Trends in the use of antihypertensive drugs by outpatients with diabetes in Taiwan, 1997-2003

PURPOSE: To analyze trends in AHD-use by diabetic outpatients in Taiwan over a 7-year period (1997-2003) and to see whether the trends are consistent with clinical trial outcomes and published guidelines. METHODS: A cross-sectional survey was implemented using National Health Insurance Research Database between January 1997 and December 2003. Adult outpatients who had diagnoses of diabetes and hypertension and who had concurrent antidiabetic and antihypertensive drug claim were identified. The prescribing trends were described in terms of the prescribing rates and patterns of AHDs in each study year. RESULTS: Of the AHDs, CCBs were the most widely prescribed class throughout the study period but the prescribing rates declined considerably over the study period. A significant downward trend was also observed for beta-blockers and other classes. Drugs acting on the RAS were the only one class showing a significant increase in prescribing rates with time. The prescribing patterns for monotherapy regimen decreased over time while those for two-, three-, and four or more drug regimens increased over time. Monotherapies maintained with CCBs, beta-blockers, diuretics, and other classes steadily declined but those maintained with drugs acting on the RAS markedly increased. CONCLUSIONS: The use of drugs acting on the RAS showed a marked increasing trend over the course of the study. Physicians' prescribing patterns for AHD are increasingly involving multi-drug regimens. These findings may imply that management of hypertension in patients with diabetes had a positive trend toward to new clinical trial outcomes and guideline's recommendation.     

Lipid-lowering drug use in Italian primary care: effects of reimbursement criteria revision

Objective To assess whether the prescribing pattern of lipid-lowering drugs (LLD) changed after reimbursement criteria revision in a general practice in southern Italy. Methods From the Caserta-1 Local Health Service database, 93 general practitioners (GPs) who had consistently sent data about their patients during the years 2003-2005 were recruited. Prevalence of use and incidence of new treatments were calculated for each year, stratified by three drug cohorts: statins, omega-3 fatty acids, and fibrates. Subanalyses by gender, age, and indication of use were performed. Results Overall, 1-year prevalence of LLD use increased from 2003 to 2004. After reimbursement criteria revision (November 2004), a slight decrease was observed for statins, from 41.1 (95% CI: 39.9–42.2) per 1,000 inhabitants in 2004 to 40.3 (39.2–41.5) in 2005, while omega-3 utilization fell markedly: 14.6 (13.9–15.3) vs. 5.4 (5.0–5.8). The use of both statins and omega-3 fatty acids was reduced particularly for primary prevention. On the other hand, utilization of statins increased in diabetic patients and as secondary prevention from 2004 to 2005. Concerning individual molecules, 1-year prevalence of use of any statin declined from 2004 to 2005, except for rosuvastatin. Conclusions Revision of reimbursement criteria led to significant changes in the trend in LLD use in general practice in southern Italy: (1) statin utilization was slightly reduced in 2005, although it increased in certain categories, such as diabetic patients, and (2) omega-3 fatty acid use was strongly reduced even though a higher use in post-infarction cases was reported.     

Trends in prescribing and utilization of statins and other lipid lowering drugs across Europe 1997-2003

AIMS: To describe trends in utilization and prescribing of statins and other lipid lowering drugs across Europe from data in routine administrative databases. METHODS: Observational study in EU member states and Norway. Comparison of annual utilization data for lipid lowering agents by class and drug from national administrative databases for reimbursement over the period 1997-2003, measured in DDDs per 1000 inhabitants/day. Prescribed daily doses (PDD) of statins obtained from a commercial database (IMS Health) for 2000 and 2003, and used to calculate numbers of "patient treatment days" (PTD) in each country in each year. Analysis of PTD to explain increased utilization of statins. RESULTS: Use of lipid lowering agents varied among countries (in 2003, highest in Ireland and Norway, and lowest in Italy), but increased in all countries studied (between 2000 and 2003 by 274% in Ireland and by 56% in France). This increase was entirely due to increases in statin use. Prescribed daily doses of statins increased in all countries for which data was available between 2000 and 2003, but still usually fell below the doses used in the major trials of statins. As a result, the numbers of PTDs increased to a lesser extent than suggested by utilization (e.g. by 192% in Ireland and by 35% in France). One-third of the total rise in utilization was explained by increased PDD, and two-thirds by an increase in numbers of PTDs. Statins dominated the markets in all countries, although fibrates remained strong in France and Belgium (approximately 25% of all lipid lowering agents) and to a lesser extent Germany (10%). CONCLUSIONS: Use of statins across Europe has increased hugely over the study period. Some of the increase in use is due to higher prescribed daily doses, but two-thirds is due to increases in numbers of patient days of treatment, either due to more patients treated or less likely to better compliance.     

