Effect of 1PC111, a Fixed-dose Combination of Pitavastatin and Ezetimibe,Versus Pitavastatin or Ezetimibe Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia or Mixed Dyslipidemia: A Randomized,Double-blind,Multicenter, Phase III Study

PurposeThis study aimed to show that the efficacy of 1PC111 is superior to that of either ezetimibe or pitavastatin alone (monotherapy) for the treatment of hypercholesterolemia.MethodsThis was a multicenter, randomized, double-blind, Phase III study. Patients with hypercholesterolemia or mixed dyslipidemia were randomized to receive 1PC111 (which was a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg), pitavastatin 2 mg, or ezetimibe 10 mg daily for 12 weeks. The primary end point was the difference in the percent change in LDL-C from baseline to week 12 between the 1PC111 and each monotherapy group. The secondary end points were the percent change in other lipid profiles from baseline to each visit. All patients were assessed for adverse events until end of study.FindingsA total of 388 patients were randomly assigned to the 1PC111 (n = 128), pitavastatin (n = 132), or ezetimibe (n = 128) group. Generally, baseline characteristics were similar among the 3 groups. A statistically significant decrease in the LDL-C level at week 12 was observed in the 1PC111 group (–50.50% [14.9%]) compared with either the pitavastatin (–36.11% [11.4%]; P < 0.001) or ezetimibe (–19.85% [12.4%]; P < 0.001) group. Also, there was a statistically significant difference between 1PC111 and each monotherapy group in the reduction in total cholesterol, non–HDL-C, and apolipoprotein B levels. Moreover, there was a trend toward more efficient lowering of LDL-C levels in elderly patients (age ≥65 years) than in younger patients (age <65 years) by 1PC111 treatment. In patients given a class I recommendation for atherosclerotic cardiovascular disease prevention, the percentage of patients achieving the LDL-C target of <100 mg/dL at week 12 was significantly higher in the 1PC111 group than in both monotherapy groups (P < 0.001). Overall, the incidence of adverse events was similar among 3 groups.Implications1PC111 was more effective in improving lipid profiles and achieving the LDL-C goal than pitavastatin or ezetimibe alone for hypercholesterolemia treatment. Furthermore, 1PC111 may provide more benefit in treating elderly patients. ClinicalTrials.gov identifier: NCT04643093.     

Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV,Prospective, US,Multicenter, Randomized,Double-blind,Superiority Trial

Purpose

Results from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18–80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia.

Methods

This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg.

Findings

A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m²) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was –38.1% for pitavastatin 4 mg and –26.4% for pravastatin 40 mg; the difference in median percent change between treatments was –12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non–HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis.

Implications

Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.     

Efficacy and Tolerability of Pitavastatin Versus Pitavastatin/Fenofibrate in High-risk Korean Patients with Mixed Dyslipidemia: A Multicenter,Randomized, Double-blinded,Parallel, Therapeutic Confirmatory Clinical Trial

PurposeDyslipidemia is an important risk factor for cardiovascular disease (CVD). Statins are known to effectively reduce not only low-density lipoprotein cholesterol (LDL-C) level but also death and nonfatal myocardial infarction due to coronary heart disease. The risk for CVD from atherogenic dyslipidemia persists when elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C) levels are not controlled with statin therapy. Therefore, statin/fenofibrate combination therapy is more effective in reducing CVD risk. Here, we assessed the efficacy and tolerability of pitavastatin/fenofibrate combination therapy in patients with mixed dyslipidemia and a high risk for CVD.MethodsThis multicenter, randomized, double-blind, parallel-group, therapeutic-confirmatory clinical trial evaluated the efficacy and tolerability of fixed-dose combination therapy with pitavastatin/fenofibrate 2/160 mg in Korean patients with a high risk for CVD and a controlled LDL-C level (<100 mg/dL) and a TG level of 150–500 mg/dL after a run-in period with pitavastatin 2 mg alone. In the 8-week main study, 347 eligible patients were randomly assigned to receive pitavastatin 2 mg with or without fenofibrate 160 mg after a run-in period. In the extension study, patients with controlled LDL-C and non–HDL-C (<130 mg/dL) levels were included after the completion of the main study. All participants in the extension study received the pitavastatin/fenofibrate combination therapy for 16 weeks for the assessment of the tolerability of long-term treatment.FindingsThe difference in the mean percentage change in non–HDL-C from baseline to week 8 between the combination therapy and monotherapy groups was −12.45% (95% CI, −17.18 to −7.72), and the combination therapy was associated with a greater reduction in non-HDL-C. The changes in lipid profile, including apolipoproteins, fibrinogen, and high-sensitivity C-reactive protein from baseline to weeks 4 and 8 were statistically significant with combination therapy compared to monotherapy at all time points. Furthermore, the rates of achievement of non–HDL-C and apolipoprotein B targets at week 8 in the combination therapy and monotherapy groups were 88.30% versus 77.98% (P = 0.0110) and 78.94% versus 68.45% (P = 0.0021), respectively. The combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy.ImplicationsIn these Korean patients with mixed dyslipidemia and a high risk for CVD, combination therapy with pitavastatin/fenofibrate was associated with a greater reduction in non–HDL-C compared with that with pitavastatin monotherapy, and a significantly improvement in other lipid levels. Moreover, the combination therapy was well tolerated, with a safety profile similar to that of statin monotherapy. Therefore, pitavastatin/fenofibrate combination therapy could be effective and well tolerated in patients with mixed dyslipidemia. ClinicalTrials.gov identifier: NCT03618797.     

