Long-term efficacy and safety of rosuvastatin 40 mg in patients with severe hypercholesterolemia.

Patients with elevated low-density lipoprotein (LDL) cholesteral levels are at high risk of cardiovascular events but are often undertreated and fail to achieve lipid goals. This open-label, noncomparative, multicenter study assessed efficacy and safety of rosuvastatin 40 mg for < or =96 weeks in 1,380 patients with severe hypercholesterolemia, including heterozygous familial hypercholesterolemia. Patients > or =18 years old with fasting LDL cholesterol > or =190 and < or =260 mg/dl and triglycerides <400 mg/dl entered a 6-week dietary lead-in, before receiving rosuvastatin 40 mg for 48 weeks. An optional additional 48-week treatment period followed. The initial period had 2 primary end points: percentage of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL cholesterol goals at 12 weeks, and long-term safety, assessed during 48 weeks by incidence and severity of adverse events (AEs) and abnormal laboratory values. Safety was the primary end point in the extension period. At 12 weeks, 83% of patients achieved NCEP ATP III LDL cholesterol goals, which were maintained during 48 and 96 weeks (81% and 84%, respectively). At 48 weeks, rosuvastatin 40 mg reduced LDL cholesterol from baseline by 52% and increased high-density lipoprotein (HDL) cholesterol by 11% (both p <0.0001). At 96 weeks, LDL cholesterol was reduced by 54% and HDL cholesterol increased by 13%. Rosuvastatin 40 mg was well tolerated during 96 weeks. The overall pattern and incidence of AEs and abnormal laboratory values were consistent with the published safety profile of rosuvastatin and higher doses of other statins. In conclusion, long-term treatment with rosuvastatin 40 mg is safe and effective in patients with severe hypercholesterolemia.

Rising to the challenge of treating high-risk patients.

Guidelines from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) focus the need for the most intensive efforts to lower low-density lipoprotein cholesterol (LDL-C) in the patients at greatest risk of a major future clinical coronary heart disease event. Major clinical trials, such as Pravastatin or Atorvastatin Evaluation and Infection Therapy and the Heart Protection Study, demonstrated the value of lowering LDL-C levels in high-risk patients to well below the ATP III target of <100 mg/dL. In 2004, the NCEP writing group suggested that a more aggressive LDL-C goal of <70 mg/dL is an option when treating high-risk patients, particularly those with the presence of established cardiovascular disease plus major multiple risk factors (especially diabetes), severe and poorly controlled risk factors (ie, cigarette smoking), multiple criteria of the metabolic syndrome, or an acute coronary syndrome. With stricter targets, high-risk patients are less likely to achieve their cholesterol goals than lower risk patients. Recent large trials comparing rosuvastatin with other statin monotherapies have shown a greater LDL-C reduction and better attainment of goals with rosuvastatin. In addition, the MERCURY [Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy] trials demonstrate that switching to rosuvastatin significantly increased the percentage of patients who achieved their ATP III LDL-C targets.

How safe is aggressive statin therapy?

The most recent guidelines of the National Cholesterol Education Program recommend more aggressive low-density lipoprotein cholesterol goals: <100 mg/dL for patients at moderate or high risk of cardiovascular disease, and <70 mg/dL for patients at very high risk. These lower goals are more likely to be achieved using the more powerful statins--atorvastatin, rosuvastatin, and simvastatin. Although statins are widely used, extensively studied, and known to have an excellent safety profile, the perception of many health care providers and patients is that safety concerns about the more efficacious statins, especially at high doses, limit their use. However, clinical data consistently support the view that adverse events are uncommon even when intensive therapy is used to reach aggressive low-density lipoprotein cholesterol goals. Overall, the more potent statins have similar safety profiles. The benefits of aggressive statin treatment in reducing the risk of cardiovascular events appear to far outweigh any potential risks of adverse events.

Emerging data on the incidence of concussion in football practice at all levels of amateur play.

There has been increasing concern, particularly in the US, about potential long-term neurological deterioration syndromes seen in the US football players. Recurrent concussions are a potential area of concern. The authors of this paper have used data bases from three levels of amateur US football to identify the rate and risk of concussion injury in both football games and practice at the youth, high school, and college levels. This information is very important initial data around concussion rates at these levels.

