The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone.

OBJECTIVE: This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500-2,500 mg) in 743 patients (A1C > or =7.0 and < or =10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points. RESULTS: Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (-0.59, -0.69, and -0.58 vs. +0.13%; all P < 0.0001), FPG (-14.31, -22.03, and -20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (-8,891, -9,586, and -8,137 vs. -3,291 mg . min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). beta-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo. CONCLUSIONS: Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.

Impact of C-reactive protein on the likelihood of peripheral arterial disease in United States adults with the metabolic syndrome, diabetes mellitus, and preexisting cardiovascular disease.

We sought to determine, in United States (US) patients with the metabolic syndrome (MS), diabetes mellitus (DM), or preexisting cardiovascular disease, whether higher levels of C-reactive protein (CRP) would identify those with an increased likelihood of peripheral arterial disease (PAD). In a cross-sectional evaluation of the National Health and Nutrition Examination Survey (NHANES), 1999 to 2000, of 1,600 adults (representing a US population of 62.9 million) aged > or =40 years who had valid ankle-brachial index measurements available, subjects were categorized as having MS (without DM), DM, preexisting cardiovascular disease, or none of these conditions. The presence of PAD was defined as an ankle-brachial index <0.9. Subjects were also divided into groups according to CRP levels that were low (<1 mg/L), intermediate (1 to 3 mg/L), and elevated (>3.0 mg/L). Weighted multiple logistic regression analysis examined the odds of PAD by CRP group and disease category compared with the reference group of subjects who did not have MS, DM, or cardiovascular disease and had a CRP level of <1 mg/L. Those with MS (including DM) had an increased likelihood of PAD (odds ratio 4.8, 95% confidence interval 1.4 to 16.1, p = 0.01) as did those with MS without diabetes and an elevated CRP level (odds ratio 3.9, 95% confidence interval 1.1 to 14.6, p = 0.04); those with DM and an elevated CRP had the highest likelihood of PAD (odds ratio 8.6, 95% confidence interval 2.2 to 34.0, p = 0.001). In conclusion, the likelihood of PAD in US adults with MS and DM is enhanced by elevated CRP levels.

Prevalence and control of dyslipidemia among persons with diabetes in the United States.

OBJECTIVE: We assessed the prevalence, treatment, and control of dyslipidemia among United States (U.S.) adults with diabetes. METHODS: Among 498 adults (projected to 13.4 million) aged >or=18 years with diabetes representative of the U.S. population and surveyed within the cross-sectional National Health and Nutrition Examination Survey 1999-2000, control of lipids was classified according to American Diabetes Association criteria. The extent of low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and triglyceride (TG) control was examined by gender and ethnicity, in comparison to those without diabetes, and according to lipid-lowering treatment. Analyses were weighted to the U.S. population. RESULTS: Less than one-third of men and only one-fifth of women with diabetes are in control for LDL-C, defined as <2.6 mmol/l (<100mg/dl); over 70% are not at goal. Over half of men and over two-thirds of women have low levels of HDL-C (or=1.7 mmol/l [150 mg/dl]). Low HDL-C was more common in Caucasians (70.1%) than in Hispanics (58.8%) or African-Americans (41.5%) (p<0.001). 28.2% of subjects with diabetes were on lipid-lowering treatment. Control of LDL-C did not differ by treatment status and only 3% of subjects were controlled to target levels for all lipids. CONCLUSION: Many persons with diabetes remain uncontrolled for dyslipidemia. Intensified efforts at screening and treatment according to current guidelines are warranted.

Hypertension knowledge, awareness, and attitudes in a hypertensive population.

