News

Lefamulin Approved For Community-Acquired Pneumonia

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In August 2019, the U.S. Food and Drug Administration (FDA) approved a new antibiotic for community-acquired bacterial pneumonia (CAP) and acute bacterial skin infections. Lefamulin (Xenleta, Nabriva Therapeutics) is in a class of antibiotics known as the pleuromutilins and represents the first antibiotic developed for systemic use in humans with a novel mechanism of action in over a decade (retapamulin was approved in 2007 for topical use).

Pleurotus fungus

Pleuromutilins were discovered in 1950 from the fungi Pleurotus mutilis and Pleurotus (now Clitopilus) passeckerianus (the pleuromutilins were not named for the membranes surrounding the lungs).

Like clindamycin, linezolid, and the macrolides, the pleuromutilins block bacterial protein synthesis via binding to the 50S ribosomal subunit. They bind at a different site on the subunit such that there is no cross-resistance with other antibiotics.

Lefamulin shows robust activity against gram-positive and fastidious gram-negative bacteria, and the organisms often referred to as “atypicals,” such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila.

Lefamulin has equivalent oral and intravenous bioavailability and can be taken with or without food, making the oral formulation a convenient option. It also has a good safety profile, the most common side effects being diarrhea and nausea. More rarely, hepatic enzyme elevation has been observed, and concomitant administration with cytochrome P450 (CYP) 3A4 inhibitors should be avoided due to the risk of QT-prolongation.

Given the trend toward worsening bacterial resistance against current CAP antibiotics and the increasing number of FDA warnings concerning quinolones, lefamulin looks to be a promising addition to the antibiotic armamentarium. Antibiotic stewardship programs should be reinforced to maintain its excellent efficacy and resistance profiles.

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Omega-3 Fatty Acid Supplements Do Not Decrease Risk of Early Preterm Delivery

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Pregnant women who received omega-3 (n-3) long-chain polyunsaturated fatty acid supplements did not have a lower risk of early preterm delivery (prior to 34 weeks gestation), according to a new phase 3 trial.

Maria Makrides, PhD, with the South Australian Health and Medical Research Institute, Women’s and Children’s Hospital, North Adelaide, Australia, and colleagues reported their findings in the September 12, 2019 issue of The New England Journal of Medicine.

The World Health Organization (WHO) estimates 15 million babies are born preterm (prior to completing 37 weeks gestation), over 10% of births worldwide. Preterm birth is associated with increased rates of disability and is the leading cause of death in children under five.

Omega-6 (n-6) fatty acids are precursors of several mediators of inflammation, such as prostaglandins. Prostaglandin E2 and prostaglandin F2α have been shown to initiate labor by inducing cervical ripening and uterine contractions. The n-3 fatty acids, on the other hand, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of several anti-inflammatory mediators. They are inefficiently produced in mammals and often require dietary sources, such as fish, flaxseed, some vegetables, or supplements containing DHA or EPA, to maintain proper levels. The typical western diet, relatively low in n-3 fatty acids and high in n-6 fatty acids, shifts production to more pro-inflammatory mediators and, as a result, may influence preterm delivery.

Several epidemiological studies have shown an association between lower dietary fish intake and increased rates of preterm delivery, leading to the WHO recommendation that pregnant women take 300 mg of n-3 long-chain polyunsaturated fatty acids daily. A 2018 birth cohort study in Denmark corroborated this by showing a correlation between low plasma concentrations of EPA and DHA in pregnancy with an increased rate of early preterm birth.

A previous randomized controlled study, called DOMInO (DHA to Optimise Mother Infant Outcome), showed that while DHA had no effect on postpartum depression or infant brain development, a secondary analysis showed a decreased incidence in early preterm delivery compared with control. Thus, it is unclear whether supplementation with n-3 long-chain polyunsaturated fatty acids results in a lower rate of early preterm delivery.