Clinical use of dipeptidyl peptidase-4 and sodium-glucose cotransporter 2 inhibitors in combination therapy for type 2 diabetes mellitus.

OBJECTIVE: To review the efficacy, safety, and tolerability of combination treatment regimens including a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or sodium-glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes mellitus (T2DM). METHODS: Clinical trials of combination therapies including a DPP-4 and/or SGLT2 inhibitor were identified through a PubMed database search. To be included, studies had to have a primary end point of change from baseline to ≥24 weeks in glycated hemoglobin, include ≥1 other oral antidiabetic drug (OAD), and have randomized more than 200 patients. Results were limited to medications approved by the US Food and Drug Administration at the time of the search (March 2015). RESULTS: A total of 1534 articles for the DPP-4 inhibitor class and 434 articles for the SGLT2 inhibitor class were retrieved from PubMed. Of these, 33 articles from the DPP-4 inhibitor class and 24 articles from the SGLT2 inhibitor class were included for review. In each study, the addition of a DPP-4 or SGLT2 inhibitor as a second or third agent resulted in improved glycemic control versus comparator arms. Reductions in weight or lack of weight gain were consistently observed, as were low rates of hypoglycemic events, particularly when the combination regimen also included metformin. Overall, the pattern of adverse events observed in combination treatment groups was consistent with the known effects of the individual agents. CONCLUSION: Combination treatment with a DPP-4 and/or SGLT2 inhibitor is an efficacious option for patients with T2DM starting pharmacological therapy, or for patients who have received treatment but require additional glycemic control. Study findings indicate that the underlying mechanisms of action of DPP-4 inhibitors and SGLT2 inhibitors complement a variety of OADs.

Practice pearl: the effect of canagliflozin on HbA1c and blood pressure in patients with type 2 diabetes mellitus.

Review of: Wilding JPH, Blonde L, Leiter LA, et al. Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus. J Diabetes Complications. 2015;29(3):438-444; and Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertension. 2014;16(12):875-882. Two authors did secondary analyses on the original research data for canagliflozin. Wilding et al. found that the degree of the lowering of the HbA1c in patients was greater in patients with a higher baseline HbA1c. Weir et al. found that the blood pressure lowering seen with canagliflozin was greater if the baseline blood pressures were higher. This shows that canagliflozin will have increased effects in more complicated patients.

Sodium-glucose co-transporter 2 inhibitors and the potential for cardiovascular risk reduction in patients with type 2 diabetes mellitus.

BACKGROUND: Clinical development programs of investigational antidiabetic agents now include evaluation of cardiovascular (CV) risk as a major research focus. Recently, several compounds in a new class of antihyperglycemic therapy have reached the final stages of development. Treatment with inhibitors of sodium-glucose co-transporters 2 (SGLT2) leads to urinary excretion of glucose in patients with type 2 diabetes mellitus (T2DM), and is associated with clinically significant reductions in blood glucose levels. The glucosuria-based mechanism of this class has the potential to induce weight loss through reduced caloric availability, and, in addition, may affect blood pressure (BP) via osmotic diuresis or other as yet incompletely characterized mechanisms. METHODS: Searches of the PubMed database were conducted for published studies evaluating the use of SGLT2 inhibitors that reported data on CV risk factors (eg, weight, BP, lipid levels) or CV events. Searches for presentations at recent major diabetes congresses were performed using the Online Submission and Invitation System. RESULTS: Treatment with SGLT2 inhibitors has consistently been associated with reduction in body weight and BP. Qualitative graphical assessment of 21 studies shows unadjusted reductions in systolic BP and body weight typically ranging between 3 to 5 mm Hg and 2 to 3 kg, respectively. A few reports have suggested the potential for improvement in lipid parameters, such as high-density lipoprotein cholesterol levels; however, not all studies have demonstrated significant changes, and some have noted small increases in low-density lipoprotein cholesterol levels. CONCLUSION: Inhibition of SGLT2 in patients with T2DM may be associated with significant weight loss and BP reduction that are sustainable over the average time span of an investigational clinical study (ie, 3-6 months). When considered in terms of the potential for combination therapy, these features may offer a means of further reducing metabolic and CV risk in patients with T2DM.

