5Australian Diabetes Association Guidelines Hba1c target summary Hba1c goal for most diabetics <7%More intensive targetsWomen planning pregnancy <6%Requiring lifestyle modification ±metforminHba1c ≤ 6.0 %Requiring any oral antidiabetic agents other than metformin or insulinHba1c ≤ 6.5 %? Risk of hypoglycaemia with sulphonylureas
6Australian Diabetes Association guidelines for Hba1c targets Hba1c target of <8%Elderly life expectancy, less than 10 yearsAdvanced cardiac or renal failureCKD stage 4 or 5NYHA cardiac failure stage 3 or 4 (GFR<30 mls/min)Incurable malignancyModerate DementiaHypoglycaemic unaware
7UKPDS3867 patients with a new diagnosis (treatment naive) of Type 2 diabetesRandomised to intensive therapy (either metformin, sulphonylurea or insulin) or conventional treatment with dietMean Hba1c of less than 7% in the first five years of the trial for the intensive groupTight glycaemic control was later lost
8UKPDSPatients in the intensive treatment group for the first five yearsSignificant reductions in microvascular complications, myocardial infarction and death from any causeDespite loss of the tight control the benefit endured for the next ten years
9UKPDS Legacy effect 12% reduction in any diabetes related endpoint for patients who had intensive glycaemic control for the first five years
10The Legacy Effect Are we meeting the Hba1c guidelines? 60% of Australian patients are not meeting Hba1c targetsClinical inertia/patient compliance
11Case History Mike, a 65 year old Type 2 diabetic Complicated by mild diabetic retinopathy, no other comorbiditiesMedicationsMetformin 2 grams dailyDiamicron MR 120 g dailyTried Byetta (unable to tolerate due to nausea)Declining bariatric surgeryHba1c 7.8%, weight 100kgHow would you manage this patient?
12Starting Basal Insulin in a Type 2 Diabetic Add basal insulin 10 units daily of Protaphane or LantusOr Add once daily premixed insulinNovomix units with dinnerIncrease dose by 2-4 units until fasting BSL 4-7 mmol/L0.2 units per kg/day is a reasonable starting dose for add on basal insulin
18Intensifying Glycaemic Control for Type 2 Diabetics The traditional way Step 1 Diet and ExerciseStep 2 MetforminStep 3 Metformin plus a sulphonylureaStep 4 Metformin plus a sulphonylurea plus a glitazoneStep 4 Insulin
19Intensifying glycaemic control for Type 2 diabetics A new approach Step 1Diet and Exercise plus MetforminStep 2Dual therapyMetformin plus a SulphonylureaDPPIV inhibitor plus either a Sulphonylurea or MetforminByetta and Metformin or a SulphonylureaStep 3Triple therapyConsider Byetta plus Metformin and a sulphonylureaStep 4Insulin +/- oral hypoglycaemic agents
20Comparing sulphonylureas and DPPIV inhibitors and GLP1 agonists (Byetta) CostCheapExpensiveRisk of hypoglycaemiaYesNoEffect on weightWeight gainWeight neutralWeight lossLong term safety data and evidence of reduction of microvascular complicationsGLP1 agonist (Byetta)CheapExpensiveLong term safety dataNo long term safety data
23Case History Carol, 45 year old Type 2 diabetic Comorbidities no complicationsComorbiditiesOSA, GORD, OA (waiting TKR)MedicationsMetformin 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
24Case 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 6/12What is the next step?
25Management Refer for bariatric surgery In the meantime, cease Byetta Continue Metformin and Diamicron and start insulinNovomix 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
27Indications for bariatric surgery Failed weight loss by lifestyle changeAt least one year of determined effortBMI>40BMI>35 and severe comorbiditiesDiabetes, severe osteoarthritis, obstructive sleep apnoea, obesity related cardiomyopathyMotivated and informedCanberra Bariatric holds patient information sessions
28Gastric Sleeve Tubular stomach, has fewer ghrelin producing cells
30Effects of Bariatric Surgery Mean weight loss 61%Diabetes resolved 77%Hyperlipidaemia improved 70%Hypertension resolved 62%Obstructive sleep apnoea resolved 86%Gastroesophageal reflux symptoms improvedMortality 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)
31Complications of Gastric Banding Restrictive procedureEasily reversibleLowest mortality rate of all bariatric procedures (0.05%)High rate of revision surgery required (40-50%)ComplicationsAcute stomal infection, band infection, haemorrhage, pulmonary emboli, band erosion, band slippage, prolapse or tubing malfunction
32Complications of Sleeve Gastrectomy Lower rate of complications than gastric bypassMortality 0.39%Common complications (3-24%)BleedingNarrowing or stenosis of gastric stomaGastric leaksReflux
33Costs of Bariatric Surgery If patient has private health insurance$6000-$7000 out of pocketIf patient has no private health insurance$Public funding coming soon….Limited numberStrict criteria for eligibility
34Case History Jan, 45 year old Type 2 diabetes Diabetes for 10 years Insulin for 4 yearsNo complicationsMedicationsMetformin 2 grams dailyDiamicron MR 120 mg dailyLantus 30 units nocte
35Case History Hba1c 8% Fasting sugar readings 5-6 mmol/L Weight 98 kg, BMI 33How would you treat this patient?
