Fall in prevalence of impaired awareness of hypoglycaemia in individuals with type 1 diabetes.

AIMS: Impaired awareness of hypoglycaemia (IAH) has been reported to affect up to a third of people with type 1 diabetes. Whether the increased use of sensor technology has changed its prevalence remains unknown. The aim of this study was to investigate the current prevalence of IAH and its change over time in a cohort of individuals with type 1 diabetes. METHODS: IAH was assessed using the modified Clarke questionnaire in adults with type 1 diabetes. Participants were recruited from the diabetes outpatient clinic from February 2020 through April 2021. The scores were compared to similar data collected during previous assessments in 2006, 2010 and 2016 respectively. RESULTS: A total of 488 individuals (51.2% male) with a mean (±SD) age of 51.3 ± 15.9 years, median [Q1-Q3] diabetes duration of 30 [16-40] years and mean HbA1c of 60 ± 12 mmol/mol (7.7 ± 1.1%) were included. Sensors were used by 85% of the study population. IAH was present among 78 (16.0%) participants, whereas 86 (17.6%) participants had a history of severe hypoglycaemia. By comparison, the prevalence of IAH equalled 32.5% in 2006, 32.3% in 2010 and 30.1% in 2016 (p for trend <0.001), while the proportion of individuals reporting severe hypoglycaemia equalled 21.2%, 46.7% and 49.8% respectively (p for trend 0.010). Comparing sequential assessments over time, the proportion of individuals with persistent IAH decreased from 74.0% and 63.6% between 2006 and 2016 to 32.5% in 2020. CONCLUSIONS: Among individuals with type 1 diabetes and high use of sensor technology, the current prevalence of IAH was 16%, about 50% lower as compared to previous years.

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases. Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.

Genetic determinants of impaired awareness of hypoglycemia in type 1 diabetes.

OBJECTIVE: It is likely that impaired awareness of hypoglycemia (IAH) and severe hypoglycemia are in part determined by genetic factors. The aim of this study was to investigate candidate genes for associations with IAH and severe hypoglycemia in a cohort of patients with type 1 diabetes. PARTICIPANTS AND METHODS: Consecutive patients with type 1 diabetes were genotyped for single-nucleotide polymorphisms in or near the genes for the ß1 and ß2 adrenergic receptor (ADRB1, ADRB2), SORCS1, and BNC2, and for the insertion/deletion polymorphism in the ACE gene. IAH and severe hypoglycemia were assessed using a validated questionnaire. RESULTS: Of 486 patients, 32.5% were classified as having IAH. The Arg16Gly polymorphism of ADRB2 was associated with IAH (odds ratio: 1.49, 95% confidence interval: 1.01-2.20, P=0.046) Gly16 (GG) versus carriers of the A allele. In a haplotype analysis, the association was the highest in patients with GG at position 16 and heterozygous at position 27 (odds ratio: 2.19, 95% confidence interval: 1.33-3.61, P=0.03). There were no associations between IAH and other genes, and none of the studied genes was associated with severe hypoglycemia. CONCLUSION: Genotypes at two variants of ADRB2 are associated with IAH. This association is comparable with the risk of classical risk factors for IAH.

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol.

BACKGROUND: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. METHODS/DESIGN: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. DISCUSSION: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02045667.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