Regional variation in the prescribing for diabetes and use of secondary preventative therapies in Ireland

PURPOSE: To compare the prescribing of secondary preventative therapies for patients with both insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) in the eight health board regions of Ireland. METHODS: We utilized data from the national general medical services (GMS) prescribing database to examine the variability of prescribing for diabetes and associated secondary therapies between regions in those aged 45 years or more. Age-sex standardized prescribing rates of six secondary preventative therapies (aspirin, beta-blockers, statins, ACE inhibitors, angiotensin receptor (AT2) antagonists, and fibrates) were calculated for each region. RESULTS: Variations exist between regions for treated NIDDM (1.5-fold) and IDDM (1.5-fold). Wide variations were observed between regions for prescribing of secondary preventative therapies with the highest variability observed for statin prescribing (1.5- to 1.6-fold) and for AT2 antagonist prescribing (2.0-fold) in NIDDM patients. In those with NIDDM, men were more likely to receive aspirin OR=1.26 (1.21--1.31), ACE inhibitors 1.14 (1.101.18), and fibrates OR=1.55 (1.23--1.96) than women and those aged over 75 years were less likely to receive statins OR=0.60 (0.56--0.65) and fibrates OR=0.25 (0.17--0.37) than those aged 45--74. Similar results were also shown for patients with IDDM. CONCLUSIONS: The results suggest that access to secondary preventative therapy in diabetes patients is not equitable across regions, gender, and age in Ireland. While much of the variability remains unexplained, it may be due to differences in screening and health promotion between regions, prescriber uncertainty, variability in clinical need, or may be derived from a socioeconomic disparity among regions.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus

INTRODUCTION: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy. AREAS COVERED: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin-fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial. EXPERT OPINION: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance,metabolic syndrome and type 2 diabetes mellitus

Introduction: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy.

Areas covered: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin–fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial.

Expert opinion: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.     

Whom are we treating with lipid-lowering drugs? Are we following the guidelines? Evidence from a population-based study: the Tromsø study 2001

Objective: The beneficial effect of lipid-lowering drugs (LLDs) is well documented. Despite increasing sales of LLDs, little is known about what characterizes LLD users. Our objective was to describe LLD users in a general population according to socio-demographic factors, cardiovascular risk factors and coronary heart disease (CHD), and to study the achievement of cholesterol treatment goals according to national guidelines. Methods: The Tromsø study is a population-based study of chronic diseases, risk factors and drug use in the municipality Tromsø, in north Norway. The fifth survey was conducted in 2001 and included 7,973 men and women (attendance rate 78.1%). Self-reported use of LLDs and/or proprietary LLDs was included as LLD use in the analysis. Results: LLD use was reported in 9.6% of all women and 14.0% of all men, of whom 36.5% achieved the nationally recommended lipid goal. Among individuals with CHD, 49.9% of all women and 55.4% of all men were LLD users. The individuals with a risk condition (hypertension and/or diabetes) and total cholesterol level above the target of 5.0 mmol/l and the healthy individuals with total cholesterol level 8.0 mmol/l constituted 47.2% of the study population without CHD. In this group, which was eligible for primary prevention, 8.0% of the women and 7.4% of the men reported LLD use. Conclusions: Only half of all subjects with CHD were taking a LLD. The large discrepancy between national recommendations and actual LLD use in primary prevention should be addressed in future revisions of the guidelines.     

The role of a new formulation of fenofibric acid in the treatment of mixed dyslipidemia in type 2 diabetes

Diabetes, due to its multifactorial effects, increases the risk of developing cardiovascular disease. Dyslipidemia is an important modifiable risk factor. Mixed dyslipidemia (low high-density lipoprotein cholesterol [HDL-C], elevated triglycerides and a high percentage of small, dense lowdensity lipoprotein cholesterol [LDL-C]) is a common lipid disorder in diabetics and is considered especially atherogenic. Research suggests that in patients with dyslipidemia, combination therapy with fibrates and statins may be more effective than statin monotherapy alone. The choline salt of fenofibric acid (choline fibrate) is indicated for the treatment of mixed dyslipidemia, either as a single treatment or in combination with statin therapy. It does not require first-pass metabolism, but dissociates in the gastrointestinal tract into the pharmacologically active fenofibric acid. This new formulation of fenofibric acid in combination with a low or moderate dose of statin has been shown to be effective in increasing HDL-C and lowering triglycerides beyond that provided by statin monotherapy alone. The ACCORD trial failed to show a mortality or morbidity benefit after combination therapy, although the data suggested that combination therapy may benefit patients with mixed dyslipidemia.     

