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