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Intensifying glycaemic control in Type 2 diabetics Dr Miriam Blackburn Staff Specialist The Canberra Hospital.

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Presentation on theme: "Intensifying glycaemic control in Type 2 diabetics Dr Miriam Blackburn Staff Specialist The Canberra Hospital."— Presentation transcript:

1 Intensifying glycaemic control in Type 2 diabetics Dr Miriam Blackburn Staff Specialist The Canberra Hospital

2 Outline Hba1c Targets Guidelines for intensifying glycaemic control Bariatric surgery Oral hypoglycaemic agents – Side effects and PBS listing Starting Byetta Starting Insulin Summary



5 Australian Diabetes Association Guidelines Hba1c target summary Hba1c goal for most diabetics <7% More intensive targets – Women planning pregnancy <6% – Requiring lifestyle modification ±metformin Hba1c ≤ 6.0 % – Requiring any oral antidiabetic agents other than metformin or insulin Hba1c ≤ 6.5 % ? Risk of hypoglycaemia with sulphonylureas

6 Australian Diabetes Association guidelines for Hba1c targets Hba1c target of <8% – Elderly life expectancy, less than 10 years – Advanced cardiac or renal failure CKD stage 4 or 5 NYHA cardiac failure stage 3 or 4 (GFR<30 mls/min) – Incurable malignancy – Moderate Dementia – Hypoglycaemic unaware

7 UKPDS 3867 patients with a new diagnosis (treatment naive) of Type 2 diabetes Randomised to intensive therapy (either metformin, sulphonylurea or insulin) or conventional treatment with diet Mean Hba1c of less than 7% in the first five years of the trial for the intensive group Tight glycaemic control was later lost

8 UKPDS Patients in the intensive treatment group for the first five years – Significant reductions in microvascular complications, myocardial infarction and death from any cause – Despite loss of the tight control the benefit endured for the next ten years

9 UKPDS Legacy effect 12% reduction in any diabetes related endpoint for patients who had intensive glycaemic control for the first five years

10 The Legacy Effect Are we meeting the Hba1c guidelines? 60% of Australian patients are not meeting Hba1c targets Clinical inertia/patient compliance

11 Case History Mike, a 65 year old Type 2 diabetic – Complicated by mild diabetic retinopathy, no other comorbidities Medications – Metformin 2 grams daily – Diamicron MR 120 g daily – Tried Byetta (unable to tolerate due to nausea) Declining bariatric surgery Hba1c 7.8%, weight 100kg How would you manage this patient?

12 Starting Basal Insulin in a Type 2 Diabetic Add basal insulin 10 units daily of Protaphane or Lantus Or Add once daily premixed insulin – Novomix units with dinner Increase dose by 2-4 units until fasting BSL 4-7 mmol/L 0.2 units per kg/day is a reasonable starting dose for add on basal insulin

13 Guidelines for Intensifying Glycaemic Control


15 Treating a Newly Diagnosed Type 2 Diabetic



18 Intensifying Glycaemic Control for Type 2 Diabetics The traditional way Step 1 Diet and Exercise Step 2 Metformin Step 3 Metformin plus a sulphonylurea Step 4 Metformin plus a sulphonylurea plus a glitazone Step 4 Insulin

19 Intensifying glycaemic control for Type 2 diabetics A new approach Step 1 – Diet and Exercise plus Metformin Step 2 – Dual therapy Metformin plus a Sulphonylurea DPPIV inhibitor plus either a Sulphonylurea or Metformin Byetta and Metformin or a Sulphonylurea Step 3 Triple therapy Consider Byetta plus Metformin and a sulphonylurea Step 4 – Insulin +/- oral hypoglycaemic agents

20 Comparing sulphonylureas and DPPIV inhibitors and GLP1 agonists (Byetta) GLP1 agonist(Byetta)GLP1 agonist(Byetta) CheapExpensiveExpensiveExpensive Long term safety dataNo long term safety dataNo long term safety dataNo long term safety data SulphonylureasDPPIV inhibitorsGLP1 agonists Byetta CostCheapExpensive Risk of hypoglycaemia YesNo Effect on weightWeight gainWeight neutralWeight loss Long term safety data and evidence of reduction of microvascular complications YesNo


22 Expected Reduction in Hba1c DPPIV inhibitors % Byetta 1% Metformin 1-2% Sulphonylurea 1-2% Insulin %

23 Case History Carol, 45 year old Type 2 diabetic – no complications Comorbidities – OSA, GORD, OA (waiting TKR) Medications – Metformin 2 grams daily, Diamicron MR 120 mg daily, Byetta 10mcg bd s/c, Crestor 20 mg daily, Perindopril plus 5mg/1.25 mg, Amlodipine 5mg, Aspirin 100mg

24 Case History Weight 120kg, BMI 45 Hba1c 9% Had dietician and exercise physiologist review and lost 4kg in 6/12 then gained 6kg in the next 6/12 What is the next step?