BACKGROUND: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are likely to use both HIV and HCV treatment. Drug-drug interactions have been demonstrated between boceprevir, an HCV protease inhibitor, and frequently prescribed antiretroviral drugs, such as efavirenz and boosted HIV protease inhibitors. Concomitant administration of boceprevir with these drugs should be avoided. This study was designed to investigate the absence of a drug-drug interaction between boceprevir and raltegravir, an HIV integrase inhibitor. METHODS: This was an open-label, randomized, 2-period, crossover phase 1 trial in 24 healthy volunteers. All subjects were randomly assigned to receive boceprevir 800 mg every 8 hours for 9 days plus a single dose of raltegravir 400 mg on day 10 followed by a washout period and a single dose of raltegravir 400 mg on day 38, or the same medication in reverse order. Blood samples for pharmacokinetics were collected and pharmacokinetic parameters were calculated. RESULTS: The geometric mean (GM) of raltegravir area under the concentration-time curve (AUC)(0-12h) and maximum plasma concentration (C(max)) for raltegravir + boceprevir vs raltegravir alone were 4.27 (95% confidence interval [CI], 3.22-5.66) vs 4.04 (95% CI, 3.09-5.28) mg * hour/L and 1.06 (95% CI, .76-1.49) vs 0.93 (95% CI, .70-1.23) mg/L, respectively. GM ratio estimates of raltegravir AUC(0-12h) and C(max) for raltegravir + boceprevir vs raltegravir alone were 1.04 (90% CI, .88-1.22) and 1.11 (90% CI, .91-1.36), respectively. The GM of boceprevir AUC(0-8h), C(max), and C(8h) were 5.45 (95% CI, 5.11-5.81) mg * hour/L, 1.88 (95% CI, 1.72-2.06) mg/L, and 0.09 (95% CI, .07-.11) mg/L, respectively. These data are comparable to those from historical controls. CONCLUSIONS: Due to the absence of a clinically significant drug interaction, raltegravir can be recommended for combined HIV/HCV treatment including boceprevir. CLINICAL TRIALS REGISTRATION: NCT01288417.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the proton pump inhibitor omeprazole.

OBJECTIVES: Proton pump inhibitors (PPIs) can limit the solubility of concomitant drugs, which can lead to decreased absorption and exposure. Reduced efficacy can be a consequence and in the case of an antimicrobial agent this may contribute to development of resistance. Patients chronically infected with the hepatitis C virus can be treated with a boceprevir-containing regimen and it is relevant to know if interactions between PPIs and boceprevir exist. This study was designed to investigate the influence of a frequently used PPI, omeprazole, on the pharmacokinetics of boceprevir and vice versa. METHODS: In this open-label, three-period, randomized, cross-over, Phase I study, healthy subjects were randomly assigned to 40 mg of omeprazole once daily for 5 days, 800 mg of boceprevir three times daily for 5 days and 40 mg of omeprazole once daily + 800 mg of boceprevir three times daily for 5 days, or the same treatment in a different order. Every treatment was followed by a wash-out period. At day 5 of every treatment pharmacokinetic blood sampling was performed for 8 h after medication intake. ClinicalTrials.gov: NCT01470690. RESULTS: All 24 subjects (15 males) completed the study and no serious adverse events were reported. Geometric mean ratios (90% CI) of the area under the plasma concentration-time curve up to 8 h (AUC0-8) and maximum plasma concentration (Cmax) of boceprevir with omeprazole versus boceprevir alone were 0.92 (0.87-0.97) and 0.94 (0.86-1.02), respectively. For omeprazole these values were 1.06 (0.90-1.25) for AUC0-8 and 1.03 (0.85-1.26) for Cmax for the combination versus omeprazole alone. CONCLUSIONS: Omeprazole did not have a clinically significant effect on boceprevir exposure, and boceprevir did not affect omeprazole exposure.

Effect of posaconazole on the pharmacokinetics of fosamprenavir and vice versa in healthy volunteers.

OBJECTIVES: To manage the interaction between fosamprenavir/ritonavir and posaconazole, we hypothesized that ritonavir can be replaced by posaconazole as an alternative booster of fosamprenavir with no significant influence on posaconazole pharmacokinetics. METHODS: This was an open-label, randomized, three period, cross-over, single-centre trial in 24 healthy volunteers. All subjects received the following three treatments for 10 days, separated by washout periods of 17 days: posaconazole 400 mg twice daily; fosamprenavir/ritonavir 700/100 mg twice daily; posaconazole 400 mg twice daily with fosamprenavir 700 mg twice daily. RESULTS: Twenty subjects completed the trial. Geometric mean ratios (GMR; +90% confidence interval) of posaconazole AUC and C(max) when taken with fosamprenavir versus posaconazole alone were 0.77 (0.68-0.87) and 0.79 (0.71-0.89), respectively. The GMRs of amprenavir AUC and C(max) when taken as fosamprenavir and posaconazole versus fosamprenavir/ritonavir were 0.35 (0.32-0.39) and 0.64 (0.55-0.76), respectively. No serious adverse events were reported during the trial. CONCLUSION: Unboosted fosamprenavir should not be used concomitantly with posaconazole.