OBJECTIVE: Improved recognition of the importance of systolic blood pressure (SBP) has been identified as one of the major public health and medical challenges in the prevention and treatment of hypertension (HTN). SBP is a strong independent risk factor for cardiovascular disease but no information is available on whether patients understand the importance of their SBP level. The purpose of this study was to assess HTN knowledge, awareness, and attitudes, especially related to SBP in a hypertensive population. DESIGN/SETTING/PATIENTS: We identified patients with HTN (N=2,264) in the primary care setting of a large midwestern health system using automated claims data (International Classification of Diseases, Ninth Revision [ICD-9] codes 401.0-401.9). We randomly selected 1,250 patients and, after excluding ineligible patients, report the results on 826 completed patient telephone interviews (72% response rate [826/1,151]). MAIN RESULTS: Ninety percent of hypertensive patients knew that lowering blood pressure (BP) would improve health and 91% reported that a health care provider had told them that they have HTN or high BP. However, 41% of patients did not know their BP level. Eighty-two percent of all patients correctly identified the meaning of HTN as "high blood pressure." Thirty-four percent of patients correctly identified SBP as the "top" number of their reading; 32% correctly identified diastolic blood pressure (DBP) as the "bottom" number; and, overall, only 30% of patients were able to correctly identify both systolic and diastolic BP measures. Twenty-seven percent of patients with elevated SBP and DBP (as indicated by their medical records) perceived that their BP was high. Twenty-four percent of patients did not know the optimal level for either SBP or DBP. When asked whether the DBP or SBP level was more important in the control and prevention of disease, 41% reported DBP, 13% reported SBP, 30% reported that both were important, and 17% did not know. CONCLUSIONS: These results suggest that, although general knowledge and awareness of HTN is adequate, patients do not have a comprehensive understanding of this condition. For instance, patients do not recognize the importance of elevated SBP levels or the current status of their BP control. An opportunity exists to focus patient education programs and interventions on the cardiovascular risk associated with uncontrolled HTN, particularly elevated SBP levels.

Development of a parametric simulation model for forecasting goal-oriented treatment outcomes.

BACKGROUND: Treatment-to-goal (TTG) analyses are frequently used to predict guideline-directed population control rates for drug therapies based on mean efficacy data. Nevertheless, estimates are commonly inaccurate because variability in efficacy is not considered. A new methodology was developed to improve TTG forecasting. METHODS: Patient-level blood pressure (BP) lowering data sets, designed to simulate clinical trial results, were generated for testing from three underlying distributions: normal, lognormal, and beta. To emulate real-world conditions where patient-level data are unavailable, two approaches were considered: parametric--simulated BP lowering data were generated using the mean and standard deviation of the test data sets; and point-estimate--BP lowering was uniformly assigned as the mean lowering. BP control (systolic BP < 140 and diastolic BP < 90 mmHg) was forecasted by subtracting values generated by these two methods from baseline BP values in untreated hypertensive patients (n = 2483) from the Third National Health and Nutrition Examination Survey. Estimated control rates were compared to analyses where the patient-level data sets were bootstrapped. RESULTS: We assumed mean (+/- SD) BP lowering of 20 (12) mmHg systolic and 14 (7) mmHg diastolic. Parametric method predicted a BP control rate of 66.9% [95% confidence interval (CI) 65.7-67.9], similar to the bootstrapping approach (67.3%, 95% CI 65.9-68.8). The control rate projected based on the point-estimate method was 75.5%. The point-estimate method frequently led to substantially different results under a wide range of model assumptions. CONCLUSIONS: A new parametric-based forecasting method, which addresses underlying variability, improves on estimates based on mean efficacy only. In the absence of patient-level data, this method is generalizable to different therapeutic areas.

The expanding national burden of heart failure in the United States: the influence of heart failure in women.