36Management of a Type 2 Diabetic not meeting Hba1c targets on Basal Insulin Stop DiamicronStop sulphonylureas when short acting insulin startedContinue MetforminTo assist with prevention of insulin associated weight gainStart twice daily pre-mixed insulinNovomix units morning and 10 units at night
37Mechanism of action Side effects PBS criteria Antihyperglycaemic AgentsMechanism of action Side effects PBS criteria
38Thiazolidinediones Rosiglitazone (Avandia) and Pioglitazone (Actos) Side effectsWeight gainCongestive cardiac failureOsteoporosis and fracturesRosiglitazone (Avandia)Boxed warningIncreased risk myocardial infarction and congestive cardiac failureAdverse effect on lipidsPioglitazone (Actos)Increased risk of bladder cancer
39Acarbose (Glucobay) Inhibit upper gastrointestinal enzymes (alphaglucosidases) and slow the absorption of carbohydrateSide effects73% flatulenceDiarrhoeaCompliance maybe poor due to side effects
41How do DPPIV Inhibitors Work? The Incretin Effect An oral dose of glucose causes more insulin secretion than the same dose given intravenouslyGlucose in the gut stimulates release of incretins (Glucagon like peptide 1, GLP1 and gastric inhibitory polypeptide, GIP) which increase insulin secretionPatients with diabetes produce less incretins
42How do DPPIV inhibitors work? Dipeptidyl peptidase 4 (DPPIV) is an enzyme which metabolises incretinsDPPIV inhibitors inhibit DPPIV and cause higher incretin levelsThis increases insulin secretion and lowers glucose levelsGlucose dependant increase in incretin levels therefore no risk of hypoglycaemia (when used as a single agent or with Metformin)
44DPPIV Inhibitors Modest effect on Hba1c approximately 0.5% reduction Agents within this drug class have similar efficacyNo long term safety dataExpensiveWeight neutralNo risk of hypoglycaemia (unless combined with agents that cause hypoglycaemia e.g. sulphonylurea)
45Side effects of DPPIV Inhibitors Well toleratedImmune functionSmall increased risk of nasopharyngitis, urinary tract infections and headacheSlight increased risk of gastrointestinal side effects with sitagliptinLinagliptin rare reports of LFT abnormalities (monitor LFT 3/12)Reports of hypersensitivity reactionsAnaphylaxis, angioedema, Stephen Johnsons syndromePancreatitis case reportsAvoid using if history of pancreatitis or risk factors for pancreatitis (gallstones, severe hypertriglyceridaemia or alcoholism)Consider pancreatitis if severe abdominal pain develops
46Incretin Associated Pancreatitis Retrospective analysisIncidence of acute pancreatitisControl groupType 2 diabetics not on (DPPIV inhibitors or GLP1 agonists)2.7 per thousand developed pancreatitisType 2 diabetics taking DPPIV inhibitors or GLP1 agonists4.1 per thousand developed pancreatitis
47Incretin Associated Pancreatitis Type 2 diabetes increase the risk of pancreatitis two foldAcute pancreatitis increases the risk of pancreatic cancer?Incretin associated pancreatitis increase the risk of pancreatic cancerNeed large scale prospective randomised controlled trials to clarify these questions
48PBS requirements for DPPIV inhibitors Linagliptin, Sitagliptin, Vildagliptin and Saxagliptin Streamlined authorityDual 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%
49PBS requirements for DPPIV inhibitors Private script if used as a single agentPrivate script if used as triple therapy with Metformin and SulphonylureaNot to be used with insulin
50Comparing DPPIV inhibitors Linagliptin (Trajenta)Once daily, one dose 5mgNo dose adjustment required in renal impairmentSaxagliptin (Onglyza)Once daily2.5 mg and 5 mgCease if eGFR<60mls/minSitagliptin (Januvia)Twice dailyDose adjust with renal impairmentJanumet (combination with Metformin)Vildagliptin (Galvus)Once or twice dailyCease if moderate renal impairmentGalvumet (combination with Metformin)