Telmisartan/Hydrochlorothiazide combination therapy for the treatment of hypertension: a pooled analysis in older and younger patients.

Older patients frequently receive angiotensin II receptor blocker/diuretic combinations to control blood pressure (BP), although there have been relatively few trials specifically examining this patient population. A pooled analysis was performed of data from 7 randomized trials of telmisartan/hydrochlorothiazide combinations or telmisartan monotherapy in older (65 years and older) and younger (younger than 65 years) patients to better understand the response of older patients to a telmisartan/hydrochlorothiazide combination. Telmisartan doses were 40 mg and 80 mg (T40 and T80). Hydrochlorothiazide doses were 12.5 mg and 25 mg (H12.5 and H25). A total of 3654 patients were included and the mean treatment duration was approximately 8 weeks. BP reductions with telmisartan/hydrochlorothiazide combinations were broadly similar in older and younger patients. In older patients, mean BP reductions from baseline were -30.1/-19.0 mm Hg with the T80/H25 combination and -21.7/-13.0 mm Hg with T80 monotherapy. Tolerability was similar regardless of age, and the incidence of adverse events in both older and younger patients was similar to placebo. The telmisartan/hydrochlorothiazide combination, particularly high-dose T80/H25, is effective and well tolerated in patients 65 years and older as well as in younger patients.

Evolving therapeutic options for type 2 diabetes mellitus: an overview.

INTRODUCTION: Many oral antidiabetic drugs (OADs) are available for patients with type 2 diabetes mellitus (T2DM). However, it is recognized that additional therapies are needed and several new compounds are in advanced stages of development. PURPOSE: This narrative review considers the essential features of a successful OAD, the main classes of OADs that are currently used, and the therapies that may be available in the upcoming years. RESULTS AND CONCLUSIONS: The first OADs (sulfonylureas and biguanides) were discovered by chance. Although effective in reducing blood glucose levels, early sulfonylureas were associated with significant off-target effects, and the biguanide phenformin was discontinued due to adverse events. Although metformin is in the same drug class, it has a better safety profile and is now recommended as first-line treatment, except when contraindicated. Nonetheless, many patients require additional glucose control (even on metformin) with an agent that has a complementary mechanism of action. Developments in bench science have facilitated the selection of agents for specific therapeutic targets, with the thiazolidinediones providing an interesting example. This OAD class initially appeared encouraging, yet in clinical practice was associated with safety concerns. As a result, newer agents, such as dipeptidyl peptidase-4 inhibitors, are undergoing more rigorous safety evaluations than OADs of previous generations. Promising compounds with novel mechanisms of action include the sodium-glucose co-transporter 2 inhibitors, the G-protein-coupled receptor agonists, and the balanced dual peroxisome proliferator-activated receptor-α/γ agonists. There is optimism that in the next few years, novel classes of OADs that are currently under development will offer additional blood glucose control options via complementary mechanisms of action. However, history has shown that compounds of the same class can have different safety profiles and treatment effects. Therefore, high-quality clinical trial evidence is needed for every compound.

Review: a single-pill combination of telmisartan plus amlodipine for the treatment of hypertension.