BACKGROUND: Although some studies have shown that hospital admissions for heart failure doubled between 1973 and 1995, other data suggest that the heart failure hospitalization epidemic has stabilized in the United States. We sought to describe trends in heart failure hospitalizations over the past decade using data from the National Hospital Discharge Survey (NHDS). METHODS: The NHDS provides annual estimates of hospitalization discharges from a sample of hospitals in the United States. We combined the heart failure hospitalization frequencies with census estimates to calculate age and gender-specific annual hospitalization rates. RESULTS: Hospitalizations with a primary diagnosis of heart failure among adults (age > or =35) increased from 810,624 in 1990 to 989,500 in 1995 (annual increase 36,088, R2 = 0.816, P =.014), and to 1,088,349 in 1999 (annual increase 31,091, R2 = 0.780, P =.047). The age-adjusted hospitalization rate (per 1000 persons) increased from 7.186 in 1990 to 8.554 in 1999 for women (annual increase 0.14/year, R2 = 0.731, P =.002) and from 6.892 in 1990 to 7.372 in 1999 for men (annual increase 0.011/year, R2 = 0.008, P = 0.80). For women, the annual hospitalization rate increased from 1990 to 1999 in each age group (35-64, 65-74, 75-84, and > or =85), while the age-specific rates did not change in men. CONCLUSIONS: Heart failure hospitalizations have continued to increase from 1990 to 1999. Although aging and growth of the US population contribute to this trend, the increases are substantially influenced by changes in hospitalization rates in women.

Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey.

BACKGROUND: The combination of cardiovascular risk factors known as the metabolic syndrome is receiving increased attention from physicians, but data on the syndrome's association with morbidity are limited. METHODS AND RESULTS: Applying National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria, we evaluated 10 357 NHANES III subjects for the 5 component conditions of the metabolic syndrome: insulin resistance, abdominal obesity based on waist circumference, hypertriglyceridemia, low HDL cholesterol (HDL-C), and hypertension, as well as the full syndrome, defined as at least 3 of the 5 conditions. Logistic regression was used to estimate the cross-sectional association of the syndrome and each of its 5 component conditions separately with history of myocardial infarction (MI), stroke, and either MI or stroke (MI/stroke). Models were adjusted for age, sex, race, and cigarette smoking. The metabolic syndrome was significantly related in multivariate analysis to MI (OR, 2.01; 95% CI, 1.53 to 2.64), stroke (OR, 2.16; 95% CI, 1.48 to 3.16), and MI/stroke (OR, 2.05; 95% CI, 1.64 to 2.57). The syndrome was significantly associated with MI/stroke in both women and men. Among the component conditions, insulin resistance (OR, 1.30; 95% CI, 1.03 to 1.66), low HDL-C (OR, 1.35; 95% CI, 1.05 to 1.74), hypertension (OR, 1.44; 95% CI, 1.00 to 2.08), and hypertriglyceridemia (OR, 1.66; 95% CI=1.20 to 2.30) were independently and significantly related to MI/stroke. CONCLUSIONS: These results indicate a strong, consistent relationship of the metabolic syndrome with prevalent MI and stroke.

Cost of Heart Failure in Patients Receiving beta-Blockers and Angiotensin-Converting Enzyme Inhibitors.

OBJECTIVE: Numerous studies support the benefit of beta-blockers and angiotensin-converting enzyme inhibition (ACE-I) in the management of heart failure. However, the real-world cost of heart failure in patients who take these medications is not well documented; furthermore, it is unclear if heart failure costs remain significant when current, appropriately aggressive care is delivered. DESIGN: This study describes 1-year medical costs in patients hospitalised for heart failure who received these therapies, alone or in combination. METHODS: The study population was derived from 2.5 million patients with at least 3 years' continuous eligibility in Pharmetrics((R)), an integrated claims and pharmacy database on approximately 25 million covered lives from 40 US health plans. The enrolment period was from 1 January 1996 to 31 December 2000. Costs included all recorded payments over a 1-year period. A total of 3073 patients (age >18 years) hospitalised with heart failure were identified (mean [+/- SD] age 72 +/- 13 years; 46% female). RESULTS: The 1-year cost was $US16 786 in patients who received neither ACE inhibitors nor beta-blockers as compared with $US19 567, $US22 785 and $US27 078 in patients who received ACE inhibitors, beta-blockers or both drugs at maximum dosage, respectively (p < 0.001) [year of costing 2000]. Follow-up costs were substantial, representing almost twice the initial hospitalisation cost. Adjusted for age, sex, diabetes mellitus, coronary disease, hypertension and renal failure, costs remained significant in heart failure patients who received ACE inhibitors and/or beta-blockers. CONCLUSIONS: The 1-year cost of therapy for patients with heart failure is substantial, and there remains considerable need for more effective therapy to reduce the societal economic burden.

