome to perform with a Markov model. DES models allow inclusion of more variables without aggregation, which may improve model precision. The capacity of DES for additional data capture helps explain why this model consistently predicts better survival and thus greater savings than the Markov model. The DES model is better than the Markov model in isolating long-term implications of small but important differences in crucial input data.

Cost-effectiveness analysis of lopinavir/ritonavir and atazanavir+ritonavir regimens in the CASTLE study.

INTRODUCTION: The purpose of the study was to conduct a cost-effectiveness analysis and budget impact analysis comparing lopinavir with ritonavir (LPV/r) and atazanavir plus ritonavir (ATV+RTV) for antiretroviral-naïve patients with a baseline CD4+ T-cell distribution and total cholesterol (TC) profile as reported in the CASTLE study. METHODS: This decision analysis study used a previously published Markov model of HIV disease, incorporating coronary heart disease (CHD) events to compare the short- and long-term budget impacts and CHD consequences expected for the two regimens. RESULTS: Patients were assumed to have a baseline CHD risk of 4.6% (based on demographic data) and it was also assumed that 50% of the population in the CASTLE study were smokers. The CHD risk differences (based on percent of patients with TC >240 mg/dL) in favor of ATV+RTV resulted in an average improvement in life expectancy of 0.031 quality-adjusted life years (QALYs) (11 days), and an incremental cost-effectiveness ratio of $1,409,734/QALY. Use of the LPV/r regimen saved $24,518 and $36,651 at 5 and 10 years, respectively, with lifetime cost savings estimated at $38,490. A sensitivity analysis using a cohort of all smokers on antihypertensive medication estimated an average improvement in life expectancy of 31 quality-adjusted days in favor of ATV+RTV, and a cost-effectiveness ratio of $520,861/QALY: a ratio that is still above the acceptable limit within the US. CONCLUSION: The use of an LPV/r-based regimen in antiretroviral-naïve patients with a baseline CHD risk similar to patients in the CASTLE study appears to be a more cost-effective use of resources compared with an ATV+RTV-based regimen. The very small added CHD risk predicted by LPV/r treatment is more than offset by the substantial short- and long-term cost savings expected with the use of LPV/r in antiretroviral-naïve individuals with average to moderately elevated CHD risk.

Impact of lipoatrophy on quality of life in HIV patients receiving anti-retroviral therapy.

Metabolic and morphological side-effects occur in HIV-infected individuals receiving anti-retroviral treatment (ART). Peripheral fat loss that occurs particularly in the face, limbs and/or buttocks is referred to as lipoatrophy and has been found to be highly stigmatizing and to adversely impact the health-related quality of life (HRQL). Consumer Health Sciences Survey data collected between November 2003 and January 2006 were utilized to evaluate the impact of lipoatrophy on the HRQL in HIV-infected individuals receiving ART. This was evaluated using analysis of variance with item scores and mental component summary (MCS) and physical component summary (PCS) scores from the Medical Outcomes Trust questionnaire, SF-8 as dependent variables and lipoatrophy as the independent variable controlling for baseline age, sex and ethnicity. Clinical meaningfulness (mean difference divided by population standard deviation, delta/sigma) of differences between the groups with and without lipoatrophy was also evaluated. A cohort of 1124 subjects with at least six months of ART was selected based on the availability of data on whether or not lipoatrophy was present. Subjects were primarily male (80%), between the ages of 30 and 60 years (90%), Hispanic (37%) and about 25% each of African American and White. Overall, prevalence of lipoatrophy in this cohort of HIV patients was 18.9%. Statistically significant (p<0.001) differences in quality of life (as measured by SF-8 individual item scores and MCS and PCS scores) were observed between the two groups. The differences between the groups in item and summary scores were clinically meaningful in the small to near medium range (0.28-0.43). HIV-infected patients already experience a considerable deficiency in HRQL compared to general population; this study demonstrates that lipoatrophy further enhances that negative impact on HRQL.

Impact of lipoatrophy on patient-reported outcomes in antiretroviral-experienced patients.

Lipoatrophy is a noteworthy adverse effect of antiretroviral therapy. A 2-part literature review was conducted to assess the impact of lipoatrophy in HIV-infected persons: the first reviewed the qualitative studies that reported lipoatrophy data, and the second reviewed the clinical studies that recorded patient-reported outcome end points. This literature review provided considerable evidence that lipoatrophy has a negative impact on the psychosocial well-being and health-related quality of life of HIV-infected persons receiving antiretroviral therapy. However, the patient-reported outcome measures used in clinical studies were not lipoatrophy-specific and had limited ability to show real changes in health status associated with lipoatrophy.

