Achieving Excellence in Diabetes
The Importance of Incremental Care
Kieran Walshe MD MRCGP FRCPE
GP and Diabetes Specialist
Diabetes in Ireland
• 2015: • Estimated prevalence of diabetes 5.5%
• Estimated prevalence of impaired glucose tolerance 6.6%
• 75,900 people with undiagnosed diabetes
• Mean diabetes-related expenditure per person with diabetes €4,692
• Diabetes related deaths (20-79) 1,568
• National prevalence of diabetes estimated to rise from 5.5% in 2013 to 8 % in 2035.
Based on UN 2012 (adjusted for 2013) population estimate of 3,209,000.
International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas. Last accessed March 2014.
Diabetes and obesity are closely
interlinkedRelationship between BMI and risk of Type 2
diabetes
*Results are from two different studies. The first study is from a cohort of 27,983 US male health professionals, 40–75 years of age in 1986 who completed biennial questionnaires sent out in 1986, 1988, 1990 and 1992 (follow-up: 1987–1922). The second study is from a cohort of 114,281 US female registered nurses, 30–55 years of age in 1976 who completed questionnaires (follow-up: 1976–1990).
BMI, body mass index.Adapted from: 1. Chan J, et al. Diabetes Care 1994;17:961–9; 2. Colditz GA, et al. Ann Intern Med 1995;122:481–6.
100
75
50
25
0<23 <23–23.9 <24–24.9 <25–26.9 <27–28.9 <29–30.9 <31–32.9 <33–34.9 ≥35
Normal weight Overweight Obese
Women
Men
Age
-ad
just
ed
re
lati
ve r
isk
for
Typ
e 2
dia
be
tes
BMI (kg/m2)
Increasing insulin resistance
Normal
Hyperinsulinemia
Hyperglycaemia
Plasma insulin Blood glucose
Insulin resistance -cell failure
Pathophysiology of Type 2 Diabetes
Decline in beta-cell function is already advanced at time of diagnosis1
1. Adapted from Lebovitz H. Diabetes Reviews 1999;7:139–153
0
20
40
100
-4 6-10 -8 -6 -2 0 2 4
80
60
-12 8
T2D diagnosis
Time from diagnosis (years)
Beta
-cell function (
%,
HO
MA)
UKPDS 16. Diabetes 1995; 44: 1249–58.
UKPDS – glycaemic control deteriorates after one year
0
6.0
7.0
8.0
9.0
0 1 2 3 4 5 6
Hb
A1c
(%)
Conventional therapy (primarily diet n = 297)
Intensive therapy (with insulin or sulphonylureas
n = 696)
Years
10.0
ImpairedInsulin Secretion
Decreased Glucose Storage & Use
Increased Glucose Production
Decreased Glucose Uptake & Increased FFA Release
Increased Glucose Reabsorption
NeurotransmitterDysfunction
Decreased Incretin Release
Increased Glucagon Secretion
Hyperglycaemia
FFA, free fatty acid. Adapted from: DeFronzo RA. Diabetes 2009;58:773–95.
8 Organs Regulating Plasma Glucose
8 Organs Regulating Plasma Glucose
Increased Glucose Production
Metformin Metformin
Sulphonylurea
IncretinsGLP-1raDPP4i
Pioglitazone
Acarbose
Insulin Insulin
Insulin
SGLT-2i
ImpairedInsulin Secretion
Decreased Glucose Storage & Use
Decreased Glucose Uptake & Increased FFA Release
Increased Glucose Reabsorption
NeurotransmitterDysfunction
Decreased Incretin Release
Increased Glucagon Secretion
Hyperglycaemia
FFA, free fatty acid. Adapted from: DeFronzo RA. Diabetes 2009;58:773–95.