This trial, called ORIP (Omega-3 to Reduce the Incidence of Preterm Birth), enrolled 5517 women, with a total of 5544 pregnancies, less than 20 weeks gestation, and taking no more than 150 mg of n-3 long-chain polyunsaturated fatty acid supplementation daily. 2770 pregnancies in 2766 women were randomly assigned to receive three 500-mg fish-oil capsules per day, containing approximately 800 mg of DHA and 100 mg of EPA daily until 34 weeks gestation or delivery, whichever occurred first. A control group included 2774 pregnancies in 2765 women randomly assigned to receive three 500-mg capsules of an isocaloric vegetable-oil blend, containing approximately 15 mg of DHA and 4 mg of EPA per day for the same duration. 5486 pregnancies (2734 in the n-3 group and 2752 in the control group) were included in the final analysis. The incidence of early preterm delivery was compared between groups.

Early preterm delivery occurred in 2.2% of the n-3 group and 2.0% of the control group (relative risk 1.13; 95% confidence interval [CI], 0.79 to 1.63; P=0.50).

There was no significant difference in the rate of serious adverse outcomes (5.0% in the n-3 group and 4.0% in the control group). There were more gastrointestinal side effects reported in the n-3 group, including burping, diarrhea, and constipation.

This study showed that DHA and EPA supplementation did not reduce the incidence of early preterm delivery, and does not confirm the result of the secondary outcome analysis in the DOMInO trial. The authors suggest that further studies are needed to evaluate subgroups that may show a benefit, for example, those with low levels of n-3 fatty acids.

The study was funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation.

Makrides, M, PhD, et al. A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery. N Engl J Med. 2019; 381:1035-45.

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SAGE-217 Shows Promise In Major Depression

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Patients with major depressive disorder who received SAGE-217 for fourteen days showed improvement in symptoms on day fifteen in a phase 2 safety and efficacy trial.

Handan Gunduz-Bruce, MD, with Sage Therapeutics, Cambridge, Massachusetts, and colleagues reported their findings in the September 5, 2019 issue of The New England Journal of Medicine.

Major depression is a complex mental disorder involving genetic and environmental factors, as well as multiple neurotransmitters. Gamma-aminobutyric acid (GABA) has been shown to play a major role in neural regulation as the primary inhibitory neurotransmitter of the central nervous system. Studies have shown decreased GABA levels in the plasma, cerebrospinal fluid, and brain tissue of patients with major depressive disorder.

Several medications show positive allosteric modulator activity on the GABA receptor, including benzodiazepines, barbiturates, muscle relaxants, alcohol, propofol, and etomidate, and thus are used as anxiolytics, sedatives, anticonvulsants, antispasmodics, and anesthetics. Neurosteroids are naturally occurring modulators of GABA receptors with pharmacologic activity that differs from that of glucocorticoids. Allopregnanolone, one such neurosteroid, acts as a positive allosteric modulator of the GABAA receptor. In studies of patients with post-partum depression (PPD), administration of intravenous brexanolone, the synthetic analog of allopregnanolone, resulted in significant reductions (improvement) in the Hamilton Rating Scale for Depression (HAM-D) score at sixty hours. This is consistent with the hypothesis that normalization of GABA function is clinically useful in the treatment of depression, and led to the approval of brexanolone by the U.S. Food and Drug Administration (FDA) on March 19, 2019.

This trial is a phase 2, randomized, double-blind, placebo-controlled study of the oral formulation of synthetic allopregnanolone, SAGE-217, in patients with major depressive disorder. Study investigators enrolled 89 adults with major depression with a HAM-D score of 22 or higher (moderate-to-severe depression), who were on stable doses of antidepressants for at least thirty days, or not taking any antidepressants. 45 patients were randomly assigned to receive SAGE-217 30 mg once daily for fourteen days, and 44 patients to placebo. The mean change in the baseline HAM-D scores on day fifteen was compared between groups.

The mean HAM-D score at baseline was 25.2 in the SAGE-217 group and 25.7 in the placebo group. On day 15, the mean change in the HAM-D score was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (between-group difference -7.1; 95% confidence interval [CI], -10.2 to -3.9; P<0.001).

Adverse events were reported by 53% in the SAGE-217 group and 45% in the placebo group. The most common adverse events reported in the SAGE-217 group were headache, nausea, and somnolence. No serious adverse events and no deaths were reported during the trial.

The study was funded by Sage Therapeutics.