A Multicenter,Randomized, Double-blind,Active-controlled,Factorial Design,Phase III Clinical Trial to Evaluate the Efficacy and Safety of Combination Therapy of Pitavastatin and Ezetimibe Versus Monotherapy of Pitavastatin in Patients With Primary Hypercholesterolemia

PurposePitavastatin is a unique lipophilic statin with moderate efficacy in lowering LDL-C levels by 30% to 50% with a tolerable safety profile. However, the efficacy of adding ezetimibe to pitavastatin in patients with dyslipidemia has not been well investigated. Therefore, the objective of this double-blind, multicenter, randomized, Phase III study was to compare the efficacy and safety of pitavastatin and ezetimibe combination therapy with those of pitavastatin monotherapy in Korean patients with primary hypercholesterolemia.MethodsKorean men and women aged >19 and <80 years with primary hypercholesterolemia requiring medical treatment were included in this study. During the 8-week screening period, all patients were instructed to make therapeutic lifestyle changes. The screening period consisted of a 4-week washout period and a placebo run-in period (4–8 weeks). During treatment period I, patients were randomly assigned to receive 1 of 4 treatments: pitavastatin 2 mg plus ezetimibe 10 mg, pitavastatin 2 mg, pitavastatin 4 mg plus ezetimibe 10 mg, or pitavastatin 4 mg. The 8-week double-blind treatment period then commenced. Adverse events (AEs), clinical laboratory data, and vital signs were assessed in all patients.FindingsThe percentages in LDL-C from baseline after 8 weeks of double-blind treatment decreased significantly in the pooled pitavastatin/ezetimibe (–52.8% [11.2%]) and pooled pitavastatin (–37.1% [14.1%]) groups. Treatment with pitavastatin/ezetimibe resulted in a significantly greater LDL-C–lowering effect than that with pitavastatin (difference, –15.8 mg/dL; 95% CI, –18.7 to –12.9; P < 0.001). The precentages of achieving LDL-C goal in pooled pitavastatin/ezetimibe and pooled pitavastatin groups were 94.2% and 69.1%, respectively (P < 0.001). There were no significant differences in the incidence of overall AEs and adverse drug reactions. Serious AEs were comparable between the groups.ImplicationsPitavastatin and ezetimibe combinations effectively and safely decreased LDL-C levels by >50% in patients with dyslipidemia. The safety and tolerability of pitavastatin and ezetimibe combination therapy were comparable with those of pitavastatin monotherapy. ClinicalTrials.gov identifier: NCT04584736.     

Insulin Glargine U100 Improved Glycemic Control and Reduced Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3 and 4

PurposeGlycemic control in patients with chronic kidney disease (CKD) is particularly hard to achieve because of a slower insulin degradation by the kidney. It might modify the long-acting insulin analogue pharmacokinetics, increasing its time–action and the risk of hypoglycemia. However, because this insulin has no peak action, it might be a more tolerable approach to patients with CKD. This hypothesis remains to be tested, because no study has thus far examined the efficacy and safety profile of long-acting basal analogues in patients with significant loss of renal function. The purpose of this study was to compare the glycemic response to treatment with glargine U100 or neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus (T2DM) and CKD stages 3 and 4.MethodsThirty-four patients were randomly assigned to glargine U100 or NPH insulin after a 2-way crossover open-label design. The primary end point was the difference in glycosylated hemoglobin (HbA_1c) and in the number of hypoglycemic events between weeks 1 and 24, whereas secondary end points included changes in glycemic patterns, weight and body mass index, and total daily dose of insulin. HbA_1c was determined by ion-exchange HPLC, and hypoglycemia was defined as glucose concentration of 54 mg/dL (3.0 mmol/L) detected by self-monitoring of plasma glucose or continuous glucose monitoring.FindingsAfter 24 weeks, mean HbA_1c decreased on glargine U100 treatment (−0.91%; P < 0.001), but this benefit was not observed for NPH (0.23%; P = 0.93). Moreover, incidence of nocturnal hypoglycemia was 3 times lower with glargine than with NPH insulin (P = 0.047).ImplicationsOur results found that insulin glargine U100 could be effective, once it improved glycemic control, reducing HbA_1c with fewer nocturnal hypoglycemia episodes compared with NPH insulin in this population. These clinical benefits justify the use of basal insulin analogues, despite their high cost to treat patients with T2DM and CKD stages 3 and 4. Clinical Trials identifier: NCT02451917.     