25 Management Refer for bariatric surgery In the meantime, cease Byetta Continue Metformin and Diamicron and start insulin Novomix units with dinner or Lantus 24 units before bed (based on 0.2 units per kg) Titrate insulin to get before breakfast sugar between 4-7mmol/L


27 Indications for bariatric surgery Failed weight loss by lifestyle change – At least one year of determined effort BMI>40 BMI>35 and severe comorbidities – Diabetes, severe osteoarthritis, obstructive sleep apnoea, obesity related cardiomyopathy Motivated and informed Canberra Bariatric holds patient information sessions

28 Gastric Sleeve Tubular stomach, has fewer ghrelin producing cells

29 Gastric Band Purely restrictive procedure

30 Effects of Bariatric Surgery Mean weight loss 61% Diabetes resolved 77% Hyperlipidaemia improved 70% Hypertension resolved 62% Obstructive sleep apnoea resolved 86% Gastroesophageal reflux symptoms improved Mortality due to operative complications less than 1%, adverse events 20% 30% reduction in mortality due to a reduction in the comorbidities (less cancer, IHD and diabetes related deaths)

31 Complications of Gastric Banding Restrictive procedure Easily reversible Lowest mortality rate of all bariatric procedures (0.05%) High rate of revision surgery required (40-50%) Complications – Acute stomal infection, band infection, haemorrhage, pulmonary emboli, band erosion, band slippage, prolapse or tubing malfunction

32 Complications of Sleeve Gastrectomy Lower rate of complications than gastric bypass Mortality 0.39% Common complications (3-24%) – Bleeding – Narrowing or stenosis of gastric stoma – Gastric leaks – Reflux

33 Costs of Bariatric Surgery If patient has private health insurance – $6000-$7000 out of pocket If patient has no private health insurance – $ Public funding coming soon…. – Limited number – Strict criteria for eligibility

34 Case History Jan, 45 year old Type 2 diabetes – Diabetes for 10 years – Insulin for 4 years – No complications Medications – Metformin 2 grams daily – Diamicron MR 120 mg daily – Lantus 30 units nocte

35 Case History Hba1c 8% Fasting sugar readings 5-6 mmol/L Weight 98 kg, BMI 33 How would you treat this patient?

36 Management of a Type 2 Diabetic not meeting Hba1c targets on Basal Insulin Stop Diamicron – Stop sulphonylureas when short acting insulin started Continue Metformin – To assist with prevention of insulin associated weight gain Start twice daily pre-mixed insulin – Novomix units morning and 10 units at night


38 Thiazolidinediones Rosiglitazone (Avandia) and Pioglitazone (Actos) Side effects – Weight gain – Congestive cardiac failure – Osteoporosis and fractures Rosiglitazone (Avandia) – Boxed warning Increased risk myocardial infarction and congestive cardiac failure Adverse effect on lipids Pioglitazone (Actos) – Increased risk of bladder cancer

39 Acarbose (Glucobay) Inhibit upper gastrointestinal enzymes (alphaglucosidases) and slow the absorption of carbohydrate Side effects – 73% flatulence – Diarrhoea – Compliance maybe poor due to side effects


41 How do DPPIV Inhibitors Work? The Incretin Effect An oral dose of glucose causes more insulin secretion than the same dose given intravenously Glucose in the gut stimulates release of incretins (Glucagon like peptide 1, GLP1 and gastric inhibitory polypeptide, GIP) which increase insulin secretion Patients with diabetes produce less incretins

42 How do DPPIV inhibitors work? Dipeptidyl peptidase 4 (DPPIV) is an enzyme which metabolises incretins DPPIV inhibitors inhibit DPPIV and cause higher incretin levels This increases insulin secretion and lowers glucose levels Glucose dependant increase in incretin levels therefore no risk of hypoglycaemia (when used as a single agent or with Metformin)

