Intensifying glycaemic control
in Type 2 diabetics
Dr Miriam Blackburn
Staff Specialist
The Canberra Hospital
Outline

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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 effect
12% reduction in any diabetes related endpoint for
patients who had intensive glycaemic control for the first
five years
The Legacy Effect
Are 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 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
Intensifying glycaemic control for
Type 2 diabetics
A new approach


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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 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?
Management


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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
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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 Sleeve
Tubular stomach, has fewer ghrelin producing cells
Gastric Band
Purely restrictive procedure
Effects of Bariatric Surgery
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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
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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
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

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/L
 Weight 98 kg, BMI 33
 How would you treat this patient?
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 30 20 units morning and 10 units at
night
Antihyperglycaemic Agents
MECHANISM OF ACTION
SIDE EFFECTS
PBS CRITERIA
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
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
DPPIV inhibitors
SITAGLIPTIN (JANUVIA)
SAXAGLIPTIN (ONGLYZA)
LINAGLIPTIN (TRAJENTA)
VILDAGLIPTIN (GALVUS)
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
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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
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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 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%
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
Comparing DPPIV inhibitors
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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 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 %
Management

How would you treat this patient?
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
GLP1 Agonists
EXENATIDE (BYETTA)
LIRAGLUTIDE (VICTOZA)
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
Side Effects of GLP 1
Agonists
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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 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%
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
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)
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 545 593
o The Canberra Hospital Byetta start group
o Ph: 62444616
o Fax: 62443794
o Diabetes ACT (Holder)
– Ph: 62889830
Community Centres (Gungahlin, Belconnen)
o Private Diabetes Educator (Simon Scott-Findlay)
o
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%)
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
Costs for Private Scripts

Victoza $170.85- $253.35 (depending on
the dose) for 2 pens
 Sitagliptin $90 for 28 tabs
 Byetta $175 per month
Case History
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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 ago
 BMI 27
 Current 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
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
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 daily
 Stop 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 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?
Type 1.5 Diabetes
Latent Autoimmune Diabetes in
Adults (LADA)

Stop Metformin
 Start basal bolus insulin
 Lantus 10 units daily
 Novorapid 3 units tds
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
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
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 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%
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 target
 Stop 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
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
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
Australia
 Byetta has been TGA approved in
combination with Metformin and basal
insulin