Intensifying glycaemic control in Type 2 diabetics
Dr Miriam BlackburnStaff Specialist
The Canberra Hospital
Outline Hba1c Targets Guidelines for intensifying glycaemic control Bariatric surgery Oral hypoglycaemic agents
– Side effects and PBS listing Starting Byetta Starting Insulin Summary
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
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
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
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
UKPDS Legacy effect12% reduction in any diabetes related endpoint for
patients who had intensive glycaemic control for the first five years
The Legacy EffectAre we meeting the Hba1c guidelines?
60% of Australian patients are not meeting Hba1c targets
Clinical inertia/patient compliance
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?
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 30 10 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
Guidelines for Intensifying Glycaemic Control
Treating a Newly Diagnosed Type 2 Diabetic
Intensifying Glycaemic Control for Type 2 Diabetics
The traditional wayStep 1 Diet and ExerciseStep 2 MetforminStep 3 Metformin plus a sulphonylureaStep 4 Metformin plus a sulphonylurea plus
a glitazoneStep 4 Insulin
Intensifying glycaemic control for Type 2 diabeticsA 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
Comparing sulphonylureas and DPPIV inhibitors and GLP1
agonists (Byetta)Sulphonylureas DPPIV inhibitors GLP1 agonists
Byetta
Cost Cheap Expensive Expensive
Risk of hypoglycaemia
Yes No No
Effect on weight Weight gain Weight neutral Weight loss
Long term safety data and evidence of reduction of microvascular complications
Yes No No
Expected Reduction in Hba1c
DPPIV inhibitors 0.5-0.8%Byetta 1%Metformin 1-2%Sulphonylurea 1-2%Insulin 1.5-3.5%
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
Case History
Weight 120kg, BMI 45Hba1c 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?
Management
Refer for bariatric surgery In the meantime, cease Byetta Continue Metformin and Diamicron and start
insulin Novomix 30 24 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
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
Gastric SleeveTubular stomach, has fewer ghrelin producing cells
Gastric BandPurely restrictive procedure
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)
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
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
Costs of Bariatric Surgery
If patient has private health insurance– $6000-$7000 out of pocket
If patient has no private health insurance– $19000-20000
Public funding coming soon…. – Limited number – Strict criteria for eligibility
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
Case History
Hba1c 8%Fasting sugar readings 5-6 mmol/LWeight 98 kg, BMI 33How would you treat this patient?
Management of a Type 2 Diabetic not meeting Hba1c targets on Basal
InsulinStop Diamicron
– Stop sulphonylureas when short acting insulin started
Continue Metformin– To assist with prevention of insulin associated
weight gainStart twice daily pre-mixed insulin
– Novomix 30 20 units morning and 10 units at night
MECHANISM OF ACTIONSIDE EFFECTSPBS CRITERIA
Antihyperglycaemic Agents
ThiazolidinedionesRosiglitazone (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
Acarbose (Glucobay)
Inhibit upper gastrointestinal enzymes(alphaglucosidases) and slow the absorption of carbohydrateSide effects
– 73% flatulence– Diarrhoea– Compliance maybe poor due to side effects
SITAGLIPTIN (JANUVIA)SAXAGLIPTIN (ONGLYZA)LINAGLIPTIN (TRAJENTA)VILDAGLIPTIN (GALVUS)
DPPIV inhibitors
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
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)
Action of DPPIV inhibitors
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)
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
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
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
PBS 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%
PBS requirements for DPPIV inhibitors
Private script if used as a single agentPrivate script if used as triple therapy with
Metformin and Sulphonylurea Not to be used with insulin
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)
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
Case History
Cindy is 45 year oldType 2 diabetes for 4 yearsBMI 30No complicationsMedications
– Metformin XR 2 grams daily– Gliclazide MR 120 mg daily
Hba1c 7.4 %
Management
How would you treat this patient?