43 Action of DPPIV inhibitors

44 DPPIV Inhibitors Modest effect on Hba1c approximately 0.5% reduction Agents within this drug class have similar efficacy No long term safety data Expensive Weight neutral No risk of hypoglycaemia (unless combined with agents that cause hypoglycaemia e.g. sulphonylurea)

45 Side effects of DPPIV Inhibitors Well tolerated Immune function – Small increased risk of nasopharyngitis, urinary tract infections and headache Slight increased risk of gastrointestinal side effects with sitagliptin Linagliptin rare reports of LFT abnormalities (monitor LFT 3/12) Reports of hypersensitivity reactions – Anaphylaxis, angioedema, Stephen Johnsons syndrome Pancreatitis case reports – Avoid using if history of pancreatitis or risk factors for pancreatitis (gallstones, severe hypertriglyceridaemia or alcoholism) – Consider pancreatitis if severe abdominal pain develops

46 Incretin Associated Pancreatitis Retrospective analysis – Incidence of acute pancreatitis Control group –Type 2 diabetics not on (DPPIV inhibitors or GLP1 agonists) –2.7 per thousand developed pancreatitis Type 2 diabetics taking DPPIV inhibitors or GLP1 agonists –4.1 per thousand developed pancreatitis

47 Incretin Associated Pancreatitis Type 2 diabetes increase the risk of pancreatitis two fold Acute pancreatitis increases the risk of pancreatic cancer ?Incretin associated pancreatitis increase the risk of pancreatic cancer Need large scale prospective randomised controlled trials to clarify these questions

48 PBS requirements for DPPIV inhibitors Linagliptin, Sitagliptin, Vildagliptin and Saxagliptin Streamlined authority Dual oral combination therapy with metformin or a sulfonylurea and Hba1c>7% Type 2 diabetes where a combination of metformin and a sulfonylurea is contraindicated or not tolerated and Hba1c>7%

49 PBS requirements for DPPIV inhibitors Private script if used as a single agent Private script if used as triple therapy with Metformin and Sulphonylurea Not to be used with insulin

50 Comparing DPPIV inhibitors Linagliptin (Trajenta) – Once daily, one dose 5mg – No dose adjustment required in renal impairment Saxagliptin (Onglyza) – Once daily – 2.5 mg and 5 mg – Cease if eGFR<60mls/min Sitagliptin (Januvia) – Twice daily – Dose adjust with renal impairment – Janumet (combination with Metformin) Vildagliptin (Galvus) – Once or twice daily – Cease if moderate renal impairment – Galvumet (combination with Metformin)

51 Sitagliptin (Januvia) dosing and renal impairment Creatinine clearance >/= 50 ml/min – 100mg once daily Creatinine clearance >/=30 and less than 50 ml/min – 50mg daily Creatinine clearance <30 ml/min – 25mg daily

52 Case History Cindy is 45 year old Type 2 diabetes for 4 years BMI 30 No complications Medications – Metformin XR 2 grams daily – Gliclazide MR 120 mg daily Hba1c 7.4 %

53 Management How would you treat this patient?

54 Management Discuss with patient Add Byetta (halve gliclazide dose) Or add once daily insulin (options Lantus/Novomix 30/Protaphane) The advantage of Byetta is possible weight loss compared with likely weight gain with insulin


56 How GLP1 Agonists work Bind to GLP1 receptor Glucose dependant increase insulin secretion in response to food Slows gastric emptying and suppresses appetite Suppresses inappropriately high glucagon levels Weight loss

57 Side Effects of GLP 1 Agonists Main side effects gastrointestinal – Nausea, vomiting and diarrhoea – Nausea usually wanes after a few weeks Weight loss 1.44 kg Hypoglycaemia only if combined with a sulphonylurea Case reports of pancreatitis ?causal – Avoid using if history of pancreatitis or risk factors for pancreatitis (gallstones, severe hypertriglyceridaemia or alcoholism) – Consider pancreatitis if severe abdominal pain develops

58 Side effects of GLP1 agonists Case reports of acute renal failure – Contraindicated if creatinine clearance <30mls/min – Monitor EUC if creatinine clearance mls/min Check one week after starting Byetta and one week after increasing the dose to 10mcg

59 PBS requirements for Byetta Streamlined authority Dual combination therapy with metformin or a sulfonylurea and Hba1c >7% “where a combination of metformin and a sulfonylurea is contraindicated or not tolerated” Triple combination therapy with metformin and a sulphonylurea and Hb1ac >7%