Cost effectiveness of lopinavir/ritonavir tablets compared with atazanavir plus ritonavir in antiretroviral-experienced patients in the UK, France, Italy and Spain.

BACKGROUND AND OBJECTIVE: Selection of antiretroviral therapy (ART) for antiretroviral-experienced patients should involve balancing multiple factors, including clinical efficacy, adverse-event risk, resistance concerns, cost effectiveness and expected budget impact. The efficacy of a regimen and its durability, as demonstrated in controlled clinical trials, must be considered in the light of short- and long-term economic impacts on the healthcare system. These impacts may vary based on drug costs, costs of reported adverse effects, the regimen's likelihood of contributing to viral resistance to second-line therapies and the marginal cost differences between other healthcare resources used over a patient's lifetime. Risk of coronary heart disease (CHD) may be of concern in the selection of ART, because differences in CHD risk factors have been reported for different regimens, and heart disease is both a deadly and costly condition. This study set out to estimate the long-term combined effects of HIV disease and antiretroviral-related risk for CHD on quality-adjusted survival and healthcare costs for antiretroviral-experienced patients in the UK, Spain, Italy and France. METHODS: A previously validated Markov model was updated with 2006 cost estimates for each of the four countries and supplemented with the Framingham CHD risk equation. In the model, the average patient was male, aged 37 years, with a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir (LPV/r) or ritonavir-boosted atazanavir (ATV+RTV) as the protease inhibitor (PI). Clinical trial results, local drug costs and AIDS and CHD cost estimates were used to estimate the differences between these two therapies. RESULTS: There was a significant advantage using LPV/r over ATV+RTV, which varied depending on the country's cost structure and assumptions related to drug efficacy. There was a comparative benefit for experienced patients in quality-adjusted life-months (QALM) of 4.6 (the net gain after subtracting quality-adjusted life-years [QALYs] lost owing to CHD risk). In addition, there were 5- and 10-year overall cost savings of between euro947 and euro6594 per patient after 5 years, and an impact ranging from a cost increase of euro308 (for France) to a cost saving of euro7388 (for Spain) at year 10. The lifetime incremental cost-effectiveness ratios ranged from dominant for Spain to euro11 856/QALY for Italy. CONCLUSION: LPV/r was a highly cost-effective regimen relative to ATV+RTV for the treatment of HIV for each of the four countries examined in this study. The effect of LPV/r on long-term CHD risk was minimal compared with the increased risk of AIDS/death projected for a less efficacious PI-based regimen. The cost of lipid-lowering drugs and treatment for CHD was insignificant compared with the overall cost savings from LPV/r therapy. The choice of regimen for antiretroviral-experienced patients should be based on a regimen's expected efficacy and durability for countries with similar cost structure to those examined here.

Cost effectiveness of lopinavir/ritonavir compared with atazanavir plus ritonavir in antiretroviral-experienced patients in the US.