Effects of Elobixibat,an Inhibitor of Ileal Bile Acid Transporter,on Glucose and Lipid Metabolism: A Single-arm Pilot Study in Patients with T2DM

PurposeThe ileal bile acid transporter inhibitor elobixibat was recently approved in Japan for use in the treatment of patients with chronic constipation. Elobixibat has been associated with increased plasma glucagon-like peptide 1 level through Takeda G protein receptor 5, which is a membrane receptor of bile acids. The present study assessed the metabolic effects of elobixibat in patients with type 2 diabetes mellitus (T2DM)-related constipation.MethodsIn this single-arm pilot study, 21 patients with T2DM and constipation were administered elobixibat 10 mg/d for 12 weeks (period 1). The primary end point was the change in hemoglobin (Hb) A_1c at week 12. Secondary end points included physical parameters; constipation symptoms; and blood parameters, such as low-density lipoprotein cholesterol (LDL-C), arachidonic acid (AA), and fatty acid fractions. Thereafter, the study participants chose whether to continue therapy for an additional 12 weeks (period 2), at which point HbA_1c and lipid levels were reevaluated. Safety information, including adverse events, discontinuation and interruption of the drug, was collected at each visit during the trial.FindingsPeriod 1: the levels of HbA_1c, LDL-C, and AA were significantly reduced after administration of elobixibat for 12 weeks (–0.2%, –21.4 mg/dL, and –16.1 µg/dL, respectively; P = 0.016, P < 0.001, and P = 0.010). Period 2: at week 24, the change from baseline in HbA_1c was significantly greater among those who continued elobixibat treatment than in those who discontinued after 12 weeks (–0.23% vs +0.21%; P = 0.038). No serious or severe adverse events were observed.ImplicationsElobixibat may benefit patients with T2DM by improving glucose metabolism and lowering serum LDL-C and AA levels, in addition to ameliorating constipation. This single-arm pilot study was of a small sample size. The findings provide a basis for designing a larger-scale study to confirm the effects of elobixibat on glucose and lipid metabolism. (UMIN Clinical Trials Registry identifier: UMIN000045508; https://www.umin.ac.jp/ctr/index.htm)     

Effects of changeover from voglibose to acarbose on postprandial triglycerides in type 2 diabetes mellitus patients

Introduction  In this study, we examined the effects of the α-glucosidase inhibitors acarbose and voglibose on postprandial plasma glucose and serum triglyceride levels in patients with type 2 diabetes mellitus. Methods  Twenty-one Japanese patients with type 2 diabetes were enrolled in this study. Subjects had been treated with voglibose for at least 3 months. They underwent a 400 kcal balanced food meal tolerance test before and 8 weeks after the changeover from voglibose to acarbose. Subjects were divided into two groups: the first group (low-dose group; n=11) was changed over from 0.6 mg/day voglibose to 150 mg/day acarbose, and the other (high-dose group; n=10) from 0.9 mg/day voglibose to 300 mg/day acarbose. Results  The increment rate of postprandial plasma glucose ([plasma glucose 2 hours after test meal - fasting glucose]/fasting glucose) decreased from 34.7%±23.9% to 25.0%±24.6% (P=0.13) in the low-dose group, and decreased significantly from 56.1%±53.1% to 31.5%±36.0% (P=0.03) in the high-dose group after changeover. However, there were no significant changes in blood glycated hemoglobin (HbA_1c) levels before and after changeover in either group. The increment rate of postprandial serum triglyceride (TG) ([serum TG 2 hours after test meal - fasting TG]/fasting TG) decreased significantly only in the high-dose group (52.4%±60.0% to 24.3%±16.6%) (P=0.05). No significant changes in serum high-density lipoprotein cholesterol levels were observed in either group, whereas serum low-density lipoprotein cholesterol levels decreased significantly from 3.20±0.25 to 2.65±0.18 mmol/L (P=0.04), only in the highdose group. Conclusions  In patients with type 2 diabetes our findings suggest that acarbose 300 mg/day is superior to voglibose 0.9 mg/day in improving postprandial hyperglycemia and hypertriglyceridemia.     

