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What’s new in diabetes? Dr. Neil Munro, Esher , United Kingdom

What’s new in diabetes? Dr. Neil Munro, Esher , United Kingdom. Socio-economic consequences of major hypoglycaemia in T1D and T2D. Increased treatment cost. Major hypoglycaemic events (UK, Germany and Spain). Reduced productivity. T1D: 1.1–3.2 major hypoglycaemic events/year 1

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What’s new in diabetes? Dr. Neil Munro, Esher , United Kingdom

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  1. What’s new in diabetes? Dr. Neil Munro, Esher, United Kingdom

  2. UK/DB/0811/0382 Socio-economic consequences of major hypoglycaemia in T1D and T2D Increased treatment cost Major hypoglycaemic events (UK, Germany and Spain) Reduced productivity • T1D: 1.1–3.2 major hypoglycaemic events/year1 • T2D: 0.1–0.7 severe hypoglycaemic events/year (treatment dependent)1 • Annual cost of hospitalisation and ambulances for severe hypoglycaemia in the UK estimated at £15 million • Total cost of a severe hypoglycaemic event across the survey: £362.56–£470.07 in T2D, and £160.22–£392.52 in T1D2 1UK Hypoglycaemia Study Group Diabetologia 2007;50:1140–7;2 Hammer et al. J Med Econ 2009;12:281–90

  3. CVS effects • ↑ sympathoadrenal response • ↑ heart rate • ↑ QT prolongation • ↑ inflammation • ↑ endothelial dysfunction • ↑ arterial stiffness (with duration of disease) • ACCORD – patients with type 2 diabetes who experience severe hypoglycaemia are at risk of sudden death irrespective of glucose control

  4. Cardiovascular effects of hypoglycaemia Euglycaemia Hypoglycaemia QRS complex T T PR segment ST segment PR interval QT QT QT interval • Hypoglycaemia is known to prolong both the QT interval and cardiac repolarisation – increased risk of cardiac arrhythmia UK/DB/0811/0382 Adapted from Frieret al. Diabetes Care 2011;34(Suppl 2):S132–7

  5. Pathophysiological cardiovascular consequences of hypoglycaemia CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor Desouza et al.Diabetes Care 2010;33:1389–94 UK/DB/0811/0382

  6. Insulin and hypoglycaemia • Severe hypoglycaemia cause of death in 6-10% of people with Type 1 diabetes Hypoglycaemia → hypoglycaemia ↓ Physiological response • Nocturnal hypoglycaemia • ↓hypoglycaemic awareness during sleep • 55% severe hypoglycaemic episodes occur at night • 35% patients have no hypoglycaemic awareness • Consequences • Coma/seizures/brain damage/cognitive decline • ↓recall in children with severe hypoglycaemia • ↓cognitive scores in children under 10 years of age • ↑dementia in elderly

  7. Statins and Diabetes Predictors of new-onset diabetes in patients treated with atorvastatin. Results from 3 large randomized clinical trials. We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02—1·17), with little heterogeneity (I2=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150—852) patients with statins for 4 years resulted in one extra case of diabetes. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials • Waters et al wanted to look at the risk of diabetes specifically with atorvastatin, and they did this with data from three large studies—TNT (comparing 80 mg and 10 mg/day of atorvastatin in patients with stable coronary disease), IDEAL (atorvastatin 80 mg vssimvastatin 20 mg/day in post-MI patients) and SPARCL (atorvastatin 80 mg/day vs placebo in patients with a recent stroke or transient ischemic attack). J Am CollCardiol 2011; 57:1535-1545. The Lancet, Volume 375, Issue 9716, Pages 735 - 742, 27 February 2010

  8. Biosimilar insulins • Patents expire • Glargine 2014 • Lispro 2013 • Aspart 2012 • Biopharmaceutical • Derived from cell culture/fermentation→ therapeutic protein (recombinant insulin) • May not be identical. Absorption properties can be different. Varying purity may affect anti-genicity. • Problems – alpha interferon→ differences in viral clearance. Insulin Marvel – differences in bioavailability (pK/pD values). File withdrawn. 14 EPOs developed in Thailand→ loss of effect due to antibody formation. • BNF (2007) • “When using biological products it is good practice to use brand names”

  9. Insulin innovation • Degludec • 48+ hr od, flat profile, equivalent glucose lowering compared to glargine. Less hypoglycaemia. 0.38-0.45 units/kg • Insulin patch project • Insupatin (infusion site warming device) • Heats infusion site to 38.5 for 15 minutes prior to bolus → increased absorption • Hybrid closed loop • MetronicminimedePID (external physiologic delivery) • Uses PID (proportionate-integral-derivative) closed loop controller • Treat to Target Technosphere insulin • 15 patients with T1D in phase 3 studies • ↓HbA1c 0.4% in 45 days. Bolus insulin dose ↑ x 2.5 • A 2nd dose of 5-10 units taken after meals in 1/3 of patients

