Download ADA 2011

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 T1D and T2D
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
1UK
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 T2D, and £160.22–£392.52 in
T1D2
Hypoglycaemia Study Group Diabetologia 2007;50:1140–7; 2 Hammer et al. J Med Econ 2009;12:281–90
CVS effects
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↑ 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
Date of preparation: August 2011
Cardiovascular effects of
hypoglycaemia
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):S132–7
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
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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.
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 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.
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.
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 (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
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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
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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 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
– 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
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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
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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
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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 noninvasive breath analyses