OBJECTIVE: To estimate the cost effectiveness and long-term combined effects of HIV disease and antiretroviral (ARV) therapy-related risk for coronary heart disease (CHD) on quality-adjusted survival and healthcare costs for ARV-experienced patients. METHODS: A previously validated Markov model was updated and supplemented with the Framingham CHD risk equation. The representative patient in the model was male, aged 37 years and had a baseline 10-year CHD risk of 4.6%. Patients started with either lopinavir/ritonavir (LPV/r) or ritonavir-boosted atazanavir (ATV+RTV) as the protease inhibitor (PI). The proportions of patients with viral suppression below 400 and 50 copies/mL, respectively, at week 48 reported in clinical trials were used to estimate the differences between these two therapies. The daily ARV costs were $US 24.60 for LPV/r capsules (2005 costs) and $US 26.54 for LPV/r tablets (2006 costs), $US 29.76 for ATV and $US 8.57 for ritonavir (2005 costs). Costs of other ARV drugs were taken from average wholesale drug reports for 2005. The cost of AIDS events was estimated from Medicaid billing databases and reflected a medical care system perspective and 2005 treatment costs. Cost-effectiveness calculations assumed a lifetime time horizon. The effects of different model assumptions were tested in a multiway sensitivity analysis by combining extreme values of parameters. RESULTS: The model estimated a clinical and economic advantage to using LPV/r over ATV+RTV, which varied depending upon the use of LPV/r capsules or tablets. Using LPV/r capsules was comparatively beneficial for ARV-experienced patients in quality-adjusted life-months (QALMs) of 4.6 (corrected for differences in CHD risk) compared with ATV+RTV. In addition, there were 5- and 10-year overall per-patient cost savings of $US 17,995 and $US 21,298, respectively. Estimates for the LPV/r tablet formulation approved in 2005 (assuming similar efficacy) improved cost savings over 5- and 10-year periods to $US 19,598 and $US 23,126 per patient, respectively, because of a drug price differential. Sensitivity analysis tested numerous assumptions about the model cost and efficacy parameters and found that the results were robust to most changes. Model limitations were the uncertainty associated with the model parameters used. CONCLUSION: LPV/r appears to be a highly cost-effective regimen relative to ATV+RTV for the treatment of HIV. The long-term CHD risk associated with LPV/r was minimal compared with the increased risk of AIDS/death and costs projected for a less efficacious PI-based regimen.

Economic impact of cardiovascular co-morbidity in patients with type 2 diabetes.

OBJECTIVES: To evaluate the impact of cardiovascular co-morbidity on total and diabetes-related healthcare costs in patients with type 2 diabetes. METHODS: Retrospective analysis of the West Virginia state Medicaid claims data was conducted in patients with type 2 diabetes (ICD-9 codes: 250.0x-250.9x, where x=0 or 2) in the year 2001. Patients > or =65 years of age or those with managed care coverage were excluded. Presence of cardiovascular co-morbidity in the year 2001 was identified. Semi-logarithmic regression models were used to estimate the impact of cardiovascular co-morbidity on total and diabetes-related healthcare costs in the year 2002.Two-part models were used to study the impact of cardiovascular co-morbidity on ER/hospitalization, outpatient, and prescription costs. Smearing estimates were used to interpret the results from the semi-logarithmic models. RESULTS: Presence of cardiovascular co-morbidity had a significant impact on all categories of total and diabetes-related healthcare costs, except diabetes-related prescription drug costs. Type 2 diabetes patients with cardiovascular co-morbidity had significantly higher total healthcare costs (38.9%, $12,550 vs. $9031), total ER/hospitalization costs (239.8%, $4845 vs. $1426), total outpatient costs (35.3%, $3956 vs. $2925), and total prescription drug costs (15.1%, $4686 vs. $4071) compared to those without cardiovascular co-morbidity. Similarly, type 2 diabetes patients with cardiovascular co-morbidity had significantly higher total diabetes-related healthcare costs (59.7%, $4349 vs. $2724), ER/hospitalization costs (346.8%, $1911 vs. $428), and outpatient costs (17.4%, $740 vs. $631) compared to patients without cardiovascular co-morbidity. CONCLUSIONS: Presence of cardiovascular co-morbidity in patients with type 2 diabetes had a significant impact on total and diabetes-related healthcare costs.

The effect of pioglitazone on glycemic and lipid parameters and adverse events in elderly patients with type 2 diabetes mellitus: a post hoc analysis of four randomized trials.

