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.
Age-adjusted relative risk for Type 2 diabetes Diabetes and obesity are closely interlinked Relationship between BMI and risk of Type 2 100 diabetes 75 Normal weight Overweight Obese 50 Women Men 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 BMI (kg/m 2 ) *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.
Pathophysiology of Type 2 Diabetes Insulin resistance -cell failure Hyperinsulinemia Normal Hyperglycaemia Increasing insulin resistance Plasma insulin Blood glucose
Beta-cell function (%, HOMA) Decline in beta-cell function is already advanced at time of diagnosis 1 100 80 T2D diagnosis 60 40 20 0-12 -10-8 -6-4 -2 0 2 4 6 8 Time from diagnosis (years) 1. Adapted from Lebovitz H. Diabetes Reviews 1999;7:139 153
HbA 1c (%) 10.0 UKPDS glycaemic control deteriorates after one year 9.0 8.0 7.0 6.0 0 Conventional therapy (primarily diet n = 297) Intensive therapy (with insulin or sulphonylureas n = 696) 0 1 2 3 4 5 6 Years UKPDS 16. Diabetes 1995; 44: 1249 58.
8 Organs Regulating Plasma Glucose Increased Glucose Production Impaired Insulin Secretion Decreased Glucose Storage & Use Increased Glucagon Secretion Hyperglycaemia Decreased Glucose Uptake & Increased FFA Release Decreased Incretin Release Increased Glucose Reabsorption Neurotransmitter Dysfunction FFA, free fatty acid. Adapted from: DeFronzo RA. Diabetes 2009;58:773 95.
8 Organs Regulating Plasma Glucose Sulphonylurea Insulin Metformin Increased Glucose Production Impaired Insulin Secretion Metformin Decreased Glucose Storage & Use Insulin Incretins GLP-1ra DPP4i Increased Glucagon Secretion Hyperglycaemia Decreased Glucose Uptake & Increased FFA Release Pioglitazone Insulin Decreased Incretin Release Increased Glucose Reabsorption Neurotransmitter Dysfunction FFA, free fatty acid. Adapted from: DeFronzo RA. Diabetes 2009;58:773 95. Acarbose SGLT-2i
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: 383-393 2. Chan J. Diabetes Care 2009; 32: 977-82
Controlling multiple parameters is essential for effective treatment of patients with Type 2 diabetes HbA 1c Weight Blood pressure Reductions in glycaemic control (HbA 1c ) and other parameters that are sustained over time can benefit the health of patients with Type 2 diabetes 1 5 Lipids 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
Potentially modifiable Usually not modifiable Approach to the Management of Hyperglycemia Patient/Disease Features Risk of hypoglycemia/drug adverse effects Disease Duration Life expectancy Relevant comorbidities Established vascular complications more stringent low newly diagnosed long absent absent A1C 7% Few/mild Few/mild less stringent high long-standing short severe severe Patient attitude & expected treatment efforts Resources & support system highly motivated, adherent, excellent self-care capabilities readily available less motivated, nonadherent, poor self-care capabilities limited American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2017; 40 (Suppl. 1): S48-S56
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
Relative risk reduction for metformin treatment (%) UKPDS 34: relative risk reduction with metformin vs conventional treatment 0 10 20 30 40 50 ** * * * * p < 0.05 ** p < 0.01 UKPDS 34: Lancet 1998;352:854 65
Increasing plasma GLP-1 concentrations GLP-1 dose response relationships Vomiting Diarrhoea Nausea Abdominal pain Pharmacological GLP-1 levels GLP-1 receptor agonists Appetite Food intake = Weight loss Gastric emptying Physiological GLP-1 levels DPP-4 inhbitors Insulin secretion Glucagon secretion Plasma glucose GLP-1 effects 1. Holst. Trends Mol Med 2008;14:161 8
1 2 3 Existing and novel mechanisms to reduce hyperglycaemia in Type 2 diabetes 1 4 Insulin-dependent mechanisms Insulin action Thiazolidinediones Metformin Insulin release SUs GLP-1R agonists* DPP4 inhibitors* Meglitinides Insulin replacement Insulin Adipose tissue, muscle and liver Pancreas Insulin-independent mechanism SGLT2 inhibition Glucose utilisation Glucose excretion/caloric loss *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-2 1 4 Majority of glucose is reabsorbed by SGLT-2 (90%) Proximal tubule SGLT2 Glucose Glucose filtration Remaining glucose is reabsorbed by SGLT-1 (10%) Loop of Henle Minimal to no glucose excretion 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 Reduced glucose reabsorption SGLT2 Gliflozin Proximal tubule SGLT2 Glucose Gliflozin Glucose filtration Loop of Henle Increased urinary Increased urinary excretion of excess glucose (~70 g/day, corresponding to to 280 kcal/day*) 1 ) By inhibiting SGLT-2, The gliflozins remove glucose and associated calories *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
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