Determinants of glycaemic control in a practice setting: the role of weight loss and treatment adherence (The DELTA Study).

AIMS: Examine the association between weight loss and adherence with glycaemic goal attainment in patients with inadequately controlled T2DM. MATERIALS AND METHODS: Patients ≥ 18 years with T2DM from a US integrated health system starting a new class of diabetes medication between 11/1/10 and 4/30/11 (index date) with baseline HbA1c ≥ 7.0% were included in this cohort study. Target HbA1c and weight change were defined at 6-months as HbA1c < 7.0% and ≥ 3% loss in body weight. Patient-reported medication adherence was assessed per the Medication Adherence Reporting Scale. Structural equation modelling was used to describe simultaneous associations between adherence, weight loss and HbA1c goal attainment. RESULTS: Inclusion criteria were met by 477 patients; mean (SD) age 59.1 (11.6) years; 50.9% were female; 30.4% were treatment naïve; baseline HbA1c 8.6% (1.6); weight 102.0 kg (23.0). Most patients (67.9%) reported being adherent to the index diabetes medication. At 6 months mean weight change was -1.3 (5.1) kg (p = 0.39); 28.1% had weight loss of ≥ 3%. Mean HbA1c change was -1.2% (1.8) (p< 0.001); 42.8% attained HbA1c goal. Adherent patients (OR 1.70; p = 0.02) and diabetes therapies that lead to weight loss (metformin, GLP-1) were associated with weight loss ≥ 3% (OR 2.96; p< 0.001). Weight loss (OR 3.60; p < 0.001) and adherence (OR 1.59; p < 0.001) were associated with HbA1c goal attainment. CONCLUSIONS: Weight loss ≥ 3% and medication adherence were associated with HbA1c goal attainment in T2DM; weight loss was a stronger predictor of goal attainment than medication adherence in this study population. It is important to consider weight-effect properties, in addition to patient-centric adherence counselling, when prescribing diabetes therapy.

Evaluation of cardiovascular risk factors, events, and costs across four BMI categories.

OBJECTIVE: The purpose of this study was to analyze the 1-year cost of cardiovascular (CV) events by body mass index (BMI) subgroups from a US employer health plan perspective. DESIGN AND METHODS: Patients aged 20-64 years from the GE Centricity Electronic Medical Record, National Health and Nutrition Examination Survey, and MarketScan databases were used to determine prevalence of risk factors (RFs) and CV events and 1-year costs. Risk factors included hypertension (HTN), diabetes, and hyperlipidemia (HLD) and CV events included myocardial infarction, angina, heart failure, and stroke. CV event costs were determined from claims by ICD-9 code in patients with overweight/obesity. RESULTS: Of 220,136 patients identified in GE, BMI was 25-26.9 in 19.4%, 27-29.9 in 30.4%, 30-34.9 in 27.9%, and ≥35 in 22.3%. Patients with diabetes, HTN, and HLD increased with BMI from 1.8% (25-26.9) to 11.4% (≥35) in males and 1.1% to 6.8% in females. Prevalence of CV events increased from 0.1% with no RFs up to 10.2% with multiple RFs. The average 1-year cost per patient increased from $1122 to $2383 as BMI increased. CONCLUSIONS: Patients with higher BMI values had an increased prevalence of RFs and CV events, which lead to higher average 1-year costs.

Six-month outcomes on A1C and cardiovascular risk factors in patients with type 2 diabetes treated with exenatide in an ambulatory care setting.