Gunduz-Bruce, H, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019; 381:903-11.

Comments

  • this trial further supports the hypothesis that GABAA receptors play an important role in major depression
  • the effect of SAGE-217 was similar for patients taking conventional antidepressants during the trial and those not previously on antidepressant medication 
  • although the results of this trial show promise for patients suffering major depression, it is limited by being a short phase 2 trial with a small sample size (as designed); larger studies are needed with longer-term outcomes to better define efficacy and safety

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Oral Semaglutide Shows Cardiovascular Safety In Type 2 Diabetes

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Patients with Type 2 diabetes who received oral semaglutide had a non-inferior cardiovascular outcome compared with placebo, according to a new phase 3 trial.

Mansoor Husain, MD, with the Peter Munk Cardiac Centre, University Health Network, Department of Medicine and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto General Hospital Research Institute, and the Ted Rogers Centre for Heart Research, Toronto, and colleagues reported their findings in the August 29, 2019 issue of The New England Journal of Medicine.

Patient compliance with injectable medications, such as insulin and the glucagon-like peptide-1 (GLP-1) receptor agonists is a significant challenge in the treatment of diabetes. Oral formulations are favored by patients when compared to injectable medications and are more likely to be initiated earlier. Oral semaglutide is a new oral formulation of the subcutaneous GLP-1 receptor agonist of the same name and has similar pharmacokinetic properties and effects.

In 2008, the U.S. Food and Drug Administration (FDA) began requiring cardiovascular risk assessments for new glucose-lowering drugs. All currently approved GLP-1 receptor agonists, including subcutaneous semaglutide, have shown cardiovascular safety or benefit. This study, Peptide Innovation for Early Diabetes Treatment (PIONEER) 6, is a phase 3a, randomized, placebo-controlled, preapproval cardiovascular outcomes trial with the oral formulation of semaglutide. Study participants were patients with Type 2 diabetes, fifty years of age or older with known cardiovascular disease or chronic kidney disease, or sixty years of age or older if they had cardiovascular risk factors only. The difference in time from randomization to the first occurrence of a major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was compared between groups. 1591 patients were randomized to receive oral semaglutide 14 mg daily and 1592 patients to placebo. 3172 patients (99.7%) completed the trial.

A major cardiovascular event occurred in 3.8% of patients receiving semaglutide and 4.8% of those taking placebo, a 21% relative risk reduction (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority; P=0.17 for superiority).

More patients permanently discontinued semaglutide than placebo (11.6% vs. 6.5%, respectively). This difference was driven mainly by gastrointestinal side effects, including nausea, vomiting, and diarrhea. There were fewer serious adverse events in the semaglutide group (18.9%) compared with the placebo group (22.5%), and the authors reported no unexpected adverse events in either group.

The study was funded by Novo Nordisk.

Husain M, et al. Oral semaglutide and cardiovascular outcomes in patients with Type 2 diabetes. N Engl J Med. 2019; 381:841-51.

Comments

  • the trial was relatively short because it was an event-limited trial (trial period ends when a minimum number of events occurs – median time in the trial was 15.9 months)
  • the trial was powered for non-inferiority, not superiority
  • trial validity is increased by the high completion rate (99.7%)
  • the discontinuation rate in the semaglutide group was higher than in the placebo group but comparable to that observed with other (subcutaneous) GLP-1 receptor agonists
  • patients in the semaglutide group showed decreased glycated hemoglobin, weight, and systolic blood pressure compared to those in the placebo group
  • death from any cause was lower in the semaglutide group than in the placebo group (1.4% vs. 2.8%, respectively; hazard ratio, 0.51; 95% CI, 0.31 to 0.84).
  • these results may lead to better patient compliance with (oral) GLP-1 receptor agonists and thus, better diabetic outcomes

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Serelaxin Does Not Reduce Cardiovascular Mortality In Acute Heart Failure

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Patients with acute heart failure who received the recombinant form of human relaxin-2, serelaxin, did not have a lower incidence of cardiovascular death at 180 days, or a lower incidence of worsening heart failure at 5 days, according to a new phase 3 trial.

