What’s new in diabetes?

Dr. Neil Munro, Esher, United Kingdom

Socio-economic consequences of major hypoglycaemia in T1D and T2D

• 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

Major hypoglycaemic events (UK, Germany and Spain)

Reduced productivity Increased treatment cost

1UK Hypoglycaemia Study Group Diabetologia 2007;50:1140–7; 2 Hammer et al. J Med Econ 2009;12:281–90

UK/DB/0811/0382 Date of preparation: August 2011

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

Adapted from Frier et al. Diabetes Care 2011;34(Suppl 2):S132–7

Euglycaemia Hypoglycaemia

QT interval

ST segment

QRS complex

PR interval

PR segment

• Hypoglycaemia is known to prolong both the QT interval and cardiac repolarisation – increased risk of cardiac arrhythmia

TT

QT QT

UK/DB/0811/0382

Date of preparation: August 2011

Pathophysiological cardiovascular consequences of hypoglycaemia

CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factorDesouza et al. Diabetes Care 2010;33:1389–94UK/DB/0811/0382

Date of preparation: August 2011

Insulin and hypoglycaemia• Severe hypoglycaemia cause of death in 6-10% of people with Type 1

diabetesHypoglycaemia → 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 DiabetesPredictors 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).

• 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.

J Am Coll Cardiol 2011; 57:1535-1545.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials

The Lancet, Volume 375, Issue 9716, Pages 735 - 742, 27 February 2010

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”

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 ePID (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

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%

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 + ↑7kgs

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

Fatty Liver and fibrosisInsulin 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

– 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

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 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.

The gut and diabetes

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

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

G-Coupled Receptor Agonists

GPR119 Agonist (AS1790091)• 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

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

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 non-invasive breath analyses