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