Marco Metra, MD, with the Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy; John R. Teerlink, MD, with the Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco; and colleagues reported their findings in the August 22, 2019 issue of The New England Journal of Medicine.

The Centers for Disease Control and Prevention (CDC) reports that approximately 5.7 million adults in the United States have heart failure. Hospital admission for acute decompensated heart failure is associated with increased short and long-term cardiovascular mortality. About one-half of heart failure patients are rehospitalized within six months, and up to 15% of patients die within three months of their initial hospitalization. The CDC notes that one-half of those who develop heart failure die within five years of diagnosis.

The search for new and better therapies for acute heart failure has led to research into a hormone called relaxin. Discovered in 1926, relaxin is produced primarily by cells of the corpus luteum and is associated with several cardiovascular changes of pregnancy. It acts as a vasodilator, via the nitric oxide pathway, an antifibrotic, and an anti-inflammatory agent. Discovery of these properties led to the study of relaxin in heart failure, using a recombinant form of the hormone, called serelaxin. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin was associated with a lower incidence of worsening heart failure during hospitalization and lower cardiovascular mortality at 180 days when compared to placebo. The RELAX-AHF trial was not powered to show an effect on mortality; thus, whether serelaxin reduced cardiovascular mortality in acute heart failure remained unclear.

This study, RELAX-AHF-2, is a phase 3b, multi-center, randomized, placebo-controlled, event-driven trial. The trial enrolled 6600 adults hospitalized for acute heart failure, with dyspnea and vascular congestion on chest radiography, elevated natriuretic peptide levels, mild-moderate renal impairment, and systolic blood pressure of 125 mm Hg or greater. After excluding 55 patients randomized in error, 3274 patients were randomly assigned to receive serelaxin 30 µg per kilogram per day plus usual therapy, and 3271 patients to receive placebo plus usual therapy. The rates of cardiovascular death at 180 days and worsening heart failure at 5 days were compared between groups.

Measured at day 180, cardiovascular death occurred in 8.7% in the serelaxin group, and in 8.9% in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P=0.77). Measured at day 5, worsening heart failure occurred in 6.9% in the serelaxin group, and in 7.7% in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P=0.19). The length of hospital stay and the incidence of rehospitalization due to heart failure or renal failure were also unchanged between groups.

There was no significant difference in the rate of adverse events reported between the groups (53.1% in the serelaxin group and 52.1% in the placebo group reporting at least one adverse event).

The study was funded by Novartis Pharma.

Metra, M., et al. Effects of Serelaxin in Patients with Acute Heart Failure. N Engl J Med 2019; 381:716-26.

Comments

  • RELAX-AHF-2 shows the importance of a properly powered trial: the authors conclude that the lack of cardiovascular mortality benefit observed in this trial shows that the benefit seen in the RELAX-AHF trial was consistent with a chance outcome
  • Heart failure is a complex disease – further subgroup analyses of this and other heart failure trials may identify a particular patient population that benefits from relaxin therapy
  • Heart failure is a chronic disease – attention to pre-hospital care may see greater results in reducing cardiovascular mortality

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Liraglutide Improves Glycemic Control In Children And Adolescents With Type 2 Diabetes

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Children and adolescents with Type 2 diabetes, already taking metformin (with or without insulin) showed improvement in blood sugar control with the addition of liraglutide compared to similar patients who did not receive the treatment, according to a new phase 3 trial.

William V. Tamborlane, MD, with the Department of Pediatrics, Yale University, New Haven, CT, and colleagues reported their findings in the August 15, 2019 issue of The New England Journal of Medicine.

Metformin, a biguanide antihyperglycemic is first-line therapy for pediatric Type 2 diabetes. Several studies have shown that patients experience continued worsening in β-cell function and glycemic control, eventually requiring additional treatment. The only approved drug class for add-on therapy in the pediatric population is insulin, which is used in over half of patients within a few years of starting metformin. While many drug classes are available for adults, trials specifically proving safety and efficacy in the pediatric population are required for approval.

The glucagon-like peptide-1 (GLP-1) receptor agonists have been used in the treatment of adult Type 2 diabetes for over ten years. Liraglutide, one such GLP-1 receptor agonist, was studied in a pediatric phase 2 trial and demonstrated the safety and tolerability of the adult dose range. It is unclear, however, if liraglutide is safe and effective in a pediatric Type 2 diabetes population already taking metformin.