OBJECTIVE: This analysis was conducted to evaluate the impact of pioglitazone (PIO), both as monotherapy and as part of combination therapy, on glycemic and lipid parameters and adverse events in elderly patients with type 2 diabetes. METHODS: This was a post hoc analysis of pooled data, truncated at 1 year, from patients aged > or =65 years with type 2 diabetes in 4 multicenter, randomized, double-blind, parallel-group trials. For inclusion in these trials, patients were required to be between the ages of 35 and 75 years and to have had poorly controlled type 2 diabetes, a glycosylated hemoglobin (HbA(1c)) value between 7.5% and 11.0%, and stable or worsening glycemic control for at least 3 months. Blood samples were obtained at baseline and every 4 to 10 weeks thereafter for determination of HbA(1c), fasting plasma glucose (FPG), and lipid parameters (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TC:HDL-C ratio, and free fatty acids). RESULTS: Data from 891 elderly patients (age range, 69.1-69.8 years) were included: 282 who received PIO, 123 metformin (MET), 142 sulfonylurea (SU), 105 SU + PIO, 107 SU + MET, 63 MET + PIO, and 69 MET + SU. With a few exceptions, all treatment groups were similar at baseline. From baseline to week 52, none of the changes in HbA(1c) and FPG between each treatment group and its comparator were significant. The adjusted mean (SE) percent changes in HDL-C for the monotherapies were 17.95% (1.11) for PIO, 10.71% (1.70) for MET, and 5.17% (1.51) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent changes in HDL-C were 16.77% (1.84) for SUPIO versus 7.87% (1.75) for SUMET (P < 0.05), and 16.34% (2.34) for MET + PIO versus 0.11% (2.19) for METSU (P < 0.05). The adjusted mean percent changes in LDL-C for the monotherapies were 7.00% (1.28) for PIO, -0.68% (1.91) for MET, and -6.77% (1.73) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent change in LDL-C was significant for METPIO compared with METSU (13.62% [2.69] vs -4.32% [2.58], respectively; P < 0.05). The adjusted mean percent change in TG was significant for MET + PIO compared with MET + SU (-10.93% [4.44] vs 8.37% [4.15], respectively; P < 0.05). The adjusted mean percent changes in TC for the monotherapies were 6.16% (0.88) for PIO, -1.77% (1.35) for MET, and -6.90% (1.19) for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean percent changes in TC were 2.67% (1.45) for SUPIO versus -1.40% (1.39) for SUMET (P < 0.05) and 7.89% (1.85) for METPIO compared with -1.19% (1.73) for METSU (P < 0.05). The differences in change in the TC:HDL-C ratio were not significant between groups. The adjusted mean changes in free fatty acids for the monotherapies were -0.14 (0.02) mmol/L for PIO, -0.001 (0.03) mmol/L for MET, and -0.07 (0.02) mmol/L for SU (both comparisons, P < 0.05). For the combination therapies, the adjusted mean change in free fatty acids was significant for SU + PIO compared with SUMET (-0.12 [0.03] vs 0.06 [0.03] mmol/L, respectively; P < 0.05). PIO monotherapy was associated with the lowest incidence of hypoglycemia (1.4%) among the 7 treatment groups. The SUPIO group had the highest incidence of weight gain (4.8%). The rate of deaths was <2% in all the treatment groups; no adverse event associated with death was considered related to study medication. CONCLUSIONS: In this post hoc analysis of data from elderly patients participating in 4 randomized clinical trials, PIO effectively controlled glycemic and lipid parameters over 52 weeks and was well tolerated. The effects seen in this analysis were comparable to those in the overall study populations.

Outcomes associated with introduction of thiazolidinedione therapy in Medicaid enrolled patients with type 2 diabetes: an updated and expanded retrospective analysis.

OBJECTIVES: In an earlier analysis, differences in health-care costs, medication adherence, and persistence were examined between patients with type 2 diabetes, enrolled in the North Carolina Medicaid, who had newly started thiazolidinedione (TZD) therapy and those starting other oral antidiabetic agents. In this analysis, the size of the cohort was increased by including 18 months of additional Medicaid data (until December 2004) and sought to: (1) replicate the results of the original study in a larger cohort; and (2) extend the original analysis by providing an additional 18 months of observational follow-up. METHODS: A total of 2660 patients newly starting TZD therapy between July 2001 and December 2003 were compared to 2050 patients starting other oral antidiabetic medication for health-care costs and outcomes in the post-medication start year. In addition, the initial cohort was followed for an additional 18 months to examine if there were any differences in outcomes, such as hospitalization and total health-care costs, that could be associated with the type of therapy. Multivariate regression techniques, incorporating health-care utilization in the year prior to start of new therapy, were used to determine the net cost impact of one therapy versus the other. RESULTS: Multiple regression analyses found that patients starting TZD have better treatment persistence in the post-medication start year compared to patients starting other oral antidiabetic agents (4% increase in therapy persistence index, p < 0.001). In addition, patients starting TZDs had 18.9% lower total annual health-care costs (p < 0.01) compared to patients starting other oral antidiabetic agents. Examination of the original cohort of 3191 patients, for up to an additional 18 months, showed TZD's association with improved adherence rates but not with persistence. Importantly, treatment adherence remained the strongest independent predictor of decreased hospitalization risk and health-care cost reduction in this population. CONCLUSIONS: Introduction of thiazolidinedione therapy in a Medicaid-enrolled type 2 diabetic population was associated with significantly greater treatment adherence, in the post-start year, compared to patients starting other oral antidiabetic agents.