Dulaglutide Shows Sustained Reduction in Glycosylated Hemoglobin Values: 2-Year US Real-world Study Results

PurposeDue to the chronic and progressive nature of type 2 diabetes mellitus (T2DM), it is important to understand the long-term outcomes associated with antihyperglycemic medications. There are currently few long-term studies evaluating the real-world effectiveness of dulaglutide, a glucagon-like peptide-1 receptor agonist. The primary objective of this retrospective observational study was to evaluate glycemic control over a 24-month follow-up period among dulaglutide initiators with continuous treatment. The study used US claims data from the HealthCore Integrated Research Database between May 2014 and May 2019.MethodsPatients were included if they were ≥18 years old with T2DM and had ≥1 pharmacy claim for dulaglutide during the index period between November 2014 and May 2017 (with index date = set as the earliest dulaglutide fill during index period), continuous enrollment in the 6 months' preindex and 24 months' postindex, ≥1 claim for dulaglutide or ≥60 days’ supply in every quarter during the 24-month follow-up period, and ≥1 glycosylated hemoglobin (HbA_1c) result at both baseline and 24 months.FindingsAt baseline, 872 patients (47.5% female) had a mean (SD) age of 54.5 (8.2) years and an HbA_1c value of 8.68% (1.8%) (71.36 [19.7] mmol/mol). More than two thirds were being treated for dyslipidemia, hypertension, or cardiovascular disease. A significant HbA_1c reduction was observed from baseline to 24 months (−1.3% [–14.2 mmol/mol]; P < 0.0001) for dulaglutide initiators with continuous treatment. A significant reduction in HbA_1c level was also observed for all prespecified subgroups (age, index dulaglutide dose [0.75 mg or 1.5 mg], insulin use, sodium-glucose co-transporter 2 inhibitor use, and dipeptidyl peptidase-4 inhibitor use; all, P < 0.0001). Forty-three percent of patients achieved an HbA_1c value < 7% (53 mmol/mol), and 73% achieved an HbA_1c value < 8% (64 mmol/mol) at 24 months. Most (520 [59.6%]) patients were initiated on dulaglutide 0.75 mg. Of these patients, 70% increased to dulaglutide 1.5 mg during follow-up. The mean time to first dose change was 242 (196) days for 0.75 mg–1.5 mg and 225 (160) days for 1.5 mg–0.75 mg. Antihyperglycemic medication use preindex/postindex included: insulin, 28%/35%; dipeptidyl peptidase-4 inhibitors, 37%/20%; and sodium-glucose co-transporter 2 inhibitors, 29%/44%.ImplicationsIn this real-world study among dulaglutide initiators with continuous treatment, a clinically significant reduction in HbA_1c value was seen at the 3-month assessment and persisted for up to 24 months. These data support the use of dulaglutide as an effective long-term treatment for T2DM in clinical practice.     

Pitavastatin calcium: clinical review of a new antihyperlipidemic medication

BackgroundPitavastatin calcium is a new addition to the class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”) approved for use in the United States for the treatment of primary hyperlipidemia and mixed dyslipidemia.ObjectiveThe purpose of this review was to evaluate the literature related to the medicinal chemistry, pharmacology, pharmacokinetic properties, clinical efficacy, and tolerability of pitavastatin in the treatment of hyperlipidemia.MethodsA search of MEDLINE, EMBASE, and the Journal Archive for English-language literature was conducted for articles published through January 2011 using the following search terms: itavastatin, Livalo, nisvastatin, NK 104, and pitavastatin. Articles were reviewed if they pertained to the clinical efficacy, pharmacology, pharmacokinetic properties, or tolerability of pitavastatin. Clinical trials were systematically included in the analysis of clinical efficacy if they used a randomized design to study the effects of the drug on hyperlipidemia, hypercholesterolemia, or heart disease. Trials were excluded if they did not signify the statin used, did not pertain to clinical efficacy, or enrolled <20 patients.ResultsA total of 16 studies were identified and reviewed for clinical efficacy. Based on findings from pharmacokinetic studies, pitavastatin may be given at any time of the day, with or without food. The drug had a mean plasma elimination t_1/2 of 12 hours, is expected to be associated with minimal drug–drug interactions because it is not metabolized by the cytochrome P450 3A4 isozyme, and is primarily excreted unchanged in the bile with little renal elimination. Clinical trials described the effects of pitavastatin on cholesterol, high-sensitivity C-reactive protein (hs-CRP), and progression of atherosclerosis. Pitavastatin at doses of 1 to 4 mg/d was reported to be associated with reductions in LDL-C of 38% to 44% and in triglycerides of 14% to 22%, and with increases in HDL-C of 5% to 8% (all, P < 0.05). Overall, the effect of pitavastatin on cholesterol was comparable to those of atorvastatin and simvastatin at low to intermediate doses. Studies on the effects of pitavastatin on cardiovascular outcomes were lacking. The adverse-events (AE) profile of pitavastatin compared favorably with those of other available statins. AEs included gastrointestinal symptoms (0.7%–2.2%), myopathies (0.3%–1.1%), and elevated hepatic enzyme concentrations (0.0%–8.8%).ConclusionsBased on the findings from previously published clinical trials, pitavastatin is an effective lipid lowering agent and is another therapeutic option of currently available statins.     