This study, called Ellipse (Evaluation of Liraglutide in Pediatrics with Diabetes), is a phase 3, randomized, placebo-controlled trial. Patients were between 10 and 17 years of age, had a body-mass index (BMI) greater than the 85th percentile, and had glycated hemoglobin levels between 7.0 and 11.0% if they were treated with diet and exercise alone, or between 6.5 and 11.0% if they were treated with metformin (with or without insulin). 135 patients were randomized (134 of whom received at least one dose of study drug or placebo) to receive subcutaneous liraglutide, at standard dose adjustments, or placebo for 26 weeks. The trial was continued for another 26-week open-label period in which the liraglutide group continued treatment, and the placebo group discontinued the placebo. 90.9% of patients in the liraglutide group and 84.1% in the placebo group completed 26 weeks of treatment, and 84.8% of patients in the liraglutide group and 76.8% in the placebo group completed 52 weeks. After the third week of the trial (dose escalation period), 55.6% of the liraglutide group and 72.7% of the placebo group reached the maximum dose of 1.8 mg. The mean changes in glycated hemoglobin were compared between groups.  

Measured at week 26, the mean glycated hemoglobin level decreased by 0.64 percentage points in the liraglutide group and increased by 0.42 percentage points in the placebo group (between-group difference -1.06 percentage points; 95% confidence interval [CI], -1.65 to -0.46; P<0.001). At week 52, the difference in mean glycated hemoglobin levels was increased (-1.30 percentage points; 95% [CI], -1.89 to -0.70). Secondary outcomes showed liraglutide is superior to placebo in reducing fasting plasma glucose levels, and in the number of patients reaching a glycated hemoglobin level of less than 7.0%. Unexpectedly, no difference was observed between groups in body weight or BMI score at week 26 (differences have been observed in adult trials of liraglutide).

The rate of adverse events was higher in the liraglutide group, mainly due to gastrointestinal complaints. Nausea and vomiting were the most frequently reported, however, all adverse events were reportedly mild. Hypoglycemia was also observed more frequently in the liraglutide group, but no episodes were reported as severe. One severe hypoglycemic episode did occur in the placebo group, in a patient taking insulin.

The study authors note that although the trial showed the safety and efficacy of liraglutide, a few aspects of the trial may be somewhat limiting. The relatively small number of patients in the trial may help explain the lack of difference in body weight and BMI between groups at week 26. The dosing schedule used may explain why only about one-half of the study patients received the highest dose of liraglutide. Also, the lack of diversity in the trial population may make the results difficult to generalize to other populations. Further studies will be required to help clarify these issues.

The study was funded by Novo Nordisk.

Tamborlane, WV, et al. Liraglutide in children and adolescents with type 2 diabetes. N Engl J Med. 2019; 381:637-46.

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Vitamin D Supplementation In Prediabetes Does Not Prevent Progression To Type 2 Diabetes

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Patients at high risk for developing type 2 diabetes who received high-dose vitamin D supplementation showed no reduction in the risk of developing diabetes in a recent trial.

Anastassios G. Pittas, MD, with the Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, Boston, and colleagues reported their findings in the August 8, 2019 issue of The New England Journal of Medicine.

The Center for Disease Control and Prevention (CDC) reports that approximately 84 million adults in the United States have prediabetes. The first step in preventing progression to diabetes is lifestyle adjustment, mainly diet and exercise, to achieve weight loss and serum glucose level reduction. Given the difficulty many patients have adhering to lifestyle changes, researchers are studying several supplements and pharmaceutical agents to assist patients while lifestyle adjustments are ongoing. For example, metformin, a biguanide antihyperglyemic agent has been shown to independently reduce the risk of Type 2 diabetes in prediabetic patients. Other agents such as thiazolidinediones and alpha-glucosidase inhibitors are similarly being studied.