AIM: This study evaluated changes in clinical effectiveness measures of patients with type 2 diabetes initiating exenatide therapy in a real-world setting. METHODS: Eligible patients identified in the General Electric (GE) electronic medical record (EMR) research database from 1 January 2000 through 31 December 2007 were > or =18 years old with type 2 diabetes. Patients had prescription orders in the previous 395 days for metformin, a sulfonylurea, or a thiazolidinedione as monotherapy or in combination, and had at least 6 months of follow-up activity. Baseline clinical measures were documented from 45 days prior up to 15 days after exenatide initiation and follow-up measures documented at 6 months +/- 45 days. RESULTS: A total of 1709 patients were identified for study inclusion. The overall mean A1C reduction (s.e.m.) at 6 months was -0.8% (0.05) (p<0.001), weight loss was -3.2 kg (0.14) (p<0.001), blood pressure (BP) lowering was -1.9 mmHg (0.46) systolic blood pressure (SBP) (p<0.001) and -0.5 mmHg (0.27) diastolic blood pressure (DBP) (p = 0.078). Changes in low-density lipoprotein (LDL), triglycerides and HDL were -7.4 mg/dl (1.7) (p<0.001), -23.2 mg/dl (6.7) (p = 0.001) and -0.8 mg/dl (0.33) (p = 0.012) respectively. In a quartile analysis by weight loss, mean A1C reduction ranged from -1.1 to -0.65% in the highest to lowest weight loss quartiles respectively. CONCLUSIONS: In a real-world setting, exenatide initiation is associated with significant improvements in the measures of clinical effectiveness for type 2 diabetes. These reductions were comparable to those reported in randomized, controlled registration trials after 6 months of therapy.

The effect of fixed combination of fluticasone and salmeterol on asthma drug utilization, asthma drug cost, and episodes of asthma exacerbations.

OBJECTIVE: This study evaluated the use and drug costs of inhaled corticosteroids (ICSs), long-acting beta2-agonists (LABAs), and fluticasone propionate and salmeterol in a fixed-dose combination (FSC) and their relationship to asthma exacerbations before and after the market introduction of FSC in April 2001. METHODS: This is a retrospective analysis of employer-sponsored health insurance claims filed between January 1, 1998, and December 31, 2003 to detect impact of introduction of FSC (approved by the US Food and Drug Administration in August 2000) on utilization and cost of FSC, any ICS (excluding FSC), and any LABA (excluding FSC) along with utilization of medical services related to asthma exacerbations. Asthma medications were identified using National Drug Codes and Redbook, whereas asthma exacerbations were identified using ICD-9-CM primary diagnosis code 493.x. These medical and pharmacy claims were converted to rates per 100 asthma office visits. RESULTS: For all ICSs, the average pharmacy claims per 100 office visits increased from 383 in the year before FSC was introduced to 407 (120 [29.5%] were for FSC and 287 [70.5%] were for single-entity ICSs) in 2003. LABA prescribing increased from 72 in the year before FSC to 147 (120 from FSC, 27 single-entity LABA) in 2003 (p < 0.001). An additional $13,511 per 100 asthma office visits was spent on the FSC product (p < 0.001). After the introduction of FSC, there was no significant difference in asthma admissions (p = 0.17), whereas emergency department (ED) visits increased by 0.92 visits per 100 office visits (p = 0.03). The diagnosis and severity of asthma was inferred from the pharmacy claims and patients with chronic obstructive pulmonary disease could not be excluded. In addition, the study was not designed to assess the impact of other asthma medications on the disease and/or associated costs, and patient adherence to claimed medication could not be monitored. CONCLUSIONS: The introduction of FSC was associated with increased LABAs/FSC patient exposure and expenditure with no change in asthma hospitalizations and an increase in ED visits.

Using a multihospital systems framework to evaluate and establish drug use policy.