Low myopathy rates associated with statins as monotherapy or combination therapy with interacting drugs in a group model health maintenance organization

STUDY OBJECTIVE: Because the risk for myopathy increases when 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) are used with other agents known to inhibit cytochrome P450 3A4 in patients with dyslipidemia, we sought to quantify this risk in a diverse, real-world sample of patients receiving statin therapy. DESIGN: Retrospective chart review. SETTING: Kaiser Permanente Colorado (KPCO), a group model health maintenance organization with approximately 360,000 members. PATIENTS: Four hundred sixty-eight patients who were identified as having a diagnosis of myopathy over a 4-year period using KPCO computerized data systems. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed to confirm myopathy cases associated with statin therapy. Of the 468 patients, 61 had received statin therapy before their diagnosis, and 41 (67%) of these patients had confirmed myopathy (documented creatine kinase level>or=1000 IU/L). The prevalence of myopathy was 0.12% with statin monotherapy and 0.22% with statins in combination with interacting drugs. Only 17 of the 41 (41%) patients had confirmed myopathy with no other plausible clinical explanation, such as a muscle injury. Increased risk of myopathy associated with statin therapy in combination with interacting drugs approached statistical significance (p=0.052) but was of minimal clinical significance. CONCLUSION: The prevalence of confirmed myopathy in patients receiving statin therapy is low (<1%). Combining statin therapy with interacting drugs (e.g., fibrates) was not associated with a clinically important increase in the prevalence of myopathy. The risk of developing myopathy during statin therapy is outweighed by the benefits derived from the therapeutic effects of the therapy.     

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug–drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.     

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug-drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.     

Channelling of Statin Use towards Low‐Risk Population and Patients with Diabetes

This study based on nationwide comprehensive health registers analysed trends in characteristics of statin users in the whole community‐dwelling population of Finland between 1999 and 2008. The annual number of incident users (defined as those purchasing statins for the first time ever) increased 1.6‐fold from 50,125 to 78,058 and that of ongoing users (including continuous users and re‐initiators) increased 4.6‐fold from 114,091 to 521,211. The proportion of incident users without cardiovascular disease (CVD) or diabetes increased from 23.6% to 27.8%, while the proportion of those with diabetes increased from 15.7% to 19.5%. An increasing proportion of ongoing users had diabetes (from 13.8% to 22.8%). The proportion of ongoing users without CVD or diabetes remained below one‐fifth; however, their number increased five‐fold. Over the study period, there was an obvious shift towards prescribing of higher statin doses both among incident and ongoing users. In conclusion, statin use is expanding to individuals with low cardiovascular risk despite the fact that clinical guidelines emphasize interventions other than pharmacotherapy for this population. At the same time, statin use is increasingly targeted to patients with diabetes, a high‐risk group that is likely to benefit from it.     

Combination lipid therapy in type 2 diabetes mellitus

INTRODUCTION: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia - hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) - that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes. AREAS COVERED: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes. EXPERT OPINION: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

Role of Colesevelam in Combination Lipid-Lowering Therapy

Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug–drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.     

Prescribing behaviour according to Dutch and European guidelines on the management of hypercholesterolaemia (1992-1999)

BACKGROUND: The success of the full implementation of a new guideline may depend on the observed discrepancy between daily medical practice developed before the release of the guideline and new treatment recommendations issued by the guideline. AIM: To assess whether the initiation of statin treatment for primary prevention of cardiovascular disease in an elderly population was in agreement with guidelines. METHODS: Data were obtained from the Rotterdam Study, a prospective population-based cohort study consisting of 7983 subjects aged>or=55 years. In the period 1992-1999, all patients starting statins for primary prevention were selected. Treatment eligibility was established according to Dutch guidelines based on considerations of cost effectiveness (1998) and European guidelines based on clinical effectiveness (1998 and 2003). RESULTS: Only 5.7% [95% confidence interval (CI) 3.1, 8.3] of the 299 subjects starting statins for primary prevention met the eligibility criteria of the Dutch guidelines. Most patients (92.0%, 95% CI 88.9, 95.1) met the criteria of the 2003 European guidelines. Patients who did not meet any eligibility criteria were female and had one or less cardiovascular risk factor, except for two patients with total cholesterol levels<5 mmol l-1 prior to start of statin therapy. CONCLUSIONS: The use of statins was in agreement with the most recent European guidelines in over 90% of elderly patients who started statins for primary prevention, but in only 6% of these patients according to the Dutch guidelines. As long as existing guidelines are as discrepant as they are now, variation in agreement between physicians' prescribing and guideline recommendations is unavoidable.