51Sitagliptin (Januvia) dosing and renal impairment Creatinine clearance >/= 50 ml/min100mg once dailyCreatinine clearance >/=30 and less than 50 ml/min50mg dailyCreatinine clearance <30 ml/min25mg daily
52Case History Cindy is 45 year old Type 2 diabetes for 4 years BMI 30 No complicationsMedicationsMetformin XR 2 grams dailyGliclazide MR 120 mg dailyHba1c 7.4 %
54Management 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
56How GLP1 Agonists work Bind to GLP1 receptor Glucose dependant increase insulin secretion in response to foodSlows gastric emptying and suppresses appetiteSuppresses inappropriately high glucagon levelsWeight loss
57Side Effects of GLP 1 Agonists Main side effects gastrointestinalNausea, vomiting and diarrhoeaNausea usually wanes after a few weeksWeight loss 1.44 kgHypoglycaemia only if combined with a sulphonylureaCase reports of pancreatitis ?causalAvoid using if history of pancreatitis or risk factors for pancreatitis (gallstones, severe hypertriglyceridaemia or alcoholism)Consider pancreatitis if severe abdominal pain develops
58Side effects of GLP1 agonists Case reports of acute renal failureContraindicated if creatinine clearance <30mls/minMonitor EUC if creatinine clearance mls/minCheck one week after starting Byetta and one week after increasing the dose to 10mcg
59PBS requirements for Byetta Streamlined authorityDual 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%
60Starting Byetta Start with Byetta 5mcg BD s/c In combination with Metformin, a Sulphonylurea or bothAfter 30 days the Byetta 5mcg pen will be finished start the Byetta 10mcg penReduce Sulphonylurea if concerned about hypoglycaemia
61Starting Byetta Never use in Type 1 diabetics If already on insulin do not stop insulin and start ByettaWarn the patient about nausea, which usually settles down after the first few weeksIf vomiting seek medical advice (risk of acute renal failure)
62Exenatide (Byetta) What to tell the patient Injections are twice daily within one hour of morning and evening mealsAvoid extremes of temperatureLess 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 fridgeNeedles are free from the NDSSReduce meal size to reduce nausea
64Liraglutide (Victoza) TGA approved not PBS listedOnce daily injection (0.6mg. 1.2mg, 1.8mg)Weight loss 3kgMay have larger decrease in Hba1c than ExenatideSide effects nausea, vomiting and diarrhoea (10-40%)
65Liraglutide (Victoza) Minor hypoglycaemiaIncreased Medullary thyroid cancer in ratsThought to be species specificExpression of GLP1 receptor in C-cells is lowHumans have fewer C-cells than ratsContraindicated if creatinine clearance <30mls/min or hepatic impairment
66Costs for Private Scripts Victoza $ $ (depending on the dose) for 2 pensSitagliptin $90 for 28 tabsByetta $175 per month
67Case HistoryMarcia is a 40 year old woman who presents with polyuria, polydipsia and fatigueNo ketonuriaHer father has Type 2 diabetesBMI 32Random BSL 28 mmol/L, Hba1c 12%How would you treat this patient?
68Treatment of a Newly Diagnosed Symptomatic Type 2 Diabetic Diet and exerciseStart 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 agentsDiabetic eye review – warn about blurred vision, don’t get glasses prescription changed for at least 6 weeks
69Case History Greg is 33 years old Type 2 Diabetes diagnosed 6 months agoBMI 27Current treatmentDiet, Exercise and Metformin 2 grams dailyNow Hba1c 7.1 %How would you treat this patient?
70Treatment Add a DPPIV inhibitor or Byetta to achieve an Hba1c <6.5% Risk of hypoglycaemia with a sulphonylureaWhat would have been the best option if his Hba1c was 8%?
71Case History Hba1c 6.3% Bobby is a 70 year old male Type 2 diabetes for 12 yearsIschaemic heart disease (CABG)Ischaemic cardiomyopathy (NYHA IV)Peripheral vascular diseaseChronic renal failure (eGFR 42 mls/min)Medications (only diabetes related medications are listed)Metformin 3 grams dailyAmaryl (Glimepiride) 2mg dailyHba1c 6.3%
72Management What is your Hba1c target? How does his renal impairment affect your management?
