Progressive use of medical therapies in type 2 diabetes

Korzyści wynikające z bardziej intensywnego leczenia hiperglikemii, nadciśnienia tętniczego, dyslipidemii i nadkrzepliwości u chorych na cukrzycę typu 2 są oczywiste. Wciąż nowe doniesienia i rozwój badań klinicznych sprawiają, że kryteria wyrównania metabolicznego stają się coraz bardziej wymagające. Artykuł ten zawiera przegląd metod leczenia skojarzonego, prowadzących do minimalizacji czynników ryzyka u chorych na cukrzycę typu 2. W ostatniej dekadzie nastąpiły rewolucyjne zmiany dotyczące leczenia cukrzycy, spowodowane postępem w wielu dziedzinach. Wyniki 4 znaczących badań klinicznych [1–8] udowodniły hipotezę hiperglikemii, wskazując, że optymalna glikemia u osób chorych na cukrzycę powinna być tak niska, jak to możliwe, bez nadmiernego ryzyka hipoglikemii i innych działań niepożądanych. Do 1995 roku insulina i pochodne sulfonylomocznika były jedynymi lekami w Stanach Zjednoczonych, dopuszczonymi do stosowania w leczeniu cukrzycy. Następnie zaakceptowano analogi insulin, nowe pochodne sulfonylomocznika oraz 4 inne grupy leków [9]. Towarzyszyły temu także znaczne postępy technologiczne dotyczące monitorowania glikemii, ułatwiające prowadzenie samokontroli [10]. Wyniki badań klinicznych potwierdziły korzyści interwencji eliminujących czynniki ryzyka chorób sercowo-naczyniowych w leczeniu makroangiopatii — głównej przyczyny śmierci i niepełnosprawności chorych na cukrzycę [11, 12]. Zmiany systemu ubezpieczeń zdrowotnych oraz federalnych i stanowych aktów prawnych przyczyniły się do poprawy finansowania leków, zaopatrzenia medycznego i edukacji, co pozwoliło na obniżenie docelowych wartości glikemii, ciśnienia tętniczego i stężenia lipidów. Artykuł ten opisuje praktyczne i konstruktywne wytyczne dotyczące opieki diabetologicznej. Cele kontroli glikemii i metody modyfikacji trybu życia nie są tu przedmiotem dyskusji. Na początku zostały omówione dostępne klasy leków stosowanych w cukrzycy oraz sugerowane sposoby progresywnego leczenia hiperglikemii. Następnie przedstawiono poglądy na temat zwalczania czynników ryzyka chorób sercowo-naczyniowych z krótkim omówieniem leków i ich zastosowania

Medications for type 2 diabetes: how will we be treating patients in 50 years?

The past 50 years have seen the development of many new options for treating and preventing type 2 diabetes. Despite this success, the individual and societal burden of the disease continues unabated. Thus, the next 50 years will be critical if we are going to quell the major non-communicable disease of our time. The knowledge we will gain in the next few years from clinical studies will inform treatment guidelines with regard to which agents to use in whom and whether more aggressive approaches can slow the development of hyperglycaemia in those at high risk. Beyond that, we anticipate identification of novel targets and techniques for therapeutic intervention. These advances will lead to more personalised approaches to treatment. Most importantly, we will need to focus our political and economic efforts on enhancing and implementing public health approaches aimed at prevention of diabetes and its co-morbidities. This is one of a series of commentaries under the banner ‘50 years forward’, giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965–2015)

Novel measures of inflammation and insulin resistance are related to obesity and fitness in a diverse sample of 11-14 year-olds:The HEALTHY Study

BACKGROUND: GlycA is a novel serum marker of systemic inflammation. There is no information on GlycA in pediatric populations, how it differs by gender or its association with body mass index (BMI) or fitness. LP-IR is a serum measure of insulin resistance which is related to changes in BMI group in adolescents, but its relationship with fitness is unknown. The current study examined the independent associations between fitness and BMI with GlycA and LP-IR among US adolescents. METHODS: Participants were 1664 US adolescents from the HEALTHY study with complete 6th and 8th grade BMI, fitness and blood data. GlycA and LP-IR were measured by NMR spectroscopy. Three BMI groups and three fitness groups were created. Linear mixed models examined associations between GlycA, LP-IR, fitness and BMI. RESULTS: LP-IR decreased between 6th and 8th grade. GlycA increased among girls but decreased among boys. At 8th grade, median GlycA values were 27 (7.6%) μmol/l higher (381 versus 354) for girls than boys. Median GlycA 6th grade values were 9% higher in obese girls than healthy weight girls. Overall there was strong evidence (P CONCLUSIONS: GlycA was associated with BMI and fitness among in US adolescents. These findings suggest that there are independent effects for BMI and fitness group with both GlycA and LP-IR. Future studies should validate the role of GlycA and LP-IR to evaluate the effects of interventions to modify obesity and fitness in order to improve systemic inflammation and insulin resistance.International Journal of Obesity accepted article preview online, 04 May 2016. doi:10.1038/ijo.2016.84

Liraglutide and renal outcomes in type 2 diabetes

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown

Re-engineering The Clinical Research Enterprise in Response to COVID-19: The Clinical Translational Science Award (CTSA) experience and proposed playbook for future pandemics

The 2020 COVID-19 pandemic has had a profound impact on the clinical research enterprises at the 60 Clinical and Translational Science Award (CTSA) Hubs throughout the nation. There was simultaneously a need to expand research to obtain crucial data about disease prognosis and therapy and enormous limitations on conducting research as localities and institutions limited travel and person-to-person contact. These imperatives resulted in major changes in the way research was conducted, including expediting Institutional Review Board review, shifting to remote interactions with participants, centralizing decision-making in prioritizing research protocols, establishing biobanks, adopting novel informatics platforms, and distributing study drugs in unconventional ways. National CTSA Steering Committee meetings provided an opportunity to share best practices and develop the idea of capturing the CTSA program experiences in a series of papers. Here we bring together the recommendations from those papers in a list of specific actions that research sites can take to strengthen operations and prepare for similar future public health emergencies. Most importantly, creative innovations developed in response to the COVID-19 pandemic deserve serious consideration for adoption as new standards, thus converting the painful trauma of the pandemic into “post-traumatic growth” that makes the clinical research enterprise stronger, more resilient, and more effective

Effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on colorectal cancer incidence and its precursors

Incretin-based antihyperglycemic therapies increase intestinal mucosal expansion and polyp growth in mouse models. We aimed to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1ra) initiation on colorectal cancer incidence

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials

AIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. METHODS: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc

Effects of Sensor-Augmented Pump Therapy on Glycemic Variability in Well-Controlled Type 1 Diabetes in the STAR 3 Study

Compared with multiple daily injections (MDI), sensor-augmented pump (SAP) insulin therapy may reduce glycemic variability and oxidative stress in type 1 diabetes in a glycosylated hemoglobin (A1C)-independent manner

Primum non nocere: Refocusing our attention on severe hypoglycemia prevention

Severe hypoglycemia, defined as low blood glucose requiring assistance for recovery, is arguably the most dangerous complication of type 1 diabetes as it can result in permanent cognitive impairment, seizure, coma, accidents, and death. Since the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive intervention to normalize glucose prevents long-term complications but at the price of a threefold increase in the rate of severe hypoglycemia, hypoglycemia has been recognized as the major limitation to achieving tight glycemic control. Severe hypoglycemia remains prevalent among adults with type 1 diabetes, ranging from ∼1.4% per year in the DCCT/EDIC (Epidemiology of Diabetes Interventions and Complications) follow-up cohort to ∼8% in the T1D Exchange clinic registr