Real-World Evidence of Tolerability of 20% Subcutaneous Immunoglobulin Treatment.

PURPOSE: The safety and efficacy of subcutaneous immune globulin 20% (human) solution (Ig20Gly) were demonstrated in clinical trials. However, real-world evidence of the tolerability of self-administered Ig20Gly in elderly patients is lacking. We describe real-world patterns of Ig20Gly usage for 12 months in patients with primary immunodeficiency diseases (PIDD) in the USA. METHODS: This retrospective chart review of longitudinal data from 2 centers included patients aged ≥ 2 years with PIDD. Ig20Gly administration parameters, tolerability, and usage patterns were assessed at initial and subsequent 6- and 12-month infusions. RESULTS: Of 47 enrolled patients, 30 (63.8%) received immunoglobulin replacement therapy (IGRT) within 12 months before starting Ig20Gly, and 17 (36.2%) started IGRT de novo. Patients were predominantly White (89.1%), female (85.1%), and elderly (aged > 65 years, 68.1%; median age = 71.0 years). Most adults received at-home treatment during the study, and most self-administered at 6 months (90.0%) and 12 months (88.2%). Across all time points, infusions were administered at a mean rate of 60-90 mL/h/infusion, using a mean of 2 sites per infusion, on a weekly or biweekly frequency. No emergency department visits occurred, and hospital visits were rare (n = 1). Forty-six adverse drug reactions occurred in 36.4% of adults, mostly localized site reactions; none of these or any adverse events led to treatment discontinuation. CONCLUSION: These findings demonstrate tolerability and successful self-administration of Ig20Gly in PIDD, including elderly patients and patients starting IGRT de novo.

Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes.

Colesevelam's glucose-lowering mechanism of action is not completely understood. Clinical trials of colesevelam suggest that its mechanism, and often adverse effects, differ from those of other oral antidiabetes drugs. Colesevelam does not affect insulin sensitivity (unlike thiazolidinediones), insulin secretion (unlike sulfonylureas and meglitinides), or early insulin response or glucagon (unlike dipeptidyl peptidase-4 inhibitors). Colesevelam may have some effect on glucose absorption, but likely via a different mechanism than α-glucosidase inhibitors. Colesevelam and metformin have similarities regarding hepatic glucose production, but divergent effects on gluconeogenesis versus glycogenolysis, suggesting differing mechanisms of drug action for improving glycemic control. Colesevelam is thought to be a portal glucagon-like peptide-1 (GLP-1) secretagogue with primarily hepatic effects. Bile acid binding by colesevelam leads to TGR5 activation, increased secretion of GLP-1 or other incretins, and inhibition of hepatic glycogenolysis. Colesevelam's mechanism of action appears to be atypical of other antidiabetes medications, making it a potentially suitable component of many combination regimens in the treatment of type 2 diabetes.

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.

Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension.

BACKGROUND: The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends initial combination therapy for patients whose blood pressure (BP) is >20/10 mm Hg above goal. This study evaluated the efficacy and safety of initial combination therapy versus that of monotherapy in patients with stage 2 hypertension, who by definition meet the JNC 7 recommendation for initial combination antihypertensive therapy. METHODS: This multicenter, double-blind, 12-week study randomized 364 patients with stage 2 hypertension to fixed-dose combination therapy with amlodipine besylate/benazepril HCl (5/20 mg/d titrated to 10/20 mg/d) or amlodipine besylate monotherapy (5 mg/d titrated to 10 mg/d). RESULTS: Significantly more patients randomized to combination therapy (74.2%) compared with those randomized to monotherapy (53.9%; P <.0001) achieved the primary end point (reductions in systolic BP > or =25 mm Hg, if baseline systolic BP was <180 mm Hg, or > or =32 mm Hg, if baseline systolic BP was > or =180 mm Hg). Significantly more patients randomized to combination therapy compared with monotherapy attained BP goals of <140/90 mm Hg (61.0% v 43.3%; P =.0007) and < or =130/85 mm Hg (35.7% v 19.1%; P =.0004). Among patients with baseline systolic BP > or =180 mm Hg, combination therapy resulted in significantly greater reductions in systolic BP compared with monotherapy (-42.3 v -30.4 mm Hg; P =.001). More than 90% of patients in each group were titrated to the higher dose. Both treatments were well tolerated. CONCLUSIONS: Combination therapy was well tolerated and resulted in significantly greater BP reductions and attainment of BP goals compared with monotherapy in patients with stage 2 hypertension. This evidence supports the recommendation of combination therapy as first-line treatment in stage 2 hypertension.

Efficacy and tolerability of a switch to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride after monotherapy with amlodipine besylate: Data from the African-American subpopulation of a practice-based, open-label study (the LOGIC study).

BACKGROUND: The LOGIC (LOtrel: Gauging Improved Control) study assessed the efficacy and tolerability of switching from amlodipine besylate monotherapy to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride (HCI) in patients who were experiencing uncontrolled blood pressure (BP) or edema with monotherapy. OBJECTIVE: This article reports the efficacy and tolerability of amlodipine besylate/benazepril HCI combination therapy in the predefined African-American population of the LOGIC study. METHODS: This multicenter (1518 centers across the United States), practice-based, open-label, clinical trial enrolled patients with mild to moderate essential hypertension. Patients in group 1 had uncontrolled BP (sitting diastolic BP [DBP] ≥90 mm Hg and ≤110 mm Hg) during treatment with amlodipine besylate monotherapy 5 or 10 mg/d, and those in group 2 had controlled BP (sitting DBP ⩽90 mm Hg), but also had experienced edema during amlodipine besylate monotherapy. Participants were instructed to discontinue amlodipine besylate and were given amlodipine besylate/benazepril HCl 5/10 mg/d or 5/20 mg/d for 4 weeks. For group 1, the primary efficacy outcome was the change in mean sitting DBP (MSDBP) from baseline to week 4; a secondary efficacy outcome was the change in mean sitting systolic BP (MSSBP) from baseline to week 4. The primary efficacy outcome for group 2 was the percentage of patients whose edema improved with the switch to combination therapy. The secondary efficacy variables in group 2 were the changes in MSDBP and MSSBP from baseline to week 4. Patients in groups 1 and 2 were questioned about any adverse events that may have occurred since the previous visit. At both study visits, medications were reviewed, and the level of edema was assessed. RESULTS: A total of 2055 African-American patients were enrolled in the study. At study end, African-American patients in group 1 (n = 1422 assessable patients) experienced significant reductions in MSSBP (13.9 mm Hg) and MSDBP (10.4 mm Hg) from those achieved during amlodipine besylate monotherapy (both P < 0.001). In group 2 (n = 266 assessable patients), 81% of African-American patients reported improvement in edema, and BP remained well controlled. CONCLUSIONS: In this study of an African-American subpopulation of patients with mild to moderate essential hypertension who had uncontrolled BP while receiving amlodipine besylate monotherapy, switching from amlodipine besylate monotherapy to fixed-dose amlodipine besylate/benazepril HCl combination therapy reduced BP to a greater extent than with amlodipine besylate alone, and reduced the incidence of edema in patients who were edematous but who had controlled BP. Fixed-dose combination therapy with amlodipine besylate/benazepril HCI has the potential to improve BP control, leading to improved clinical outcomes and enhanced treatment compliance.