Mr Rab Burtun. Dr David Kim. 8:30-10:30 WS #2: Diabetes Basic 11:00-13:00 WS #9: Diabetes Basic (Repeated)

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1 Dr David Kim Endocrinologist and General Physician Waitemata DHB and Apollo Specialist Clinic Albany Auckland Mr Rab Burtun Diabetes Nurse Specialist Waitemata DHB Waitakere Hospital Auckland 8:30-10:30 WS #2: Diabetes Basic 11:00-13:00 WS #9: Diabetes Basic (Repeated)

2 Diabetes Workshop Topics Relevant in Primary Care: Basic David Kim Endocrinologist

3 Conflicts of interest Honorarium from: Sanofi Aventis Novo Nordisk

4 What is Diabetes? Disease characterised by impaired glucose metabolism with high blood glucose either due to insulin deficiency (Type 1 diabetes) or insulin resistance +/- deficiency (Type 2 diabetes) This high blood sugar may produce symptoms of thirst with polydipsia (increased drinking) and polyuria (increased urination) +/- weight loss and lethargy

5 What is Diabetes? Rusty Gates Insulin resistance Type 2 diabetes Not enough keys Insulin deficiency in Type 1 (+ many Type 2)

6 Type 2 Diabetes: Relevance to our practice An evolving epidemic 8% of adults in New Zealand believed to have type 2 diabetes Rate of growth slowing a little, and complication rate per patient decreasing However, prevalence of diabetes ~tripled in the last 20 years with overall burden of disease still growing

7 Why do we care about diabetes? Microvascular complications - Retinopathy - Nephropathy - Neuropathy Macrovascular complications - Coronary heart disease - Stroke - Peripheral vascular disease

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9 CVD Risk Management Summary Hypertension Rx with target blood pressure: / (ACE-i/ ARB first line) Lipid lowering Rx (i.e. Statin) in secondary prevention or high CVD risk (5 year CVD risk >15% ) with aim of TC < , LDL < (Statins) Smoke cessation Aspirin in secondary prevention or primary prevention in high CVD risk (5 year CVD risk >15% )

10 Why bother optimising HbA1c? EVERY 1% reduction in HbA 1c 1% Relative Risk N=3642 Diabetesrelated deaths Myocardial infarctions Microvascular complications Amputations or deaths from peripheral vascular disorders REDUCED RISK (P<0.0001) UKPDS=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:

11 Why bother optimising HbA1c? 10 YEARS AFTER UKPDS: Despite similar HbA1c between two groups post trial, benefits maintained, including CVD rates and mortality i.e. EARLY maintenance of glycaemic control matters (Legacy effect) Holman R et al, N Eng J Med 2008; 359:

12 Normal IGT Target for most acceptable in some Rx Augmentation Insulin initiation & intensification

13 Case 1: 46 y.o. overweight male with lethargy/ polyuria, otherwise well Fasting glucose 8.0mmol/L, HbA1c 58 mmol/mol Diagnosis & (glycaemic) management?

14 Metformin for all T2DM after/with lifestyle changes Pros: Weight neutral No hypoglycaemia mortality/ CVD risk May reduce cancer risk CG testing not mandatory Funded & cheap Cons: GI side-effect up to 10% Care if low egfr Care if risk of lactic acidosis e.g. critical illness/ sepsis BD/ TDS dosing

15 More on Metformin Start gently WITH FOOD (e.g. 500mg with dinner for a couple of days then 500mg BD) BD dosing as a rule, TDS dosing only for very compliant pt lunch time dose often forgotten! Titrate doses up to meet target HbA1c up to 1.5g BD (if small patient 1g BD) Dose reduction for those with egfr between (dose adjust to 850mg BD down to 500mg daily)

16 Case 2: 50 y.o. overweight male with T2DM for 4 years on metformin 1000mg mane, 1500mg nocte HbA1c now 65 mmol/mol adequate? Reasonable glycaemic target for this patient? Further glycaemic management?

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18 Next step after Metformin - NZ version Diet & Exercise + Metformin Sulphonylurea Glipizide Gliclazide (glibenclamide) Insulin Pioglitazone or Acarbose DPP-4 inhibitor/ GLP-1 agent e.g. Sitagliptin Saxagliptin Exenatide SGLT-2 inhibitor e.g. Dapagliflozin

19 Sulphonylureas (Glipizide/ Gliclazide) Pros: Tried and true Works well with MF Funded/ cheap Cons: Hypoglyceamia, especially in elderly Weight gain? Earlier β-cell failure/ loss of effect after 5 10 years in some cases

20 Sulphonylureas Start lower dose Glipizide 2.5-5mg or Gliclazide 40-80mg 1-2 times a day Usually BD dosing with breakfast & dinner Max dose Glipizide 10mg BD/ Gliclazide 160 BD Capillary glucose testing to guide both initiation & up-titration of the regimen

21 Pioglitazone: PPAR-γ inhibitor Pros: Reduces insulin resistance HbA1c up to 10 mmol/mol Funded Once daily dosing Other favourable metabolic benefits Cons: Weight gain Ankle oedema in some Contraindicated in heart failure Osteoporosis esp. post menopausal women (# risk )

