Whats new in diabetes Dr Neil Munro Esher

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

UK/DB/0811/0382 Date of preparation: August 2011 Socio-economic consequences of major hypoglycaemia in T 1 D and T 2 D Major hypoglycaemic events (UK, Germany and Spain) Reduced productivity • T 1 D: 1. 1– 3. 2 major hypoglycaemic events/year 1 • T 2 D: 0. 1– 0. 7 severe hypoglycaemic events/year (treatment dependent)1 1 UK Increased treatment cost • 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 T 2 D, and £ 160. 22–£ 392. 52 in T 1 D 2 Hypoglycaemia Study Group Diabetologia 2007; 50: 1140– 7; 2 Hammer et al. J Med Econ 2009; 12: 281– 90

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

Cardiovascular effects of hypoglycaemia Date of preparation: August 2011 QRS complex Euglycaemia T PR segment Hypoglycaemia T ST segment QT PR interval 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 Frier et al. Diabetes Care 2011; 34(Suppl 2): S 132– 7

Date of preparation: August 2011 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

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

Statins and Diabetes Predictors of new-onset diabetes in patients treated with atorvastatin. Results from 3 large randomized clinical 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 vs simvastatin 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 Coll Cardiol 2011; 57: 1535 -1545. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin 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 (I 2=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. The Lancet, Volume 375, Issue 9716, Pages 735 - 742, 27 February 2010

Biosimilar insulins • Patents expire – Glargine – Lispro – Aspart 2014 2013 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 (p. K/p. D 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”

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 – Metronic minimed e. PID (external physiologic delivery) • Uses PID (proportionate-integral-derivative) closed loop controller • Treat to Target Technosphere insulin – 15 patients with T 1 D in phase 3 studies – ↓Hb. A 1 c 0. 4% in 45 days. Bolus insulin dose ↑ x 2. 5 – A 2 nd dose of 5 -10 units taken after meals in 1/3 of patients

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 – ↓Hb. A 1 c 1. 5% – ↓ 3. 5 kgs – Nausea 10%, diarrhoea 3%, skin/injection site problems 7%

Exenatide once weekly

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

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 + ↑ 7 kgs • Hepatitis C • Steatosis→↑ insulin resistance • Metformin may be protective against hepatocellular cancer in hepatitis C

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

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 – 1 y T 2 D ↑ 1. 85 – 2 y T 2 D ↑ 2. 86 all fractures – 1 y T 2 D ↑ 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

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

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

Pioglitazone and Bladder Cancer

Long term effects of dapagliflozin Add onto metformin 546 patients 2 y ↓ Hb. A 1 c 0. 5 -0. 8% ↓ 1. 7 kgs 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. • • •

The gut and diabetes

Gut Microbiota • • • 10 -100 trillion organisms – the gut microbiota. (10 x than no of human cells). >1000 species in gut ↑L cell receptors with probiotics and bacteria Bacterial lipopolsacharide (LPS) ↑ T 2 D and metabolic syndrome LPS crosses bowel wall → CD 14 macrophage activation → inflammatory response Bifidobacteria protective against obesity and T 2 D Prebiotics – Garlics, onions, leaks promote bifidobacteria fermentation and improve glucose handling

L Cells Receptors • Contain regulatory peptide hormones and/or biogenic amines • Activation of TGR 5→ ↑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

G-Coupled Receptor Agonists GPR 119 Agonist (AS 1790091) GPR 40 agonist (TAK 875) • G coupled receptor activation→↑insulin secretion via c. AMP • GPR receptors in β cells and enteroendodermal cells in the small intestine • PSN 821 • G Coupled receptor protein binds to free fatty acid receptor on β cell→ ↑ ER activation→ ↑ Ca++→ ↑ insulin release • Phase 2 study – Small molecule GPR 119 agonist • ↑ GIP, GLP-1 and PYY – – 12 weeks 384 completers ↓ Hb. A 1 c 0. 8% Well tolerated No hypoglycaemia

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

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 noninvasive breath analyses