Vitamin D has also been linked to diabetes. Vitamin D levels are associated with several aspects of cellular function and health outcomes. Observational studies have shown a correlation between low vitamin D levels and decreased pancreatic beta-cell function and insulin resistance. Other short-term studies have shown an improvement in beta-cell function after vitamin D supplementation. It is unclear, however, if adding vitamin D prevents progression to diabetes.

This study was a randomized, double-blind, placebo-controlled trial, called the Vitamin D and Type 2 Diabetes trial (D2d). The trial enrolled participants 30 years of age or older who had a body-mass index (BMI) of 24 to 42, and had at least two of three criteria for prediabetes: increased fasting plasma glucose level (100-125 mg per deciliter), increased glucose level two hours after a 75-g oral glucose dose (140-199 mg per deciliter), and increased glycated hemoglobin level (5.7 to 6.4%). Patients were not selected for vitamin D deficiency and could be taking up to 1000 IU of vitamin D daily at the time of entry into the trial.

A total of 7133 persons were screened and 2423 were included in the intention-to-treat population. 1211 participants were randomly assigned to receive 4000 IU of vitamin D₃ daily, and 1212 participants to receive placebo. The development of new-onset diabetes was assessed and compared between groups.

After a mean follow-up period of 2.5 years, new-onset diabetes developed in 293 participants in the vitamin D group and 323 participants in the placebo group (9.4 events and 10.7 events per 100 person-years, respectively. The hazard ratio in the vitamin D group was .88; (95% confidence interval [CI], 0.75 to 1.04; P=0.12). The mean baseline serum 25-hydroxyvitamin D level was 28.0 ng per milliliter, with no significant between-group difference. Measured at months 12 and 24, the mean 25-hydroxyvitamin D levels in the vitamin D group were 52.3 and 54.3 ng per milliliter, respectively, and in the placebo group, the levels were 28.1 and 28.8 ng per milliliter, respectively. 

There was no significant difference in the rate of adverse events reported between the groups. This included specific vitamin D-related concerns for the development of hypercalcemia, nephrolithiasis, and decreased glomerular filtration rate (GFR). 47 participants (3.9%) in the vitamin D group stopped the study drug because of an adverse event, as compared with 37 (3.1%) in the placebo group (between-group difference, 0.8%; 95% CI, -0.7 to 2.3).

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others. A full list of disclosures is provided in the journal article.

Pittas, AG, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019; 381:520-30.  

Comments

  • in an editorial accompanying this study, Deborah J. Wexler, MD notes that the hazard ratio of 0.88 for development of new-onset diabetes does not rule out a modest benefit of vitamin D; a larger or longer trial would be needed to show this benefit
  • post hoc analysis done from 103 participants who had vitamin D deficiency (<12 ng per milliliter) showed a hazard ratio for the risk of developing diabetes with vitamin D supplementation of 0.38 (95% CI, 0.18 to 0.80)
  • further studies of those with vitamin D deficiency may help determine whether vitamin D supplementation prevents prediabetes from progressing to diabetes in that subgroup

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Rimegepant Shows Effectiveness In Migraine Therapy

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A new phase 3 study shows the efficacy of rimegepant when compared with placebo in acute migraine treatment.

Richard B. Lipton, MD, with the Department of Neurology and Epidemiology and Population Health, Albert Einstein College of Medicine, and Montefiore Medical Center, New York, and colleagues reported their findings in the July 11, 2019 issue of The New England Journal of Medicine.

Migraine is a very common chronic headache disorder – it is estimated that up to one billion people worldwide suffer migraines. Since their introduction in the early 1990s, triptans have been the most commonly used prescription medication class for migraine therapy. They work by acting as serotonin (5-hydroxytryptamine [5-HT]) agonists with a strong affinity for the 5-HT1B and 5-HT1D receptors, which are associated with vasoconstriction and at least partial inhibition of the release of vasoactive peptides from trigeminal neurons. Many previous published studies have shown that triptans are highly effective, with 70-80% of patients reporting significant pain reduction within ninety minutes of one dose.

Although proven effective, triptans use has been limited by a large adverse side effect profile and many contraindications. They cannot be used in cardiac, cerebral, or peripheral vascular disease, severe hypertension, and Raynaud’s syndrome, due to their vasoconstrictive properties. Many patients report being unable to tolerate triptans because of side effects such as nausea, flushing, dizziness, malaise, chest tightness, tingling, taste disturbance, and headache recurrence.