Despite an increased proportion of patients with hypertension achieving recommended blood pressure (BP) targets, BP control remains suboptimal in many patients. A range of combination therapies utilizing medications with differing mechanisms of action have been shown to provide superior BP-lowering efficacy than monotherapy with individual components. Single-pill combinations deliver improved convenience and may help to improve patient compliance. A single-pill combination of the angiotensin receptor blocker (ARB) telmisartan and the calcium channel blocker (CCB) amlodipine has recently been approved in 4 different doses (telmisartan/amlodipine 40 mg/5 mg, 40 mg/10 mg, 80 mg/5 mg, and 80 mg/10 mg) for antihypertensive use in the United States. In an 8-week clinical study (N = 1461), these combinations were superior to monotherapy with telmisartan or with amlodipine with respect to the primary endpoint, change in diastolic BP (DBP) from baseline (mean baseline BP, 153.2 [± 12.1]/101.7 [± 4.3] mm Hg) to study end (placebo-corrected reductions of 10.3, 14.0, 12.0, and 13.9 mm Hg, respectively), as well as in multiple secondary endpoints, including change in systolic BP (SBP), DBP response, SBP response, BP control (< 140/< 90 mm Hg), and DBP control (< 90 mm Hg). The telmisartan plus amlodipine combinations were well tolerated, with the incidence of adverse events similar to placebo; the incidence of peripheral edema was lower with the 40 mg/10 mg and 80 mg/10 mg combinations than with amlodipine 10 mg alone. In another study (N = 858), the highest-dose combination (80 mg/10 mg) demonstrated superior BP-lowering efficacy than same-dose monotherapy with either telmisartan or amlodipine in patients with severe hypertension (SBP ≥ 180 and DBP ≥ 95 mm Hg). Single-pill telmisartan plus amlodipine combination therapy appears to be an effective and well-tolerated treatment as initial therapy for patients likely to require > 1 antihypertensive agent to reach BP targets.

Efficacy and tolerability of telmisartan plus amlodipine in added-risk hypertensive patients.

OBJECTIVES: Added-risk hypertensive patients with co-morbidities such as diabetes and metabolic syndrome often require two or more antihypertensives to achieve blood pressure (BP) targets. The aim of this sub-analysis was to determine the efficacy and safety of telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg in patients with hypertension, stratified according to certain criteria such as type 2 diabetes mellitus and metabolic syndrome. METHODS: Patients were treated for 8 weeks with telmisartan 20-80 mg plus amlodipine 2.5-10 mg. This post-hoc analysis included patients treated with higher doses, and stratified according to a number of sub-populations (age, race, diabetes, obesity, metabolic syndrome, elevated baseline systolic BP (SBP), renal impairment). RESULTS: Eight weeks' treatment with telmisartan plus amlodipine combinations provided consistent reductions in mean SBP/diastolic BP (DBP) across the different sub-populations, similar to the overall population. SBP/DBP reductions ranged from -13.5 to -34.7/-12.6 to -26.1 mmHg and BP goal rates (<140/90 mmHg) ranged from 29.8-100% for the four key dose combinations of telmisartan plus amlodipine. For the highest dose combination of telmisartan 80 mg plus amlodipine 10 mg, SBP/DBP reduction ranged from -19.1 to -34.7/-16.4 to -22.8 mmHg and goal attainment rate from 66.7% to 87.0%. Across the sub-populations, high SBP and DBP response rates were seen with combination treatment (83.3-97.7% and 75.0-95.7%, respectively, with telmisartan 80 mg plus amlodipine 10 mg). The combination was safe and well tolerated across all sub-populations and the incidence of peripheral oedema with telmisartan 40-80 mg plus amlodipine 10 mg was generally lower than with A10 monotherapy. CONCLUSIONS: Despite small patient numbers in some sub-populations and the post-hoc nature of the analysis, this does show that the combination of telmisartan plus amlodipine provides an effective, safe and well-tolerated antihypertensive treatment for added-risk hypertensive patients.

The safety of rosuvastatin: effects on renal and hepatic function.

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to reduce elevated serum cholesterol resulting in a reduced risk of coronary artery disease and its complications. Rosuvastatin is the latest of the class of HMG-CoA reductase inhibitors and has the most potent reduction of low-density lipoprotein and elevation of high-density lipoprotein in the class. Questions have been raised about its safety. In a careful examination of the data, rosuvastatin has the same rate of elevations of hepatic enzymes as the other statins. Whether any of the statins actually cause significant liver injury is doubtful, and this raises questions about the usefulness of routine monitoring of liver enzymes in statin patients. Rosuvastatin has been noted to produce low levels of transient proteinuria. However, transient proteinuria is seen with other comparable statins. Long-term administration of rosuvastatin and other statins have been shown not to be associated with any decline in renal function, but instead have been shown to produce modest but clear improvement in glomerular filtration rate. Therefore, it is clear that rosuvastatin, and other statins, are very safe and useful agents and do not appear to present significant risks to hepatic or renal safety.