  10. Duros and exenatide • ITCA implantable device every 3/12 • Formulation stable for 2 years • 15 minute insertion • Osmotic mini-pump • Phase 2 48 week extension study • 24 week study initially. 85% continued in extension study • ↓HbA1c 1.5% • ↓3.5kgs • Nausea 10%, diarrhoea 3%, skin/injection site problems 7%

  11. Exenatide once weekly

  12. Exenatide – XTEN (VRS-859) • Addition of longtail of natural hydrophilic amino acid provides half life sufficient for use as a monthly agent • Phase 1 studies complete • May be used in conjunction with glucagon-XTEN receptor antagonists

  13. Liver in diabetes • NAFLD • >27% over 65 are affected by NAFLD (hepatic steatosis) • ↑ mortality in NAFLD due to diabetes and cirrhosis • NASH • Steatosis + cellular ballooning, inflammation, pericellular fibrosis, mallory bodies • 15% develop cirrhosis or hepatocellular cancer • Divens study • Vitamin E ↓cell injury • Weight loss ↓ ALT • Pioglitazone – no benefit + ↑7kgs • Hepatitis C • Steatosis→↑ insulin resistance • Metformin may be protective against hepatocellular cancer in hepatitis C

  14. Fatty Liver and fibrosis Insulin resistance ↓ FFA + insulin + cytokines ↓ ER Mitchondria ↓ ↓ Inflammation Apoptosis ↓ ↓ Stellate cell activation ↓ Fibrosis

  15. Bone and diabetes • TZD • ↑ risk of lower and upper limb facture in women (ADOPT) • ↑ risk of fracture in women (2.04 OR)(Pro Active) • UKGPRD • 1y T2D ↑ 1.85 • 2y T2D ↑ 2.86 all fractures • 1y T2D ↑ 2.6 hip fractures in women, ↑ 2.5 hip fractures in older men • Loss of trabecular bone (cortex preserved) • Postmenopausal women with diabetes at most risk. Older men also affected

  16. Bone and diabetes • Glyburide • ADOPT – no ↑ risk but risk of hypoglycaemia remains • Insulin • No direct effect on bone but may contribute to falls (marker of disease severity) • GLP 1 • ↓bone absorption. May improve bone matrix. • Glycaemic control • ACCORD – no ↑ risk seen in intensively treated group despite 92% using TZD and 56% being on insulin. Would have expected to see ↑20% incidence • Vitamin D and ca supplements made no difference

  17. A Helping Hand • Diabetes is challenging for individuals and societies and developments do not always go to plan. Health professionals and pharmaceutical companies are there to lend a hand

  18. Pioglitazone and Bladder Cancer

  19. Long term effects of dapagliflozin • Add onto metformin • 546 patients 2y • ↓ HbA1c 0.5-0.8% • ↓1.7kgs • 1 in 409 discontinued because of urinary or vulvovaginal symptoms • 9 bladder cancers in intervention group (n=5478) vs 1 in control (n=3156). 6 out 10 had haematuria at enrolment and were included in trial. No SGLT receptors in bladder.

  20. The gut and diabetes

  21. Gut Microbiota • 10-100 trillion organisms – the gut microbiota. (10x than no of human cells). >1000 species in gut • ↑L cell receptors with probiotics and bacteria • Bacterial lipopolsacharide (LPS) ↑ T2D and metabolic syndrome • LPS crosses bowel wall → CD 14 macrophage activation → inflammatory response • Bifidobacteria protective against obesity and T2D • Prebiotics • Garlics, onions, leaks promote bifidobacteria fermentation and improve glucose handling

  22. L Cells Receptors • Contain regulatory peptide hormones and/or biogenic amines • Activation of TGR5→ ↑cyclic AMP→ membrane depolarisation (independent of KATP closure) • Receptor (GQ receptor) • Responds to amino acids and glucose • Promotes SGLT 1, SGLT 2, PPY, oxyntomodulin and proglucagon • Agonists • GPR (G-protein coupled receptors) 43 stimulated by colonic bacteria

  23. G-Coupled Receptor Agonists GPR119 Agonist (AS1790091) GPR 40 agonist (TAK 875) G Coupled receptor protein binds to free fatty acid receptor on β cell→ ↑ ER activation→ ↑ Ca++→ ↑ insulin release Phase 2 study 12 weeks 384 completers ↓ HbA1c 0.8% Well tolerated No hypoglycaemia • G coupled receptor activation→↑insulin secretion via cAMP • GPR receptors in β cells and enteroendodermal cells in the small intestine • PSN 821 • Small molecule GPR 119 agonist • ↑ GIP, GLP-1 and PYY

  24. Scout DS Device • Measures • Multiple spectral signatures from fluorophores in epidermis (AGE, NADH, flavoproteins, collagen and elastin) • Skin scattering from haemoglobin • Being investigated as possible means of non-invasive detection of diabetes

  25. Exhaled breath glucose monitoring • Altered metabolism →↑breath acetone + >3000 volatile organic compounds(voc) • Investigation of sets of 4 vocs • Acetone, methyl nitrate, ethanol and ethyl benzene • 2-pentyl nitrate, propane, methanol and acetone • Glucose levels can be predicted by non-invasive breath analyses

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