60 Starting Byetta Start with Byetta 5mcg BD s/c In combination with Metformin, a Sulphonylurea or both After 30 days the Byetta 5mcg pen will be finished start the Byetta 10mcg pen Reduce Sulphonylurea if concerned about hypoglycaemia

61 Starting Byetta Never use in Type 1 diabetics If already on insulin do not stop insulin and start Byetta Warn the patient about nausea, which usually settles down after the first few weeks If vomiting  seek medical advice (risk of acute renal failure)

62 Exenatide (Byetta) What to tell the patient Injections are twice daily within one hour of morning and evening meals Avoid extremes of temperature – Less than 25 degrees, pen being used doesn’t need to be in the fridge – “If you are comfortable so is the Byetta” – Keep unused pens in the fridge Needles are free from the NDSS Reduce meal size to reduce nausea

63 Diabetes Educators to assist with Byetta starts Byetta helpline: o The Canberra Hospital Byetta start group o Ph: o Fax: o Diabetes ACT (Holder) – Ph: o Community Centres (Gungahlin, Belconnen) o Private Diabetes Educator (Simon Scott-Findlay)

64 Liraglutide (Victoza) TGA approved not PBS listed Once daily injection (0.6mg. 1.2mg, 1.8mg) Weight loss 3kg May have larger decrease in Hba1c than Exenatide Side effects nausea, vomiting and diarrhoea (10-40%)

65 Liraglutide (Victoza) Minor hypoglycaemia Increased Medullary thyroid cancer in rats – Thought to be species specific Expression of GLP1 receptor in C-cells is low Humans have fewer C-cells than rats Contraindicated if creatinine clearance <30mls/min or hepatic impairment

66 Costs for Private Scripts Victoza $ $ (depending on the dose) for 2 pens Sitagliptin $90 for 28 tabs Byetta $175 per month

67 Case History Marcia is a 40 year old woman who presents with polyuria, polydipsia and fatigue No ketonuria Her father has Type 2 diabetes BMI 32 Random BSL 28 mmol/L, Hba1c 12% How would you treat this patient?

68 Treatment of a Newly Diagnosed Symptomatic Type 2 Diabetic Diet and exercise Start Byetta (in combination with two oral hypoglycaemic agents) or insulin (Novomix units twice daily) to give symptom relief, once glucose toxicity resolves may be able to change to dual oral agents Diabetic eye review – warn about blurred vision, don’t get glasses prescription changed for at least 6 weeks

69 Case History Greg is 33 years old Type 2 Diabetes diagnosed 6 months ago BMI 27 Current treatment – Diet, Exercise and Metformin 2 grams daily – Now Hba1c 7.1 % How would you treat this patient?

70 Treatment Add a DPPIV inhibitor or Byetta to achieve an Hba1c <6.5% Risk of hypoglycaemia with a sulphonylurea What would have been the best option if his Hba1c was 8%?

71 Case History Bobby is a 70 year old male Type 2 diabetes for 12 years Ischaemic heart disease (CABG) Ischaemic cardiomyopathy (NYHA IV) Peripheral vascular disease Chronic renal failure (eGFR 42 mls/min) Medications (only diabetes related medications are listed) – Metformin 3 grams daily – Amaryl (Glimepiride) 2mg daily Hba1c 6.3%

72 Management What is your Hba1c target? How does his renal impairment affect your management?

73 Management Hba1c target 7 - 8% – (long duration of diabetes, age, ischaemic heart disease/CCF) Metformin and renal failure – NICE (UK) guidelines – Stop Metformin if eGFR < 30 mls/min – Reduce dose if eGFR < 45 mls/min

74 Management Low dose Metformin 1 gram daily Stop sulphonylurea – Hba1c too low – Risk of hypoglycaemia Could add in Linagliptin if blood sugar levels too high on low dose Metformin

75 Case History Peter is a 45 year old Presents with diabetes for 6 months No family history of diabetes Current treatment Metformin BMI 20 Hba1c 9% How would you treat this patient?