Utilization and costs for compliant patients initiating therapy with pioglitazone or rosiglitazone versus insulin in a Medicaid fee-for-service population.

OBJECTIVE: To compare health care utilization and costs for type 2 diabetes patients initiating therapy with one of two thiazolidinediones (TZDs, pioglitazone or rosiglitazone) or insulin in a Medicaid population. METHODS: The study used a retrospective cohort design and included type 2 diabetes patients who initiated therapy with TZDs or insulin treatment during the 3-year period (1999-2001). These patients were identified from a Medicaid administrative claims database for approximately 230,000 fee-for-service Medicaid recipients using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes: 250.0x-250.9x, where x = 0 or 2). The first pharmacy claim for a TZD or insulin was treated as an index pharmacy claim, and utilization and costs were assessed for each patient for a 12-month follow-up period after the index date of the first pharmacy claim. A 12-month preperiod without a pharmacy claim for a TZD or insulin confirmed that the patient was newly prescribed with these medications. Analysis was restricted to a compliant sample receiving at least 6 pharmacy claims for either TZD or insulin in the 12-month follow-up period. The propensity matching technique was used to control for selection bias and potential imbalances between these groups at baseline. Patients initiating therapy with insulin or TZD were matched on the basis of demographics, year of index pharmacy claim, presence of microvascular/macrovascular complications, comorbidity, type 2 diabetes-related medical utilization and costs in the 12-month preperiod, overall health care utilization and costs in the preperiod, and type of oral hypoglycemic agents/other medications in the preperiod. Nonparametric bootstrapping was used to estimate the impact of therapy on both overall and type 2 diabetes-related health care utilization and costs in the matched sample. RESULTS: A total of 2,842 patients with type 2 diabetes patients met the inclusion criteria prior to exclusion of 881 patients (31.0%) who did not receive at least 6 pharmacy claims for either TZD or insulin in the 12 months following the index pharmacy claim, leaving 1,961 type 2 diabetes patients who initiated therapy with one of the two TZDs or insulin in the 3-year enrollment period (TZDs = 1,523; insulin = 438). Propensity matching eliminated 1,271 patients (64.8%), resulting in a final sample consisting of 690 patients.345 patients per treatment group.with comparable demographic and utilization parameters at baseline. In the 12-month follow-up period for the measures of overall utilization, patients initiated on TZDs did not differ significantly in the number of emergency room (ER)/hospitalization episodes and the number of pharmacy claims compared with the patients initiated on insulin, but they did have an average of 1.2 fewer physician office visits (9.3 vs. 10.5, P <0.05). Compared with the insulin group, the TZD group incurred 35% lower costs for ER visits/hospitalization (dollar 3,727 vs. dollar 5,793, P <0.01) and 18% lower total health care costs (dollar 12,737 vs. dollar 15,563, P <0.05). No significant differences were observed between the groups in overall outpatient and pharmacy costs. When the analysis was restricted to type 2 diabetes-related utilization and costs, patients initiating therapy with TZDs had 0.8 fewer physician office visits (3.6 vs. 4.4, P <0.05). However, TZD patients had 2.7 (14.1%) more diabetes pharmacy claims than patients initiating therapy with insulin (P <0.01), but there was no difference in the number of type 2 diabetes-related ER visits/hospitalizations between the groups. The TZD group had 53% higher type 2 diabetes-related pharmacy costs than the insulin group (dollar 1,678 vs. dollar 1,096, P <0.01). However, these costs were offset by lower costs for ER visits and hospitalization for the TZD group as compared with the insulin group (dollar 2,855 vs. dollar 5.090, P <0.01) resulting in 25% lower total type 2 diabetes-related costs for the TZD group compared with the insulin group (dollar 5,425 vs. dollar 7,255, P <0.05). CONCLUSION: Medicaid fee-for-service patients initiated on either pioglitazone or rosiglitazone incurred higher diabetes-related pharmacy costs, which were offset by lower total type 2 diabetes-related medical costs, contributed primarily by lower costs for ER visits and hospitalizations in this 12-month analysis.

Effect of pioglitazone on metabolic syndrome risk factors: results of double-blind, multicenter, randomized clinical trials.