A new class of migraine drugs, currently in development, are the small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants). CGRP levels correlate with the presence of migraine, and the gepants have been shown to be effective in migraine pain relief. Rimegepant, one such gepant, has been shown in a previous dose-ranging phase 2b study to be effective in treating migraine at the 75-mg dose. The gepants do not cause vasoconstriction, thus are free from the cardiovascular effects of the triptans.

This phase 3 trial was a multicenter, randomized, double-blind study, which enrolled 1186 adult migraine patients from 49 centers in the United States. 1072 of them were included in the modified intention-to-treat population. 537 patients were randomly assigned to receive rimegepant 75 mg, and 535 patients to receive placebo, for a single migraine attack of moderate or severe intensity. Pain intensity and the presence of associated symptoms were assessed and compared between groups.

Evaluated at two hours after the dose, 19.6% of the patients in the rimegepant group and 12.0% in the placebo group reported complete pain relief (between-group difference 7.6%; 95% confidence interval [CI] 3.3 to 11.9; P<0.001). Also, patient-reported relief from photophobia at two hours post-dose was 37.4% in the rimegepant group and 22.3% in the placebo group (P<0.001), relief from phonophobia was reported at 36.7% in the rimegepant group and 26.8% in the placebo group (P=0.004), and relief from the most bothersome symptom was 37.6% and 25.2%, respectively (P<0.001).

The most common adverse events were nausea (reported by 1.8% of the patients in the rimegepant group and 1.1% of the patients in the placebo group) and urinary tract infection (1.5% and 1.1%, respectively).

Although this study showed the efficacy of a single dose of rimegepant in acute migraine, Dr. Lipton and colleagues concluded that “larger and longer trials are needed to determine the consistency of response and the safety and effectiveness of the drug as compared with other migraine treatments.”

The study was funded by Biohaven Pharmaceuticals.

Lipton, RB, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019; 381:142-49.

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C-Reactive Protein Test Safely Reduces Antibiotic Use In COPD Exacerbation

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Chronic obstructive pulmonary disease (COPD) is a complex amalgam of lung diseases, associated with alveolar destruction, inflammation, mucus production, and airway obstruction. The Center for Disease Control and Prevention (CDC) estimates that approximately 16 million people suffer from COPD in the United States. Several studies have shown that each year one-half of COPD sufferers will experience at least one COPD exacerbation. This typically involves increased debility, sometimes involving hospitalization, steroid therapy, and a course of antibiotics.

Although pulmonary infection is the leading cause of COPD exacerbation, it is not present in every case, and in cases that are due to infection, many are viral in origin. Thus, antibiotic stewardship has been an ongoing challenge in the treatment of COPD exacerbation. Point-of-care tests, such as CRP, are being sought to help safely decrease antibiotic use where they not only provide no benefits, but contribute to increased costs, adverse drug effects, and antimicrobial resistance.

Christopher C. Butler, F. Med. Sci., with the Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom, and colleagues reported their findings in the July 11, 2019 issue of The New England Journal of Medicine.

The trial is called the PACE study (Point of care testing to target antibiotics for chronic obstructive pulmonary disease exacerbations). It is a multicenter, open-label, randomized, controlled trial involving 86 general medical practices in the United Kingdom. They randomized 653 COPD patients presenting with a COPD exacerbation to either usual care, or care guided by point-of-care CRP testing. Guidance was given to the treating clinicians as follows: patients who had a CRP level below 20 mg per liter were unlikely to benefit from antibiotic therapy, those who had a CRP level above 40 mg per liter were likely to benefit from antibiotic therapy, and those with a CRP level between 20 and 40 mg per liter may benefit from antibiotic therapy, especially if those patients were reporting purulent sputum production. Patient-reported antibiotic use within four weeks after randomization was compared between groups.

Patient-reported antibiotic use was lower in the CRP-guided care group than in the usual-care group (57% and 77.4% respectively, a 20.4% between-group difference; adjusted odds ratio, 0.31; 95% confidence interval [CI], 0.20 to 0.47).