Management
Discuss with patientAdd 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
EXENATIDE (BYETTA)LIRAGLUTIDE (VICTOZA)
GLP1 Agonists
How GLP1 Agonists work
Bind to GLP1 receptorGlucose dependant increase insulin
secretion in response to foodSlows gastric emptying and suppresses
appetiteSuppresses inappropriately high glucagon
levelsWeight loss
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
Side effects of GLP1 agonists Case reports of acute renal failure
– Contraindicated if creatinine clearance <30mls/min– Monitor EUC if creatinine clearance 30-50 mls/min
Check one week after starting Byetta and one week after increasing the dose to 10mcg
PBS 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%
Starting Byetta
Start with Byetta 5mcg BD s/cIn 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
Starting Byetta
Never use in Type 1 diabeticsIf already on insulin do not stop insulin and
start ByettaWarn the patient about nausea, which
usually settles down after the first few weeks
If vomiting seek medical advice (risk of acute renal failure)
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
Diabetes Educators to assist with Byetta starts
Byetta helpline: 1800 545 593o The Canberra Hospital Byetta start group
o Ph: 62444616o Fax: 62443794
o Diabetes ACT (Holder)– Ph: 62889830
o Community Centres (Gungahlin, Belconnen)o Private Diabetes Educator (Simon Scott-Findlay)
Liraglutide (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%)
Liraglutide (Victoza)
Minor hypoglycaemia Increased Medullary thyroid cancer in rats
– Thought to be species specificExpression of GLP1 receptor in C-cells is
lowHumans have fewer C-cells than rats
Contraindicated if creatinine clearance <30mls/min or hepatic impairment
Costs for Private Scripts
Victoza $170.85- $253.35 (depending on the dose) for 2 pens
Sitagliptin $90 for 28 tabsByetta $175 per month
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?
Treatment of a Newly Diagnosed Symptomatic Type 2 Diabetic
Diet and exercise Start Byetta (in combination with two oral
hypoglycaemic agents) or insulin (Novomix 30 10 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
Case History
Greg is 33 years old Type 2 Diabetes diagnosed 6 months agoBMI 27Current treatment
– Diet, Exercise and Metformin 2 grams daily– Now Hba1c 7.1 %
How would you treat this patient?
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%?
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%
Management
What is your Hba1c target?How does his renal impairment affect your
management?
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
Management
Low dose Metformin 1 gram dailyStop sulphonylurea
– Hba1c too low– Risk of hypoglycaemia
Could add in Linagliptin if blood sugar levels too high on low dose Metformin
Case History
Peter is a 45 year oldPresents with diabetes for 6 monthsNo family history of diabetesCurrent treatment MetforminBMI 20Hba1c 9%How would you treat this patient?
Stop MetforminStart basal bolus insulinLantus 10 units dailyNovorapid 3 units tds
Type 1.5 DiabetesLatent Autoimmune Diabetes in
Adults (LADA)
Type 1.5 DiabetesLatent 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
Type 1.5 DiabetesLatent Autoimmune Diabetes in
Adults (LADA)Endocrinologist reviewConfirm the diagnosis
– IA2 antibodies– GAD antibodies– C-peptide
Treatment– Basal bolus insulin
Insulin Commencement
Duration of action of different insulins
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
Starting 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/L
Hypoglycaemia reduce by 4 units or 10%
Starting Basal Insulin in a Type 2 diabetic
Starting doses 0.1-0.2 units/kg/day– If markedly hyperglycaemic 0.3-0.4
units/kg/day Typical insulin doses (after titration) for type 2
diabetics are between 60-100 units per day (0.5-1 unit/kg/day)
Add nocte basal insulin to current oral hypoglycaemic therapy
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
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
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
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
Natural History of Type 2 Diabetes
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?
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
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?
Management
Increase Lantus dose by 4 units every 3 days until fasting blood sugar less than 7 mmol/L
If next Hba1c not to targetStop Lantus and Diamicron and start
Novomix 30 20 units breakfast and 10 units dinner, continue Metformin
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
SummaryIntensifying 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
The End
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
Recent TGA listing
Bydureon (once weekly exenatide)Company not selling this privately in
AustraliaByetta has been TGA approved in
combination with Metformin and basal insulin