OBJECTIVE: To evaluate the effect of pioglitazone, metformin, and/or sulfonylurea on metabolic syndrome and its component parameters after a year of treatment. METHODS: Adult patients with poorly controlled type 2 diabetes were enrolled in 4 multicenter, double-blind studies and received pioglitazone, sulfonylurea, metformin, or a combination of any 2 agents. Post hoc analyses were performed on data from patients with evaluations at baseline and week 52, and treatment groups were compared to determine change from baseline in metabolic syndrome status and its component variables by using the McNemar test and analysis of covariance, respectively. RESULTS: Most patients (72.1%) had metabolic syndrome at baseline. Change in the proportion of patients with metabolic syndrome status was significant in each monotherapy and the pioglitazone plus metformin combination groups. Pioglitazone alone or in combination with metformin resulted in a significantly greater percent decrease from baseline in triglycerides (pioglitazone vs. metformin, 10.3%; pioglitazone vs. sulfonylurea, 6.5%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 13.4%; P < 0.05) and a greater percent increase from baseline in high-density lipoprotein (HDL) cholesterol (pioglitazone vs. metformin, 9.1%; pioglitazone vs. sulfonylurea, 12.6%; pioglitazone plus metformin vs. sulfonylurea plus metformin, 17.8%; P < 0.001) at week 52 than did the respective comparison groups. A significant decrease from baseline in the ratio of urinary albumin to creatinine was found only with pioglitazone monotherapy (-1.764 mg/ mmol; P < 0.001), which was significantly greater than the change in the metformin monotherapy group (2.1%; P < 0.05). Significant decrease in blood pressure was observed in the pioglitazone monotherapy and pioglitazone plus sulfonylurea groups, with no significant treatment group differences. CONCLUSIONS: Treatment with pioglitazone as monotherapy or combination therapy led to sustained, positive effects on important components of metabolic syndrome in patients with type 2 diabetes, independent of effects on blood glucose control and, as such, could be translated to potential for reducing the risk of cardiovascular disease.

Physician and patient determinants of pharmacologic treatment of sleep difficulties in outpatient settings in the United States.

STUDY OBJECTIVES: This study analyzed patient and physician characteristics associated with physicians' choice of medication treatment for sleep difficulties in a nationally representative sample of outpatient physician visits in the United States. DESIGN: Cross-sectional study of nationally representative survey data. SETTING: Outpatient settings in the United States. PATIENTS OR PARTICIPANTS: Patients aged 18 years or older with sleep difficulty. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The National Ambulatory Medical Care Survey data from 1996 to 2001 were utilized. The study found that approximately 4.8 billion visits were made to outpatient physician offices in the United States, and 94.6 million of these were visits related to sleep difficulties. Visits by established patients, compared with visits by new patients, were associated with an increased prescription of some type of pharmacotherapy (odds ratio: 1.92, 95% confidence interval: 1.35-2.73). Patient visits with public insurance, as compared with private insurance, as a primary payer source were associated with increased benzodiazepine prescriptions among patients receiving pharmacotherapy (odds ratio: 1.66, 95% confidence interval: 1.13-2.45). Visits by patients aged 65 years and older, as compared with those by patients aged 18 to 34 (reference group)., had almost two times increased odds of being associated with a benzodiazepine prescription (odds ratio: 1.89, 95% confidence interval: 1.13-3.14) among patient visits receiving pharmacotherapy. CONCLUSIONS: The results of this study indicate that several patient and physician characteristics influence physician prescribing of pharmacologic treatments for sleep difficulties. The study also finds variations in pharmaceutical treatment for sleep difficulties in outpatient settings in the United States.

Association between congestive heart failure and hospitalization in patients with type 2 diabetes mellitus receiving treatment with insulin or pioglitazone: a retrospective data analysis.