There was no significant difference in the rate of adverse events reported between the groups. In the four-week follow-up period two patients in the usual-care group died, one from pneumonia and one from respiratory failure, but the trial investigators deemed these events unrelated to the trial.

The study was funded by the National Institute for Health Research Health Technology Assessment Program.

Butler CC, Gillespie D, White, P, et al. C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations. N Engl J Med. 2019; 381:111-20.

Comments

The importance of this study, and others like it, cannot be overstated in that they address one of the most critical issues in medicine today: antibiotic stewardship. The pressure on clinicians to prescribe antibiotics for any of a wide range of symptoms is immense. It is well understood that antibiotics are critical and lifesaving when properly used – however, the CDC reports that 30-50% of antibiotics prescribed in both the outpatient and hospital settings are not necessary. The increasing number of multi-drug resistant bacteria and antibiotic-associated adverse events, such as Clostridium difficile colitis, greatly incentivize decreasing antimicrobial overuse. This study is good evidence that a point-of-care test can actually improve clinical decisions regarding the use of antibiotics.

NB: In spite of the much-needed attention being placed on these issues, and studies like this which are helping clinicians make good antibiotic prescription choices, it is important to realize that a significant amount of antibiotics are also used in animal agriculture and industrial farming. The exact amount or the percentage relative to what is used in humans is difficult to define (some reports state as much as 70-80% of ALL antibiotic use in the U.S. is in the farming industry). What is clear is that we continue to ignore the warning of Alexander Fleming at our peril – the discoverer of penicillin stated in a 1945 interview how the misuse of antibiotics would most certainly lead to the development of resistant bacteria.

C-Reactive Protein Test Safely Reduces Antibiotic Use In COPD Exacerbation Read More »

Canagliflozin Decreases Risk Of Kidney Failure In Type 2 Diabetes

/ News /

Diabetes wreaks havoc on the kidneys – it is currently the leading cause of renal failure in the world. A relatively new class of diabetic drugs, called sodium-glucose cotransporter protein 2 (SGLT2) inhibitors has been shown to improve blood sugar control and improve cardiovascular outcomes. Unlike other diabetic drugs, the SGLT2 inhibitors work by blocking the reuptake of glucose in the kidneys, causing the glucose to be excreted directly into the urine. Previous trials done for cardiovascular outcomes showed trends toward improved renal outcomes, and these data led to the current trial, specifically evaluating kidney disease and the use of SGLT2 inhibitors.

Dr. Vlado Perkovic and colleagues reported their findings in the June 13, 2019 issue of The New England Journal of Medicine. The trial is called CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation). They enrolled 4401 patients with type 2 diabetes and preexisting chronic kidney disease. 2202 patients were randomly assigned to receive canagliflozin 100 mg orally once per day, and 2199 patients to receive a placebo. All patients were required to take either an angiotensin-converting-enzyme inhibitor or angiotensin II-receptor blocker for at least four weeks prior to randomization. End-stage renal disease outcomes (dialysis, transplantation, or sustained GFR below 15 ml/min) were compared between groups.

At a mean follow-up of approximately 2.6 years, the trial was ended (early) because of a significant reduction in renal outcomes in the canagliflozin group compared with the placebo group (43.2 and 61.2 per 1000 patient-years, respectively; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). Investigators also noted improved cardiovascular outcomes, which included a lower risk of cardiovascular death, myocardial infarction (MI), and stroke.

There was no significant difference in the rate of adverse events reported between the groups, including rates of amputation or fracture.

The study was funded by Janssen Research and Development.

Comments

  • approximately four hundred million people worldwide have diabetes, at least 40% will go on to develop renal injury
  • there has been no significant new renal treatment/prevention in the past two decades since the development of angiotensin-converting-enzyme inhibitors (ACE inhibitors) and angiotensin II-receptor blockers (ARBs)
  • although this trial enrolled only those with preexisting renal disease (caveat – those with severe renal disease were excluded), a risk reduction of 30% is very significant, especially with concomitant improvement in cardiovascular outcomes as noted
  • look for continuing updates to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines

Canagliflozin Decreases Risk Of Kidney Failure In Type 2 Diabetes Read More »