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND,a Randomized,Pragmatic Trial

OBJECTIVEBEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control.RESEARCH DESIGN AND METHODSParticipants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA_1c at 6 months.RESULTSBaseline characteristics were similar among the three groups (mean HbA_1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA_1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA_1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group.CONCLUSIONSBEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.     

Lemon balm: A promising herbal therapy for patients with borderline hyperlipidemia—A randomized double-blind placebo-controlled clinical trial

ObjectiveMelissa officinalis is a perennial herb from the Lamiaceae family which has shown to have modulating effects on serum lipid profile. The aim of the current study is to explore the effects of M. officinalis supplementation on serum biochemical parameters of patients with borderline hyperlipidemia.Methods58 hyperlipidemic patients were allocated randomly to 2 groups: first group received capsules containing 1000 mg M. officinalis leaf powder (MO group), and the second group received placebo capsules (P group) 3 times per day for 2 months. Fasting blood glucose (FBG), HDL, LDL, Triglyceride, Creatinine and liver function enzymes including AST and ALT were evaluated before and after study.ResultsThe mean of LDL in MO group significantly decreased compared with P group after the supplementation (P = 0.02). Although the level of Cholesterol, FBG, HDL, Triglyceride, Creatinine and ALT did not show significant difference between two groups after 2 months (P ≥ 0.05), the level of AST exhibited a significant difference between two groups (P = 0.009).ConclusionsOur findings demonstrated that M. officinalis supplementation as a rich source of antioxidants and bioactive compounds can be effective in remission of LDL and AST levels in patients with borderline hyperlipidemia.     

Comparison of shock reversal with high or low dose hydrocortisone in intensive care unit patients with septic shock: A retrospective cohort study

PurposeThis study aims to describe differences in shock reversal between hydrocortisone 200 mg and 300 mg per day dosing regimens in patients with septic shock.MethodsThis is a multi-center retrospective study including patients admitted to intensive care units with septic shock receiving vasopressors and hydrocortisone between 2013 and 2018. We compared patients who received low dose hydrocortisone (50 mg every 6 h) versus high dose hydrocortisone (100 mg every 8 h) on the primary outcome of shock reversal.Results319 patients (low dose group, n = 134 and high dose group, n = 185) were included. In the multivariate regression model, high-dose steroids were associated with shock reversal [OR (95% CI) = 2.278 (1.063–4.880), p = 0.034]. This was not confirmed in the propensity score matched analysis [OR (95% CI) =2.202 (0.892–5.437), p = 0.087]. High dose steroids were associated with a lower need for additional vasopressor therapy (22% vs. 34%, p = 0.012) and lower shock recurrence (6.7% vs. 16%, p = 0.013), which was confirmed with propensity score matching.ConclusionsLow and high dose hydrocortisone have similar rates of shock reversal in septic shock patients. Hydrocortisone 100 mg every 8 h may reduce rates of recurrence of shock and reduce the need for additional vasopressors.     

Outcomes and adverse effects of extremely high dose insulin infusions in ICU patients

PurposeDescribe the characteristics, hospital course, and outcomes of adult ICU patients receiving extremely high dose insulin infusions compared to those with lower insulin requirements.Materials and methodsRetrospective observational study of 128 adult ICU patients receiving IV insulin infusions at a large academic medical center. Extremely high dose insulin infusions were defined as maximum rate ≥ 35 units/h. The primary endpoint was rate of hypoglycemia (BG < 70 mg/dL) and time to glucose control. A post-hoc matching analysis was performed for baseline imbalances.ResultsAnalysis included 32 patents with extremely high dose insulin infusions and 96 patients without, and most had a goal BG 100–150 mg/dL. Patients in the extreme group were more likely to have type 2 diabetes, a higher median hemoglobin A1c, preadmission insulin, be admitted for a medical reason, and receive inpatient steroids. The extreme group were more likely to experience hypoglycemia (<70 mg/dL, 63% v. 34%, p = 0.005), longer time to glucose control (19.8 h v. 5.7 h, p < 0.001) and higher mortality (34% v. 15%, p = 0.014).ConclusionsICU patients with extremely high dose insulin infusions had more hypoglycemia and took longer to achieve glucose targets compared to those with lower requirements. An individualized approach may be required for appropriate management.     