PURPOSE: In order to develop rational drug purchasing and use policy for a class of pharmaceuticals used in a consortium system of 14 university based hospitals, the antiemetic use patterns of inpatients receiving cancer chemotherapy were evaluated to assess the comparative effectiveness of granisetron, ondansetron, and conventional antiemetics. PATIENTS AND METHODS: A prospective, observational study was conducted in 14 academic health centers linked under research and purchasing consortium arrangements from October to December 1994. The use of antiemetics was evaluated in hospitalized patients receiving cancer chemotherapy agents with a known propensity for causing, alone or in combination, varying degrees of nausea or vomiting. Clinical outcomes measured were the impact of chemotherapy administration on the functional status of patients, and the occurrence of post-treatment vomiting. RESULTS: The most often prescribed cancer chemotherapy regimens consisted of cisplatin, paclitaxel, etoposide and cyclophosphamide, and the most often prescribed antiemetics were the 5-hydroxytryptamine subtype-3 antagonists (5-HT3 antagonists, granisetron and ondansetron), dexamethasone and lorazepam. Of the 439 patients studied, 329 (75%) reported no episodes of emesis. Of the patients receiving highly emetogenic chemotherapy, those receiving 5-HT3 antagonists experienced better overall outcomes (as measured by functional health status and the absence of vomiting) than patients receiving conventional (non-5-HT3 antagonist) antiemetics. In contrast, patients receiving chemotherapy associated with moderate or low emetogenicity experienced similar outcomes, regardless of the antiemetic regimen selected. No statistical difference was seen between granisetron and ondansetron in achieving positive patient outcomes. CONCLUSION: The study results suggest that 5-HT3 antagonists are associated with better clinical outcomes than other antiemetics in patients receiving highly emetogenic chemotherapy. Less costly conventional antiemetic therapy (or, in some cases, no antiemetic therapy) provide comparable outcomes in patients receiving chemotherapy associated with moderate or low emetogenic potential. Granisetron and ondansetron were found to be clinically comparable.

The challenge of integrating monoclonal antibodies into the current healthcare system.

Although there are few monoclonal antibody (MoAb) products on the market, the biotechnology industry has made considerable progress over the last decade. The industry has developed new technology to address the primary hurdles facing the development of MoAbs--including the immune response to murine-derived antibodies as well as lack of tumor specificity. As the techniques for development become more refined, more products will be approved by the Food and Drug Administration. Integrating these products into the existing healthcare system will be a challenge, given their high acquisition costs. Recent pharmacoeconomic examples outlined in this paper confirm that MoAb products will need to be supported with proven clinical and economic profiles. As long as a global clinical and economic perspective is taken and patient care benefits can be demonstrated, the place of MoAbs in the future of healthcare will be assured.

Patterns of antihypertensive use among patients in the US Department of Defense database initially prescribed an angiotensin-converting enzyme inhibitor or calcium channel blocker.

The US Department of Defense recently assembled electronic records of outpatient prescriptions dispensed through the Uniformed Services Prescription Database Project (USPDP) going back to 1990. The objectives of this portion of a larger study were: (1) to examine longitudinally the patterns of antihypertensive drug use during the first year of therapy in patients whose initial therapy was with an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker (CCB); (2) to determine continuous and noncontinuous users of antihypertensive drugs; and (3) to estimate the direct medication costs for each pattern of medication use. Filtering criteria for patient and prescription identification were developed, because the USPDP contains no records of confirmatory diagnoses of hypertension. Once data filters were implemented, information for 771 patients was analyzed. An ACE inhibitor was the initial therapy for 328 patients, accounting for 1935 antihypertensive medication prescription fills, and a CCB was the initial therapy for 443 patients, accounting for 2459 fills (including refills). Slightly more than half of the patients (n = 401, 52.0%) were classified as continuous users (> or = 80% medication-possession ratio [supply of medication in days divided by the number of days in the 12-month study period]). In the first year, 177 of these continuous users (44.1%) had no change in therapy in the first year, 49 (12.2%) had an increase in dose, 8 (2.0%) had a decrease in dose, 15 (3.7%) had a change to a different therapeutic class of antihypertensive medication, 14 (3.5%) were changed to a different medication in the same therapeutic class, 20 (5.0%) had a new medication added to the regimen, and 118 (29.4%) had complex regimens involving more than one change. For continuous users, the mean medication supply in days was 354.6, and the average time before a medication change was 152.1 days for those continuous users who had one change in therapy. The overall average wholesale price (AWP) and average manufacturer price (AMP) for continuous users during 1 year of therapy were $471.31 and $378.51, respectively. For those patients whose therapy was changed to an ACE inhibitor/CCB combination and who were continuous users, the average AWP was $598.47 per year ($492.05 AMP). Once the change from monotherapy to an ACE inhibitor/CCB combination occurred in continuous users, AWP costs per member per month increased by approximately $22.00 ($18.00 AMP). Over half of the patients whose initial therapy was an ACE inhibitor or CCB had at least one change in their first year of therapy. Research into the reasons for these changes and their outcomes is needed.