73Management Hba1c target 7 - 8% Metformin and renal failure (long duration of diabetes, age, ischaemic heart disease/CCF)Metformin and renal failureNICE (UK) guidelinesStop Metformin if eGFR < 30 mls/minReduce dose if eGFR < 45 mls/min
74Management Low dose Metformin 1 gram daily Stop sulphonylurea Hba1c too lowRisk of hypoglycaemiaCould add in Linagliptin if blood sugar levels too high on low dose Metformin
75Case History Peter is a 45 year old Presents with diabetes for 6 monthsNo family history of diabetesCurrent treatment MetforminBMI 20Hba1c 9%How would you treat this patient?
76Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA) Stop MetforminStart basal bolus insulinLantus 10 units dailyNovorapid 3 units tds
77Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA) Diagnostic cluesLess than 50 years of ageBMI<25Personal or family history of autoimmune diseaseNo family history of Type 2 diabetesWeight loss or ketones
78Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA) Endocrinologist reviewConfirm the diagnosisIA2 antibodiesGAD antibodiesC-peptideTreatmentBasal bolus insulin
81Progressing insulin therapy if not meeting Hba1c targets Basal insulinLantus or protaphane or Novomix 30 once dailyBD insulin (two prandial injections)Novomix 30, Mixtard 30Lantus or protaphane plus Novorapid or ActrapidBasal bolus (three prandial injections)Once daily Lantus or protaphane plus Novorapid or Actrapid three times per day with meals
82Starting Basal Insulin in a Type 2 Diabetic Starting dose 10 units or 0.2 units per kgCheck fasting BSL increase insulin every 3 days by 2-4 units until fasting BSL between 4-7mmol/LHypoglycaemia reduce by 4 units or 10%
83Starting Basal Insulin in a Type 2 diabetic Starting doses units/kg/dayIf markedly hyperglycaemic units/kg/dayTypical 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
84Starting Basal Insulin in a Type 2 Diabetic Basal insulin optionsProtaphane, Lantus,Novomix 30 (a mixture of protaphane and Novorapid) taken with dinnerThe 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
85How can you predict insulin requirements? Very high sugar readings initially likely to need higher doses of insulin due to glucose toxicityInsulin resistance is proportional to weightThin patients will need small doses of insulinObese patients will need higher dosesOlder frail patients start low go slow
86Reasons people refuse insulin Fear of needlesShow them the deviceShow them a 4mm needle, explain it hurts less than finger prickingDiabetes educator reviewA “trial” of insulinIf phobia is severe diabetes psychologist
87Reasons 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 eventuallyFear of weight gain2kg per yearUse insulin in combination with Metformin to try to limit insulin associated weight gain
89Case History Alice is an 80 year old woman Type 2 diabetes Severe COPD No complications,eGFR 60 mls/minMedicationsMetformin 2 grams dailyDiamicron MR 120 mg dailyHba1c 10%BMI 19, weight 48 kgsHow would you treat this patient?
90Treatment of an Elderly Type 2 Diabetic Requiring Insulin Elderly, thinStart basal insulin (Lantus, protaphane) or once daily Novomix 30 in addition to oral agents8 units per dayStart low go slow!OrStop oral agentsStart Novomix 30 8 units with breakfast and dinner
91Case History Bobby is a 55 year old Type 2 Diabetic Hba1c 8 %, weight 98kg, fasting BSL average10 mmol/LMedicationsLantus 30 units nocteMetformin 2 grams dailyDiamicron MR 120 mg dailyHow would you treat this patient?
92ManagementIncrease Lantus dose by 4 units every 3 days until fasting blood sugar less than 7 mmol/LIf next Hba1c not to targetStop Lantus and Diamicron and start Novomix units breakfast and 10 units dinner, continue Metformin
93SummaryAim 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
94Summary Intensifying glycaemic control in Type 2 diabetics If BMI> 35 consider bariatric surgeryIf BMI less than 35Step 1: MonotherapyMetforminStep 2: Dual TherapyAdd in DPPIV inhibitor, Sulphonylurea or ByettaStep 3: Triple therapyConsider Byetta with Metformin and SulphonylureaStep 4: InsulinInsulinBasal insulinBD insulinBasal Bolus