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)
Cost
Cheap
Expensive
Risk of hypoglycaemia
Yes No
Effect on weight
Weight gain
Weight neutral
Weight loss
Long term safety data and evidence of reduction of microvascular complications
GLP1 agonist (Byetta)
Cheap
Expensive
Long term safety data
No long term safety data

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 Comorbidities
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

37. Mechanism of action Side effects PBS criteria
Antihyperglycaemic Agents
Mechanism of action Side effects PBS criteria

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

40. DPPIV inhibitors
SITAGLIPTIN (Januvia) Saxagliptin (Onglyza) Linagliptin (Trajenta) Vildagliptin (GALVUS)

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

55. Exenatide (byetta) LiRagluTIDe (VICTOZA)
GLP1 Agonists
Exenatide (byetta) LiRagluTIDe (VICTOZA)

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:
The Canberra Hospital Byetta start group
Ph:
Fax:
Diabetes ACT (Holder)
Ph:
Community Centres (Gungahlin, Belconnen)
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 Hba1c 6.3% 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% Metformin and renal failure
(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. Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA)
Stop Metformin
Start basal bolus insulin
Lantus 10 units daily
Novorapid 3 units tds

77. Type 1.5 Diabetes Latent Autoimmune Diabetes in Adults (LADA)
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