Diabetes and mortality
Adapted from the emerging risk factor collaboration. NEJM 2011; 364: 829 - 41
The Big Idea
• The benefits of using protocol driven care translates into a Life expectancy closer to normal with a
– 60% drop in micro/macrovascular complications vs. conventional treatment followed over 13 yrs. 1
– 60% drop in all cause mortality and end stage renal disease over 2 years 2
1. Steno 2 study: NEJM 2003; 348: 383-3932. Chan J. Diabetes Care 2009; 32: 977-82
Controlling multiple parameters is essential
for effective treatment of patients with Type
2 diabetes
Lipids
Blood pressure
Weight
HbA1cReductions in glycaemic control
(HbA1c) and other parameters
that are sustained over time can
benefit the health of patients with Type 2 diabetes1–5
1. Stratton IM, et al. BMJ 2000;321:405–12; 2. Pi-Sunyer FX. Postgrad Med 2009;121:94–107; 3. Williamson DF, et al. Diabetes Care 2000;23:1499–504; 4. Patel A, ADVANCE Collaborative Group. Lancet 2007;370:829–40; 5. Pyǒrälä K, et al. Diabetes Care 1997;20:614–20.
The Reality… England and Wales
• T2DM: only 20.8% of 2.4 million patients audited* had
– HbA1c of < 58mMol/mMol {<7.5%}
– BP <140/90 mmHg
– Cholesterol < 5mmol/L
[BBC TV News 13/1/2015: Type 1 Diabetes Patients in the UK …only 16% have attained all current treatment targets]
*National Diabetes Audit 2011-12; Report 1 (2013) . HSC Information Centre, Leeds
Approach to the Management of Hyperglycemia
low high
newly diagnosed long-standing
long short
absent severeFew/mild
absent severeFew/mild
highly motivated, adherent, excellent self-care capabilities
readily available limited
less motivated, nonadherent, poor self-care capabilities
A1C
7%more
stringent
less
stringentPatient/Disease Features
Risk of hypoglycemia/drug adverse effects
Disease Duration
Life expectancy
Relevant comorbidities
Established vascular complications
Patient attitude & expected
treatment efforts
Resources & support system
American Diabetes Association Standards of Medical Care in Diabetes.
Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
Usu
ally
no
t m
od
ifia
ble
Pote
nti
ally
m
od
ifia
ble
Antihyperglycemic Therapy in T2DM
American Diabetes Association Standards of Medical Care in Diabetes.
Approaches to glycemic treatment. Diabetes Care 2017; 40 (Suppl. 1): S64-S74
Donard Commissioning Group. Dundrum Co-Down 1999-2016
• 1,000+ Diabetes patients managed in Primary Care; with support from a Diabetes Specialist Nurse [DSN] and GP Specialist
• Common computer system [EMIS]and agreed protocol of care [15 GP’s]
• Care is PRACTICE-BASED; the DSN [advising the Practice Nurse & GP], along with Podiatry& Dietetic support at the GP Diabetes clinics
• ‘Real’ &‘Virtual’ clinics run by DSN{with GP Specialist supervision} for those failing to achieve targets. Action is implemented by patient’s GP, following DSN input
Donard Commissioning Group 2015-16
• The Objective is to ‘Treat To Target’. The agreed targets {‘individualised’} are as follows;
• A1c <7.5% [ =53-58mmol/mol ] BP<140/90 Chol <4 & LDL-c <2mMol
• NB: ‘Treat to target’ means action is mandatory when the A1c is > than 7.5%[58mMol+], over a 3-6 month period ….don’t ‘wait for failure’!
• 66 % achieve the ‘individualised’ A1c target• 75% achieve the ‘individualised’ BP target• 87% achieve the ‘individualised’ Lipid target
from the 2015-16 Audit, Dundrum Clinic, Donard GP Commissioning Group
UKPDS 34: relative risk reduction with metformin vs conventional treatmentR
elat
ive
risk
red
uct
ion
fo
r m
etfo
rmin
tre
atm
ent
(%)
10
20
30
40
50
0
* p < 0.05 ** p < 0.01
*
***
*
UKPDS 34: Lancet 1998;352:854–65
Physiological GLP-1 levels
Pharmacological GLP-1 levels
Gastric emptying
Plasma glucoseInsulin secretion
Glucagon secretion
GLP-1 effects
Appetite
Food intake
= Weight loss
Incr
easi
ng
pla
sma
GLP
-1 c
on
cen
trat
ion
s
Vomiting
Diarrhoea
Nausea
Abdominal pain
1. Holst. Trends Mol Med 2008;14:161–8
GLP-1 receptor agonists
DPP-4 inhbitors
GLP-1 dose–response relationships
1
2
3
Existing and novel mechanisms to reduce hyperglycaemia in Type 2 diabetes1−4
Insulin action• Thiazolidinediones
• Metformin
Insulin release• SUs
• GLP-1R agonists*
• DPP4 inhibitors*
• Meglitinides
Insulin replacement• Insulin
Glucose utilisation
Insulin-dependent mechanisms
Adipose tissue, muscle and liver
Pancreas
Glucose excretion/caloric loss
Insulin-independent mechanism
SGLT2 inhibition
*In addition to increasing insulin secretion, which is the major mechanism of action, GLP-1R agonists and DPP4 inhibitors also act to decrease glucagon secretion.