A decision analysis model in the evaluation of NSAIDs in a managed care setting: a case study.

The objective of this study is to utilize a clinical trial based on a decision-analysis model to assess the economic benefit of a lower incidence of gastrointestinal lesions in elderly patients with osteoarthritis receiving nabumetone therapy compared with ibuprofen alone and in combination with misoprostol. An arthritic population of an HMO (> 60 yr of age) was applied to the decision analysis based on the HMO's nonsteroidal anti-inflammatory drug and antiulcer usage and acquisition costs. Results indicate the potential for a decrease in overall medical resource utilization through the use of nabumetone in elderly patients with rheumatoid and osteoarthritis. Based on this information, nabumetone has been added to the HMO formulary as a second-tier agent with a repeat of the analysis scheduled in one year to verify the economic benefits and modify prescribing guidelines accordingly.

Cytotoxicity, uptake, polyglutamate formation, and antileukemic effects of 8-deaza analogues of methotrexate and aminopterin in mice.

In contrast to methotrexate (MTX) and aminopterin (AMT), the 8-deaza analogues of these antifolates are not substrates for rabbit liver aldehyde oxidase. Since they are not converted to 7-hydroxy derivatives, they have been investigated with regard to their cytotoxicity for CCRF-CEM cells, transport into these cells, and conversion to polyglutamate forms. For this purpose 3H-labeled analogues were synthesized. The drug concentrations of the analogues required to inhibit cell growth by 50% are significantly lower than for the parent compounds particularly for a short exposure of cells to the drug. Vmax and Km for unidirectional influx do not differ greatly among the four drugs, but amounts of uptake over 1 h are markedly different and increase in the order MTX less than 8-deazaMTX less than AMT less than 8-deazaAMT. During 1 h of uptake a much greater proportion of the 8-deaza analogues is converted to polyglutamate forms than in the case of parent drugs. Only 52% of MTX is converted to polyglutamates, whereas in the case of the other three compounds the conversion is greater than or equal to 90%. However, MTX is relatively efficient in adding two glutamate residues, whereas the other drugs predominantly accumulate as forms with only one additional glutamate (+Glu1). During 1 h of efflux the drugs without additional glutamates decrease to low concentrations and there is also a major loss of +Glu1 form, but there is also an increase in longer chain forms, especially in the case of MTX. The net result is a still greater disparity in total intracellular levels of the four drugs after the period of efflux. MTX has much lower toxicity in mice in vivo than the other three compounds, 8-deazaAMT being the most toxic. At the maximum tolerated dose MTX produced a considerably greater increase in life span for mice bearing P388 than any of the other drugs, and a somewhat greater increase for mice bearing L1210. Thus the 8-deaza analogues do not offer a therapeutic advantage over MTX against leukemias in the mouse, primarily due to their much greater toxicity.

Folate analogues as inhibitors of thymidylate synthase.

Recent demonstrations that deazafolate analogues may act as potent inhibitors of thymidylate synthase (TS) provided a firm rationale for the synthesis of N10-propargyl derivatives of 8-deazafolate and 8-deazaaminopterin (4). A complete assignment of the 1H NMR spectra of these compounds was made possible through application of 2D (COSY) techniques at 200 MHz. Data describing the inhibition of TS derived from human leukemia (K562) cells are presented. IC50 values of 2.25 and 1.26 microM were determined for 8-deaza-10-propargylfolate (3) and 8-deaza-10-propargylaminopterin, respectively. Comparison of the data for various folate analogues reveals a striking dependence of TS inhibitory potency upon the number of nitrogens in the folate pyrazine ring.