BACKGROUND: Thiazolidinediones (TZDs) are widely used oral antihyperglycemic drugs that facilitate insulin action and increase insulin-stimulated glucose metabolism, thereby decreasing insulin resistance. However, concerns have been raised regarding the association between TZD use and a heightened risk for congestive heart failure (CHF). OBJECTIVE: This study used claims data to conduct a retrospective examination of the CHF risk in patients with type 2 diabetes mellitus and to compare the association with CHF in those receiving the TZD pioglitazone and those receiving insulin. METHODS: Patients with type 2 diabetes aged > or =18 years who had begun treatment with pioglitazone or insulin between January 1999 and December 2001 were identified using the PharMetrics Patient-Centric database. The sample was restricted to patients for whom there were > or =12 months of data before the index date (date of the first prescription for pioglitazone or insulin) and > or =3 months of follow-up data. Patients receiving a diagnosis of CHF before the index date were excluded. The propensity score for receiving pioglitazone was estimated using logistic regression based on available observed patient characteristics. Patients receiving insulin were matched in a 1:1 ratio with patients receiving pioglitazone based on a difference of no more than +/-0.01 in the estimated propensity score for receiving pioglitazone therapy. CHF risk was examined using the Cox proportional-hazards model. RESULTS: After exclusion of ineligible patients, 1668 matched pairs of patients receiving pioglitazone or insulin were identified (50.9% men, 49.1% women; mean [SE] age, 51.2 [0.2] years). The 2-year crude incidence rate of CHF was significantly lower in the pioglitazone group compared with the insulin group (primary/secondary diagnosis of CHF, 2.0% vs 4.0%, respectively; P < 0.001; inpatient hospitalization for CHF, 0.7% vs 2.5%; P < 0.001). The hazard ratio for pioglitazone versus insulin was 0.501 (95% CI, 0.331-0.758; P = 0.001) for a primary or secondary diagnosis of CHF in any setting and 0.263 (95% CI, 0.135-0.511; P < 0.001) for any occurrence of an inpatient hospitalization for CHF. CONCLUSIONS: In this retrospective analysis of data from patients with type 2 diabetes, pioglitazone therapy was associated with significantly lower incidence rates of CHF and inpatient hospitalization compared with insulin therapy.

Healthcare costs and prescription adherence with introduction of thiazolidinedione therapy in Medicaid type 2 diabetic patients: a retrospective data analysis.

OBJECTIVES: Outcomes in patients with type 2 diabetes may vary depending on the antidiabetic medication used. Observational studies of outcomes of diabetes pharmacotherapy are needed to understand the implications of choice of controller in different populations. This study compared differences in total health care costs, medication adherence, and persistence in patients with type 2 diabetes enrolled in the North Carolina Medicaid Program that were newly started on thiazolidinedione (TZD) therapy with patients starting other oral antidiabetics during the same period. In addition differences among the TZDs with respect to these outcomes were examined. METHODS: A total of 1774 patients newly starting TZD therapy between July 2001 and June 2002 were compared to 1709 patients starting other oral antidiabetic medication (metformin or sulfonylureas) for health care costs and outcomes in the post-medication start year. In addition, a sub-group analysis of health care costs in patients starting either TZD (pioglitazone [n = 1086] versus rosiglitazone [N = 688]) was compared. All included patients had complete enrollment for the 24 months of follow-up. Multivariate techniques incorporating health care utilization in the year prior to start of new therapy were utilized to determine the cost impact of one therapy versus another. RESULTS: Results of multiple regression analyses suggest that patients starting TZD have better treatment adherence and persistence in the post-medication start year compared to patients starting other oral antidiabetics (13% increase in Medication Possession Ratios, and 10% increase in therapy persistence index, both p < 0.001). In addition, patients starting TZDs had 16.1% lower total annual health care costs (p < 0.01) compared to patients starting other oral antidiabetics. There were no differences in adherence and cost outcomes between the 2 TZDs. CONCLUSIONS: Introduction of thiazolidinedione therapy in a Medicaid-enrolled type 2 diabetic population was associated with significantly improved treatment adherence, persistence, and lower annual health care costs in the post-start year compared to patients starting other oral antidiabetics.

Pioglitazone is effective therapy for elderly patients with type 2 diabetes mellitus.