DPP4, dipeptidyl peptidase-4; GLP-1R, glucagon-like peptide-1 receptor; SUs, sulphonylureas. 1. Washburn WN. J Med Chem 2009;52:1785–94; 2. Bailey CJ. Curr Diab Rep 2009;9:360–7; 3. Srinivasan BT, et al. Postgrad Med J 2008;84:524–31; 4. Rajesh R, et al. Int J Pharma Sci Res 2010;1:139–47.
In normal renal glucose handling, ~90% of glucose is reabsorbed by SGLT-21–4
Proximal tubule
Glucose
filtration
SGLT2
Glucose
Majority of glucose
is reabsorbed by
SGLT-2 (90%)
Remaining
glucose is
reabsorbed by
SGLT-1 (10%)
Minimal to no
glucose excretion
Loop of
Henle
• The kidneys filter and reabsorb 180g of glucose per day
• SGLTs are responsible for this reabsorption
SGLT, sodium-glucose co-transporter. 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Marsenic O. Am J Kidney Dis 2009;53:875–83.
C/D/E-gliflozin inhibits SGLT-2 and removes excess glucose in the urine independently of insulin
*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes….Data on file AZ 2015
Reduced glucose
reabsorption
SGLT2
Increased urinary
excretion of excess
glucose (~70 g/day,
corresponding to
280 kcal/day*1)
Glucose
filtration
‘Gliflozin
SGLT2
Glucose
‘Gliflozin
• By inhibiting SGLT-2, The gliflozins remove glucose and associated calories
Increased urinary
excretion of excess
glucose (~70 g/day,
corresponding to
280 kcal/day*)
Proximal tubule
Loop of
Henle
Hypoglycaemia in clinical practice
• 3% of people with type 2 diabetes experienced severe hypoglycaemia over a 12 month period [50% due to SU’s]
• People of all ages who experienced severe hypoglycaemia had a 79% increased risk of suffering an acute cardiovascular event
• Hypoglycaemia directly preceded an acute cardiovascular event in over 25% of people
• People who experienced severe hypoglycaemia incurred a 2 fold greater health related expenditure
Johnston et al. Diabetes care March 2011
Weight gain
• For every BMI increase of 1kg/M2, the risk of heart failure increases by 5% in men and 7% in women….(Kenchaiah 2002)
• a 5kg increase in body weight increases the risk of CHD by up to 29%...(Anderson 2001, 2003)
• Obese : 3 subsets #1: The FEASTERS [<GLP1,<signalling &find it hard to stop #2: Emotional Eaters eat food to manage emotion [CBT] #3: The Constant Cravers,linked to genes, constantly hungry[5:2 Diet] cf bbc.co.uk/rightdiet 13/1/2015
Positivity/Optimism
• More targeted drugs [ultra-quick insulin, hepatoselective insulin, oral insulin ]; drugs that are activated as glucose rises. Better weight loss medication to > insulin sensitivity.
• CGM {continuous glucose monitoring} which eradicated hypoglycaemia and facilitates better BG control . Stem cells to cure and vaccines to eradicate Type1
• Drugs which selectively block the development of diabetic
complications
The key to Diabetes { & much more!}is knowledge, behavioural skills & self-responsibility
The end of man is knowledge, but there is one thing he can’t know.
He can’t know whether knowledge will save him or kill him.
He will be killed, all right, but he can’t know whether he is killed because of the knowledge which he has got or because of the knowledge which he hasn’t got and which if he had it would save him.
Robert Penn Warren ‘All the King’s Men’ 1946
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