Efficacy and Safety of a Fixed-Dose Combination of Candesartan and Rosuvastatin on Blood Pressure and Cholesterol in Patients With Hypertension and Hypercholesterolemia: A Multicenter,Randomized, Double-Blind,Parallel Phase III Clinical Study

PurposeThe aim of this study was to evaluate the blood pressure–lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia.MethodsThis study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non–HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A_1c. Tolerability of combination therapy was compared with other monotherapy groups.FindingsThe percentage changes of LDL-C were ?48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and ?49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non–HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A_1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, ?8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group.ImplicationsOnce-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. ClinicalTrials.gov identifier: NCT02770261.     

HbA1c Reduction in Dulaglutide-Treated Patients Irrespective of Duration of Diabetes,Microvascular Disease,and BMI: A Post Hoc Analysis From the REWIND Trial

OBJECTIVETo evaluate participant characteristics and long-term changes in glycated hemoglobin (HbA_1c) levels in patients treated with dulaglutide 1.5 mg in a post hoc analysis of the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial.RESEARCH DESIGN AND METHODSChange from baseline in HbA_1c was assessed during and up to 72 months of treatment before and after adjustment for duration of diabetes, prior microvascular disease (nephropathy or retinopathy), and BMI. Slope analyses were used to assess the change in HbA_1c during 0–12 months and 12–72 months of therapy.RESULTSHbA_1c was significantly reduced in patients treated with dulaglutide compared with placebo during 72 months of treatment (least-squares mean difference = −0.61%, P < 0.001), regardless of diabetes duration, prior microvascular disease, and BMI (all interaction P > 0.07). Significant reductions were apparent at all time points and were independent of these baseline characteristics. Slope analyses revealed that the dulaglutide group experienced a higher rate of HbA_1c reduction compared with the placebo group from 0 to 12 months before and after adjustment. The dulaglutide group also experienced a higher rate of HbA_1c increase from 12 to 72 months compared with the placebo group that became nonsignificant after adjustment for diabetes duration, prior microvascular disease, and BMI combined. Despite the greater rate of HbA_1c increase in the dulaglutide group during this period, mean HbA_1c values remained below baseline in the dulaglutide group and below mean HbA_1c values in the placebo group.CONCLUSIONSDulaglutide 1.5-mg treatment was statistically associated with a long-lasting decrease in HbA_1c over 72 months, irrespective of baseline duration of diabetes, microvascular disease, and BMI.     

Exenatide Once Weekly: Effectiveness,Tolerability, and Discontinuation Predictors in a Real-world Setting

PurposeThe goal of this study was to evaluate the effectiveness and safety of exenatide once weekly (EOW) and to determine predictors of treatment response and drug discontinuation in patients with type 2 diabetes mellitus (T2DM) followed up for 18 months in a real-world setting.MethodsThis retrospective cohort study included patients with T2DM who initiated EOW 2 mg between 2014 and 2019 in an outpatient diabetes clinic in Italy. Data were collected at baseline and at follow-up visits (6, 12, and 18 months after EOW). We estimated glycosylated hemoglobin (HbA_1c) and body weight mean changes from baseline to follow-up visits and assessed the proportion of patients reaching HbA_1c target ≤7% and a 5% weight loss after 12 months of treatment. We then attempted to establish predictors of glycemic and weight response, and compared patient characteristics between subjects who persisted on treatment versus those who discontinued EOW.FindingsOne-hundred eighty-six patients (46.2% male) were included in the study. The mean (SD) age and diabetes duration were 63.2 (8.9) years and 10.7 years (18.3), respectively. Significant reductions in HbA_1c values (−0.9%; 95% CI, −1.1 to −0.8) and body weight (−2.8 kg; 95% CI, −3.4 to −2.2) were observed after 6 months. Sixty-one percent of patients (87 of 143) achieved target HbA_1c values ≤ 7% after 12 months, and 34% (45 of 134) exhibited a weight loss of at least 5% of baseline body weight. Blood glucose and weight reductions were maintained after an 18-month follow-up. Predictors of adequate glycemic and weight response were shorter diabetes duration and nonuse of a different GLP-1RA, respectively. Patients on sulfonylureas failed to reach metabolic and body weight targets. The most common adverse events were gastrointestinal side effects (7.5%) and injection site reactions (6.4%), followed by headache (1.1%) and allergic reactions (1.1%). Forty-three percent of patients (79 of 186) discontinued EOW. The main reasons for discontinuation were insufficient HbA_1c improvement and/or limited weight reduction (19.9%), side effects (16.1%), or patient decision (6.5%). Predictors of discontinuation were higher HbA_1c levels at baseline and use of basal insulin therapy before EOW treatment.ImplicationsEOW treatment, in a real-world setting, offers sustained and effective glycemic control and weight loss over 18 months in patients with T2DM. Diabetes duration and basal insulin therapy, however, may affect the outcome of EOW treatment, suggesting that early initiation of EOW could improve glycemic control and reduce the risk of treatment discontinuation.     