Blood pressure lowering and life expectancy based on a Markov model of cardiovascular events.

The life expectancy benefits of antihypertensive treatment, based on both systolic and diastolic blood pressure reduction, was estimated with a cardiovascular disease event Markov model with prospective data from 57 573 men and women. Seven patient states were defined, including (1) no cardiovascular disease, (2) stroke, (3) myocardial infarction, (4) revascularization, (5) history of cardiovascular disease, (6) noncardiovascular disease death, and (7) cardiovascular death. Risk functions were developed from gender-specific multivariate Cox proportional hazards models for primary events and age-, smoking-, and diabetes-adjusted models for secondary events. At baseline we assumed (1) hypothetical pretreatment blood pressures of 160/95 or 150/90 mm Hg; (2) strategies A and B lower blood pressure by 20/13 and 13/8 mm Hg, respectively; and (3) baseline age of 35 years. For subjects initially at 160/95 mm Hg, those with antihypertensive treatment, antihypertensive treatment and diabetes, or antihypertensive treatment, diabetes, and currently smoking had corresponding gains in life expectancy of 2.43, 2.80, and 2.43 years for Strategy A. An initial blood pressure of 150/90 mm Hg resulted in similar gains. Compared with Strategy B, with blood pressure reductions of 13/8 mm Hg, Strategy A provided additional gains in life expectancy of 0.84, 0.99, and 0.87 years for those with antihypertensive treatment, antihypertensive treatment and diabetes, or antihypertensive treatment, diabetes, and currently smoking. The initial blood pressure level did not affect the magnitude of life expectancy gains for equivalent blood pressure reductions. Greater gains in life expectancy among hypertensive and diabetic women suggest that blood pressure lowering may yield greater benefits in selected subgroups.

Patient knowledge and awareness of hypertension is suboptimal: results from a large health maintenance organization.

Patient knowledge and awareness of hypertension are important factors in achieving blood pressure control. To examine hypertensive patients' knowledge of their condition, the authors randomly surveyed 2500 hypertension patients from a large health maintenance organization; questionnaires were supplemented with clinic blood pressure measurements. Approximately 72% of the subjects completed surveys. Of patients with uncontrolled hypertension (systolic blood pressure [SBP] > or =140 mm Hg and/or diastolic blood pressure [DBP] > or =90 mm Hg), only 20.2% labeled their blood pressure as "high" and 38.4% as "borderline high". Forty percent of respondents couldn't recall their most recent clinic-based SBP and DBP values. Overall, 71.7% and 61% were unable to report a target SBP or DBP, respectively, or identify elevated targets based on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) criteria. Most patients perceived DBP to be a more important risk factor than SBP. Hypertensive patients awareness of blood pressure targets and current hypertension control status, particularly with respect to SBP, is suboptimal. The authors' findings support the need to improve patient education for better management of hypertension.

The cost-effectiveness of irbesartan in the treatment of hypertensive patients with type 2 diabetic nephropathy.

BACKGROUND: End-stage renal disease (ESRD)-related health care costs are substantial. Improving clinical outcomes in patients at risk of progression to ESRD could lead to considerable health care savings. OBJECTIVE: We estimated the cost-effectiveness of irbesartan compared with placebo or amlodipine in the treatment of patients with type 2 diabetes mellitus, hypertension, and overt nephropathy. METHODS: Three treatments for hypertension patients with type 2 diabetes mellitus and nephropathy were assessed: (1) irbesartan, (2) amlodipine, and (3) placebo. A Markov model was developed based on primary data from the Irbesartan in Diabetic Nephropathy Trial and the United States Renal Data System. Projected survival and costs were compared for each treatment at 3-, 10-, and 25-year time horizons. Different assumptions of treatment benefits and costs were tested with use of sensitivity analyses. RESULTS: At 10 and 25 years, the model projected irbesartan to be both the least costly and most effective (ie, demonstrating a survival advantage) strategy. At 25