BACKGROUND: Pioglitazone as monotherapy and in combination with sulfonylurea, metformin, or insulin has consistently demonstrated improved glycaemic and lipid parameters in patients with type 2 diabetes mellitus. OBJECTIVE: We performed a subanalysis to examine the effect of pioglitazone on glycaemia and lipids in patients <65 and > or =65 years of age in two double-blind, placebo-controlled monotherapy studies and in three separate multi-centre trials. METHOD: In Study 1, 197 patients were randomised to receive pioglitazone 30 mg/day or placebo for 16 weeks. Study 2 was a forced dose-titration trial in patients randomised to receive pioglitazone 7.5/15/30 mg/day, pioglitazone 15/30/45 mg/day, or placebo daily for 26 weeks. Each of the lower dosages was given for at least 4 weeks and the highest dosage for 16 weeks. The three combination studies evaluated efficacy of pioglitazone 30 or 45 mg/day over a 24-week period in combination with sulfonylureas, metformin, or insulin. RESULTS: In both placebo-controlled monotherapy studies, at 16 weeks, and at maximum pioglitazone dosage, 0.53-0.55% and 0.57-1.27% mean reductions from baseline in glycosylated haemoglobin (HbA(1c)) were seen in patients aged <65 (n = 225) and > or =65 (n = 45) years, respectively. There were statistically significant differences between the placebo and pioglitazone groups in each age cohort. Similar effects were observed in fasting plasma glucose (FPG) levels, with 2.03-2.59 mmol/L and 3.20-4.44 mmol/L mean reductions from baseline, respectively, which were significantly different from the changes in the placebo group, but there was no difference between pioglitazone groups. At treatment endpoint in combination trials, pioglitazone added to sulfonylurea produced a mean decrease in HbA(1c) of 0.78-1.61%, and 1.64-1.96% in patients aged <65 (n = 557) and > or =65 (n = 115) years, respectively. Pioglitazone added to metformin produced a mean decrease in HbA(1c) of 0.78-1.03% and 0.78-0.98% in patients aged <65 (n = 686) and > or =65 (n = 112) years, respectively. Pioglitazone added to insulin produced a mean decrease in HbA(1c) of 1.13-1.37% and 1.39-1.66% in patients aged <65 (n = 500) and > or =65 (n = 156) years, respectively. In patients aged > or =65 years, hypoglycaemia was observed in 1 of 14 patients and in 0 of 13 patients in the two monotherapy studies. In the combination studies, the incidence of hypoglycaemia among patients aged > or =65 years was as follows: 26.7-28.8% combined with sulfonylurea; 0-4.4% combined with metformin; and 53.4-56.4% combined with insulin. CONCLUSION: Pioglitazone monotherapy, or added to a sulfonylurea, metformin, or insulin demonstrated no significant differences in effectiveness while exhibiting similar adverse events in patients aged > or =65 years compared with patients aged <65 years. Well-controlled randomised clinical trials are recommended to confirm the impact of pioglitazone therapy on the glycaemic and lipid control in elderly patients with type 2 diabetes.

Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus: a longitudinal cohort study.

BACKGROUND: The cost of treating diabetes mellitus and its complications is high (91.8 billion dollars in the United States in 2002). It is important to understand predictors of adherence to therapy with different antidiabetic medications and to determine the relationships between adherence and health care service utilization in older adults (aged >or=65 years) with type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to examine the relationship between self-reported health status data, subsequent antidiabetic medication adherence, and health care service utilization in older adults with type 2 diabetes mellitus in a managed care setting. METHODS: This was a longitudinal cohort study of older adults in the south-eastern United States with type 2 diabetes mellitus who completed a health status assessment, used antidiabetic medications, and were enrolled in a health maintenance organization (HMO) continuously for 1 to 5 years. The baseline assessment included questions related to demographics, health care service utilization in the year before enrollment, lifestyle, and quality of life. Demographic, clinical, and utilization-related economic variables were also retrieved from the administrative claims data of the patients' HMO. Prescription refill patterns were used to measure adherence. Associations were examined with a sequential, mixed-model, regression approach. Model appropriateness was tested via sensitivity analyses with logged and unlogged dependent variables. RESULTS: A total of 775 patients were included. Increased comorbidity severity and an emergency room visit during the year prior to enrollment in a Medicare HMO were independently associated with decreased antidiabetic medication possession ratios (MPRs) after enrollment. After controlling for type of medication therapy and other variables, increased antidiabetic MPR remained the strongest predictor of decreased total annual health care costs (8.6% to 28.9% decrease in annual costs with every 10% increase in MPR; P < 0.001). Adherence to anti-diabetic medications was a greater driver of cost reduction than other concurrent medications (eg, statins) in this population. CONCLUSIONS: This study found strong associations between decreased anti-diabetic medication adherence and increased health care service utilization in older adults with type 2 diabetes mellitus in a managed care setting. Health status assessments completed at time of enrollment had the potential to identify enrollees with higher risk for both nonadherent behaviors and poor health-related outcomes.