Evaluation of the meropenem dosage and administration schedule in patients with bacteremia initial therapy

BackgroundThe standard meropenem (MEPM) regimen allowed by insurance in Japan is 0.5 g two or three times a day. Differences in dosages and administration schedules in Japan were evaluated.MethodsPatients with bacteremia for whom MEPM was used as the initial treatment at our institution between 2016 and 2021 were included. We retrospectively investigated patients classified into two groups: those treated according to severe infections (high-dose groupand others (low-dose group). After propensity score matching, we compared the probability of achieving free drug blood levels above the minimum inhibitory concentration (MIC) in 24 h (%fT > MIC) and outcomes.ResultsThe probability of 100% fT > MIC was significantly higher in the high-dose group (96.4% vs 74.5%, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2–0.4, P = < 0.001). Regarding outcomes, the 30-day mortality rate was significantly lower in the high-dose group (1.4% vs. 11.4%, OR = 8.0, 95% CI = 1.5–43.7, P = 0.019).ConclusionsTo improve outcomes in patients with bacteremia treated with MEPM, support for appropriate antimicrobial use is necessary for compliance with the dosage and administration schedule according to severe infections in initial treatment.     

Relationship between norepinephrine dose,tachycardia and outcome in septic shock: A multicentre evaluation

PurposeSeptic shock is associated with massive release of endogenous catecholamines. Adrenergic agents may exacerbate catecholamine toxicity and contribute to poor outcomes. We sought to determine whether an association existed between tachycardia and mortality in septic shock patients requiring norepinephrine for more than 6 h despite adequate volume resuscitation.Materials and methodsMulticentre retrospective observational study on 730 adult patients in septic shock consecutively admitted to eight European ICUs between 2011 and 2013. Three timepoints were selected: T1 (first hour of infusion of norepinephrine), Tpeak (time of highest dose during the first 24 h of treatment), and T24 (24-h post-T1). Binary logistic regression models were constructed for the three time-points.ResultsOverall ICU mortality was 38.4%. Mortality was higher in those requiring high-dose (≥0.3 mcg/kg/min) versus low-dose (<0.3 mcg/kg/min) norepinephrine at T1 (53.4% vs 30.6%; p < 0.001) and T24 (61.4% vs 20.4%; p < 0.0001). Patients requiring high-dose with concurrent tachycardia had higher mortality at T1; in the low-dose group tachycardia was not associated with mortality. Resolving tachycardia (from T1 to T24) was associated with lower mortality compared to patients where tachycardia persisted (27.8% vs 46.4%; p = 0.001).ConclusionsUse of high-dose norepinephrine and concurrent tachycardia are associated with poor outcomes in septic shock.     

Multicenter Trial of a Tubeless,On-Body Automated Insulin Delivery System With Customizable Glycemic Targets in Pediatric and Adult Participants With Type 1 Diabetes

