Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

Looping with Do-It-Yourself Artificial Pancreas Systems During Ramadan Fasting in Type 1 Diabetes Mellitus: Perspectives of a User and a Physician.

Hybrid closed-loop automated insulin delivery systems have helped type 1 diabetes (T1D) users close the loop between glucose monitoring and insulin delivery, a very important step in efforts to simulate the glucose-responsive insulin secretory function of a healthy pancreas. Do-It-Yourself Artificial Pancreas Systems (DIY APS) are a form of hybrid closed-loop system that use open-source algorithms, which govern the delivery of insulin in response to interstitial glucose and other variables that are personalized to an individual. The flexibility and customization afforded by these systems make them amenable for use in different worldly circumstances, one of which is fasting during the annual occurrence of Ramadan for observant Muslims. Here, we present the views of a DIY APS user who was able to fast successfully on most days of Ramadan after adopting this system, and the overview of a physician on these systems, with a focus on fasting during Ramadan with T1D.

Looping with Do-It-Yourself Artificial Pancreas Systems During Ramadan Fasting in Type 1 Diabetes Mellitus: Perspectives of a User and a Physician.

Hybrid closed-loop automated insulin delivery systems have helped type 1 diabetes (T1D) users close the loop between glucose monitoring and insulin delivery, a very important step in efforts to simulate the glucose-responsive insulin secretory function of a healthy pancreas. Do-It-Yourself Artificial Pancreas Systems (DIY APS) are a form of hybrid closed-loop system that use open-source algorithms, which govern the delivery of insulin in response to interstitial glucose and other variables that are personalized to an individual. The flexibility and customization afforded by these systems make them amenable for use in different worldly circumstances, one of which is fasting during the annual occurrence of Ramadan for observant Muslims. Here, we present the views of a DIY APS user who was able to fast successfully on most days of Ramadan after adopting this system, and the overview of a physician on these systems, with a focus on fasting during Ramadan with T1D.

Do-It-Yourself (DIY) Artificial Pancreas Systems for Type 1 Diabetes: Perspectives of Two Adult Users, Parent of a User and Healthcare Professionals.

The artificial pancreas system or an automated insulin dosing system has been the 'holy grail' for patients with type 1 diabetes and their caregivers who have over the years wanted to 'close the loop' between monitoring of glucose and delivery of insulin. The launch of the Medtronic MiniMed 670G system in 2017 and the subsequent release of the Tandem t:slim with Control-IQ system, the DANA RS pump compatible-CamAPS FX app and the more recent announcement of the Medtronic MiniMed 780G system have come as answers to their prayers. However, in the time taken to develop and launch these commercial systems, creative and ebullient parents of young patients with type 1 diabetes, along with other patients, technologists and healthcare professionals have developed mathematical models as software solutions to determine insulin delivery that in conjunction with compatible hardware have helped 'close the loop'. Under an umbrella movement #WeAreNotWaiting, they have, as a community, refined and disseminated technologies that are open source and ubiquitously available as do-it-yourself (DIY) closed-loop systems or DIY artificial pancreas systems (APS). There are presently three systems-OpenAPS, AndroidAPS and Loop. We present perspectives of two patients, parent of a patient, and their healthcare providers; the users spanning an age spectrum most likely to use this technology-a child, an adolescent in transitional care and a 31-yr old adult patient, highlighting how looping has helped them self-manage diabetes within the routine of their lives and the challenges they faced.

Post-Transplantation Diabetes Mellitus.

Solid organ transplantation (SOT) is an established therapeutic option for chronic disease resulting from end-stage organ dysfunction. Long-term use of immunosuppression is associated with post-transplantation diabetes mellitus (PTDM), placing patients at increased risk of infections, cardiovascular disease and mortality. The incidence rates for PTDM have varied from 10 to 40% between different studies. Diagnostic criteria have evolved over the years, as a greater understating of PTDM has been reached. There are differences in pathophysiology and clinical course of type 2 diabetes and PTDM. Hence, managing this condition can be a challenge for a diabetes physician, as there are several factors to consider when tailoring therapy for post-transplant patients to achieve better glycaemic as well as long-term transplant outcomes. This article is a detailed review of PTDM, examining the pathogenesis, diagnostic criteria and management in light of the current evidence. The therapeutic options are discussed in the context of their safety and potential drug-drug interactions with immunosuppressive agents.

Heterozygous Insulin Receptor (INSR) Mutation Associated with Neonatal Hyperinsulinemic Hypoglycaemia and Familial Diabetes Mellitus: Case Series

Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.