22 Pioglitazone Start at 15-30mg daily If target not achieved in 6-8 weeks, increase dose, up to 45mg daily (unless S/E) Watch out for heart failure especially in older/ those with cardiac Hx

23 Acarbose Reduces gut CHO absorption (α-glucosidase inhibitor) Minor role to play in T2DM in general Pros: Weight neutral No hypoglycaemia May reduce blood pressure & C.V. morbidity Funded Cons: G.I. side effects in many (flatulence) <5mmol/mol in HbA1c TDS or BD dosing

24 GLP-1 agents : GLP-1 analogues e.g. Exenatide (Byetta/ Bydureon) GLP-1 is a gut hormone from the ileum which is reduced in type 2 diabetes. Restoring GLP-1 levels leads to: insulin from ß cell Glucagon from α cell Gastric emptying Appetite Pros: HbA1c mmol/mol Weight loss No hypoglycaemia CVD risk reduction Cons: COST (>$250/mo) S.C. injection (BD, but possibly once weekly) Nausea (usually wears off)

25 GLP-1 agents : DPP4-inhibitors e.g. Sitagliptin (Januvia) / Saxagliptin (Onglyza) Inhibits DPP-IV enzyme that breaks down GLP-1 Pros: Once daily, oral prep. No hypoglycaemia Minimal S/E Weight neutral Cons: COST (~$100/mo) Modest efficacy HbA1c 5-10 mmol/mol

26 SGLT-2 inhibitor Dapagliflozin (Forxiga) Works in the renal tubules to increase excretion of glucose in urine Pros: Once daily oral prep No hypoglycaemia Weight loss (modest) CVD risk reduction HbA1c 5-10 mmol/mol on average Cons: COST (~$100/mo) Increased genitourinary s/e

27 Overview of Rx modes of action Not enough insulin Type 1 (+ many Type 2) Rusty Gates - Type 2 diabetes Diet & Exercise Metformin Pioglitazone Others for T2DM (rarely used) : Acarbose GLP-1 agents: Exenatide/ DPP4-inhibitors SGLT-2 inhibitor Sulphonylureas (type 2 DM only) Insulin (both type 1 and type 2)

28 Consider BARIATRIC SURGERY if: BMI > 35, age < 55, relatively short duration of diabetes, well motivated

29 Case 3: 55 y.o. overweight male with 9 year hx of T2DM on MF 1.5g BD, Gliclazide 160mg BD. HbA1c mmol/mol over past 6 months Why does this happen despite him seemingly adhering to treatment and lifestyle measures? What next?

30 Glycaemic control deteriorates over time UKPDS 34, Lancet 1998:352:854 65; Kahn et al (ADOPT), NEJM 2006;355:

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33 When to start insulin? (ALL type 1 diabetes) In type 2 diabetes start when: - Lifestyle optimised and oral agents maximised, yet high HbA1c: mmol/mol in younger mmol/mol in older Also consider starting in following situations: - On maximum metformin (2-3g/d) monotherapy with HbA1c >75mmol/mol (>9%) - HbA1c very high >95mmol/mol (>11%) - Uncertainty re: type 1 vs. type 2 diabetes Once insulin start is deemed necessary; JUST DO IT!

34 Insulins available on NZ Market

35 Lantus (insulin glargine) Sanofi Aventis Lepore M et al. Diabetes 2000;49: Lantus Data Sheet, 26 August 2010

36 Apidra (insulin glulisine) Sanofi Aventis Becker R. Clin Pharmacokinet 2008;47:7-20

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39 How to start? 1. Conventional approach: - Bedtime basal insulin (10 units of Protaphane/ Humulin NPH/ Glargine), titrate dose up with an aim to normalise (4-7mmol/L) fasting glucose - Particularly appropriate in those waking up with raised fasting glucose

40 How to start? More than one way to skin a cat! 2. Alternative approach: - Pre-dinner premixed insulin: e.g. 12 units of NovoMix30 or HumalogMix25 - Good for those with high post prandial glucoses, large dinners and unlikely to manage more than 2 injections a day

41 Back to Case 3 55 y.o. overweight male with 9 year hx of T2DM on MF 1.5g BD, Gliclazide 160mg BD. HbA1c mmol/mol over past 6 months What was done: Lantus (glargine) started at 10 units at night, with instructions to regularly check pre-breakfast CGs

42 Plasma glucose (mmol/l) Why start with basal insulin? Comparison of 24-hour glucose levels in untreated vs treated patients with diabetes T2DM Plasma glucose (mmol/l) 0 Meal Meal Meal 06:00 10:00 14:00 18:00 22:00 02:00 06:00 0 Time of day (hours) Adapted from Hirsch I et al. Clin Diabetes 2005; 23:

43 Patient led titration with Lantus Davies et al. Diabetes Care2005;28(6):1282-8

44 FAST SCHEDULE (PHYSICIAN-MANAGED) Increase by 2 8 units of insulin depending on fasting BGL over previous 2 3 days Mean fasting blood glucose (mmol/l) Increase in insulin dose <4 * See below No change units units units >10 8 units Adapted from Phillips PJ. Medicine Today 2007; 8(3):

45 Over to you, Rab