OBJECTIVEAdvances in diabetes technology have transformed the treatment paradigm for type 1 diabetes, yet the burden of disease is significant. We report on a pivotal safety study of the first tubeless, on-body automated insulin delivery system with customizable glycemic targets.RESEARCH DESIGN AND METHODSThis single-arm, multicenter, prospective study enrolled 112 children (age 6–13.9 years) and 129 adults (age 14–70 years). A 2-week standard therapy phase (usual insulin regimen) was followed by 3 months of automated insulin delivery. Primary safety outcomes were incidence of severe hypoglycemia and diabetic ketoacidosis. Primary effectiveness outcomes were change in HbA_1c and percent time in sensor glucose range 70–180 mg/dL (“time in range”).RESULTSA total of 235 participants (98% of enrolled, including 111 children and 124 adults) completed the study. HbA_1c was significantly reduced in children by 0.71% (7.8 mmol/mol) (mean ± SD: 7.67 ± 0.95% to 6.99 ± 0.63% [60 ± 10.4 mmol/mol to 53 ± 6.9 mmol/mol], P < 0.0001) and in adults by 0.38% (4.2 mmol/mol) (7.16 ± 0.86% to 6.78 ± 0.68% [55 ± 9.4 mmol/mol to 51 ± 7.4 mmol/mol], P < 0.0001). Time in range was improved from standard therapy by 15.6 ± 11.5% or 3.7 h/day in children and 9.3 ± 11.8% or 2.2 h/day in adults (both P < 0.0001). This was accomplished with a reduction in time in hypoglycemia <70 mg/dL among adults (median [interquartile range]: 2.00% [0.63, 4.06] to 1.09% [0.46, 1.75], P < 0.0001), while this parameter remained the same in children. There were three severe hypoglycemia events not attributable to automated insulin delivery malfunction and one diabetic ketoacidosis event from an infusion site failure.CONCLUSIONSThis tubeless automated insulin delivery system was safe and allowed participants to significantly improve HbA_1c levels and time in target glucose range with a very low occurrence of hypoglycemia.     

Elevated HbA1c and Fasting Plasma Glucose in Predicting Diabetes Incidence Among Older Adults: Are two better than one?

OBJECTIVE

To determine which measures—impaired fasting glucose (IFG), elevated HbA_1c, or both—best predict incident diabetes in older adults.

RESEARCH DESIGN AND METHODS

From the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100–125 mg/dL) and elevated HbA_1c (5.7–6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA_1c ≥6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA_1c.

RESULTS

Among 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4–8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8–16.4) in those with elevated HbA_1c (versus those with HbA_1c <5.7%). When FPG and HbA_1c were considered together, odds ratios were 3.5 (1.9–6.3) in those with IFG only, 8.0 (4.8–13.2) in those with elevated HbA_1c only, and 26.2 (16.3–42.1) in those with both IFG and elevated HbA_1c (versus those with normal FPG and HbA_1c). Addition of elevated HbA_1c to the model with IFG resulted in improved discrimination and calibration.

CONCLUSIONS

Older adults with both IFG and elevated HbA_1c have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA_1c may identify older adults at very high risk for diabetes.Impaired fasting glucose (IFG) (100–125 mg/dL) has been traditionally used for identifying persons at high risk for the subsequent development of diabetes in the U.S. Recent guidelines have additionally endorsed the use of HbA_1c 5.7–6.4% to identify those at risk (1). However, multiple studies, including one conducted among older persons (2), suggest that HbA_1c may identify different individuals at risk for diabetes than traditional glucose measures (3–6). Although several recent investigations confirm that HbA_1c is strongly predictive of future diabetes in predominantly middle-aged populations (7–10), less is known about how well HbA_1c identifies older persons at risk for diabetes.Despite the high prevalence of type 2 diabetes in the elderly (10.9 million Americans in 2010) and the high incidence (390,000 new cases in 2010) of late-onset type 2 diabetes (>65 years) (11,12), there are few specific studies on prediction of diabetes in this group. One such study, based on an earlier Health, Aging, and Body Composition (Health ABC) analysis, developed a prediction rule for diabetes development, which included several factors: advanced age, female sex, elevated fasting plasma glucose (FPG), and triglyceride levels (13). However, HbA_1c was not examined as a potential predictor. In the Cardiovascular Health Study of men and women ≥65 years of age, BMI, waist-to-hip ratio, and weight gain were associated with a higher risk of diabetes, but the impact of glycemic measures on diabetes was not specifically examined (14). An Italian study of older adults (age 65–84 years) found that the combination of abnormal FPG (defined using World Health Organization [WHO] criteria: 110 to <126 mg/dL), increased waist circumference, and HbA_1c ≥7.0% increased the probability of incident diabetes roughly 14-fold (15). However, neither a direct comparison of current prediabetes categories (based upon FPG and HbA_1c) for prediction of diabetes nor an analysis of the utility of combined testing has previously been conducted in this population.We therefore evaluated the odds for diabetes based upon baseline IFG and elevated HbA_1c among the participants of the longitudinal Health ABC study. We directly compared FPG- and HbA_1c-based criteria for predicting the eventual development of diabetes, and we evaluated the utility of combined testing for identifying older persons who develop diabetes. Since HbA_1c values are consistently higher in blacks compared with whites (3,16), we additionally explored race differences in diabetes prediction.