Preserved sensitivity to beta2-adrenergic receptor agonists in patients with type 1 diabetes mellitus and hypoglycemia unawareness.

BACKGROUND AND OBJECTIVE: Use of beta(2)-adrenergic receptor agonists has been advocated for the treatment of hypoglycemia unawareness in type 1 diabetes. In vitro, however, hypoglycemia unawareness has been associated with reduced beta(2)-adrenergic sensitivity. Therefore, in vivo sensitivity to beta(2)-adrenergic receptor agonist stimulation was compared between type 1 diabetic patients with and without hypoglycemia unawareness and nondiabetic controls. METHODS: Ten type 1 diabetic patients with hypoglycemia unawareness, 12 type 1 diabetic patients with intact hypoglycemic awareness, and 11 healthy controls were enrolled. beta(2)-Adrenergic sensitivity was determined by measuring the forearm vasodilator response to intraarterial infusion of salbutamol. Salbutamol was infused in six increasing doses ranging from 0.003 to 1.0 mug(1).min(-1).dl(-1). Forearm blood flow (FBF) was bilaterally measured by venous occlusion plethysmography. Diabetic patients received low-dose insulin before FBF measurements to ensure that experiments were carried out under normoglycemic conditions. RESULTS: At baseline, FBF was 1.9 +/- 0.3 ml(1).min(-1).dl(-1) in controls, 2.3 +/- 0.4 ml(1).min(-1).dl(-1) in patients with intact awareness, and 1.4 +/- 0.1 ml(1).min(-1).dl(-1) in patients with hypoglycemia unawareness (P = 0.048 vs. aware patients). In response to salbutamol, FBF increased 9.1-fold in controls, 8.0-fold in patients with intact awareness, and 10.7-fold in patients with hypoglycemia unawareness (P = NS). Heart rate increased in all groups due to systemic spillover of salbutamol but appeared blunted, considering a greater fall in mean arterial pressure in patients with hypoglycemia unawareness. CONCLUSIONS: Sensitivity to beta(2)-adrenergic receptor agonist stimulation is preserved in type 1 diabetic patients with hypoglycemia unawareness.

Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers.

Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

The Arg16Gly variant of the beta2-adrenergic receptor predisposes to hypoglycemia unawareness in type 1 diabetes mellitus.

Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.

Effect of sex on the cardiovascular response to adrenaline in humans.

Cardiovascular responsiveness to stress conditions differs between men and women. It is not known to what extent this observation is explained by differences in the release of stress hormones like adrenaline, or by differences in the response to adrenaline. Therefore, we quantified the hemodynamic response to infusion of adrenaline (0.04, 0.06, and 0.08 microg x kg(-1) x min(-1) for 20 minutes each) in 8 healthy men and 8 healthy premenopausal women. Arterial plasma adrenaline levels were measured before and after infusion. Heart rate and intra-arterial blood pressure were monitored throughout the experiment. Arterial plasma adrenaline levels increased similarly in both sexes. There was a larger increase in systolic blood pressure in women compared with men (17.6 +/- 2.8 versus 5.1 +/- 3.1 mm Hg, P < 0.01). In contrast, men showed a larger increase in heart rate compared with women (20.3 +/- 1.4 versus 11.2 +/- 2.8 bpm, P < 0.01). In conclusion, these data suggest that the cardiovascular response to adrenaline is predominantly alpha-adrenergic in premenopausal women, and predominantly beta-adrenergic in age-matched men.