76 Stop Metformin Start basal bolus insulin Lantus 10 units daily Novorapid 3 units tds Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA)

77 Diagnostic clues – Less than 50 years of age – BMI<25 – Personal or family history of autoimmune disease – No family history of Type 2 diabetes – Weight loss or ketones

78 Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA) Endocrinologist review Confirm the diagnosis – IA2 antibodies – GAD antibodies – C-peptide Treatment – Basal bolus insulin

79 Insulin Commencement

80 Duration of action of different insulins

81 Progressing insulin therapy if not meeting Hba1c targets Basal insulin – Lantus or protaphane or Novomix 30 once daily BD insulin (two prandial injections) – Novomix 30, Mixtard 30 – Lantus or protaphane plus Novorapid or Actrapid Basal bolus (three prandial injections) – Once daily Lantus or protaphane plus Novorapid or Actrapid three times per day with meals

82 Starting Basal Insulin in a Type 2 Diabetic Starting dose 10 units or 0.2 units per kg Check fasting BSL increase insulin every 3 days by 2-4 units until fasting BSL between 4-7mmol/L Hypoglycaemia reduce by 4 units or 10%

83 Starting Basal Insulin in a Type 2 diabetic Starting doses units/kg/day – If markedly hyperglycaemic units/kg/day Typical insulin doses (after titration) for type 2 diabetics are between units per day (0.5-1 unit/kg/day) Add nocte basal insulin to current oral hypoglycaemic therapy

84 Starting Basal Insulin in a Type 2 Diabetic Basal insulin options – Protaphane, Lantus, – Novomix 30 (a mixture of protaphane and Novorapid) taken with dinner The need for prandial insulin is more likely when the daily dose of basal insulin exceeds 0.5 units/kg/day, particularly if >1 unit/kg/day

85 How can you predict insulin requirements? Very high sugar readings initially likely to need higher doses of insulin due to glucose toxicity Insulin resistance is proportional to weight – Thin patients will need small doses of insulin – Obese patients will need higher doses – Older frail patients start low go slow

86 Reasons people refuse insulin Fear of needles – Show them the device – Show them a 4mm needle, explain it hurts less than finger pricking – Diabetes educator review – A “trial” of insulin – If phobia is severe  diabetes psychologist

87 Reasons People Refuse Insulin Feeling of failure – “I should have been able to manage this with diet and exercise alone” – Explain that diabetes is a progressive disorder and most diabetics will end up on insulin eventually Fear of weight gain – 2kg per year – Use insulin in combination with Metformin to try to limit insulin associated weight gain

88 Natural History of Type 2 Diabetes

89 Case History Alice is an 80 year old woman Type 2 diabetes – Severe COPD – No complications, – eGFR 60 mls/min Medications – Metformin 2 grams daily – Diamicron MR 120 mg daily Hba1c 10% BMI 19, weight 48 kgs How would you treat this patient?

90 Treatment of an Elderly Type 2 Diabetic Requiring Insulin Elderly, thin – Start basal insulin (Lantus, protaphane) or once daily Novomix 30 in addition to oral agents – 8 units per day – Start low go slow! Or Stop oral agents – Start Novomix 30 8 units with breakfast and dinner

91 Case History Bobby is a 55 year old Type 2 Diabetic Hba1c 8 %, weight 98kg, fasting BSL average10 mmol/L Medications – Lantus 30 units nocte – Metformin 2 grams daily – Diamicron MR 120 mg daily How would you treat this patient?

92 Management Increase Lantus dose by 4 units every 3 days until fasting blood sugar less than 7 mmol/L If next Hba1c not to target Stop Lantus and Diamicron and start Novomix units breakfast and 10 units dinner, continue Metformin

93 Summary Aim for aggressive glycaemic control early in the disease (avoiding hypoglycaemia) Less aggressive glycaemic control if elderly, hypoglycaemic unaware, end stage congestive cardiac failure or chronic renal failure

94 Summary Intensifying glycaemic control in Type 2 diabetics If BMI> 35 consider bariatric surgery If BMI less than 35 – Step 1: Monotherapy Metformin – Step 2: Dual Therapy Add in DPPIV inhibitor, Sulphonylurea or Byetta – Step 3: Triple therapy Consider Byetta with Metformin and Sulphonylurea – Step 4: Insulin Insulin – Basal insulin – BD insulin – Basal Bolus

95 The End

96 Sodium glucose cotransport 2 inhibitors SGLT2 sodium dependant glucose transporter Dapagliflozin blocks SGLT2 and prevents reabsorption of glucose Glucosuria  calorie loss in the urine  weight loss

97 Recent TGA listing Bydureon (once weekly exenatide) Company not selling this privately in Australia Byetta has been TGA approved in combination with Metformin and basal insulin

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