Oral Treatments

for Type 2 Diabetes

Prescribing Support Pharmacist

Learning Outcomes

• Familiar with classes of oral hypoglycaemic agents

(OHAs) used in controlling blood glucose levels

– When to use each class

– Advice for patients

– Monitor for side effects

• Brief overview of mechanism of action and

evidence base of OHAs

• Clinical Guidelines

A brief history of diabetes medication...

CrossCross--sectional median valuessectional median values

��Time From Randomisation (years)Time From Randomisation (years)

��Conventional Treatment (n=1138)Conventional Treatment (n=1138)

��Intensive Treatment (n=2729)Intensive Treatment (n=2729)

��99

��88

��77

��66

��ADA targetADA target

��ADA actionADA action��suggestedsuggested

��00��00 ��33 ��66 ��99 ��1212 ��1515

��M

ed

ian A

1C

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ian A

1C

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Type 2 Diabetes is a Progressive

Disease: UKPDS1

� 2 Control BP

� 5 consider

tight glucose

control

� 4 Add metformin

� 3 Add statin

� 1 Lifestyle

(exercise, diet,

stop smoking)

�Let’s give our diabetic patients a

hand!

��DonDon’’t turn the t turn the

hand aroundhand around

Why is good glycaemic control

important?

Where does controlling Blood Glucose fit

into the picture?

• No arguments in favour of poor BG control

• Importantly data from RCTs, found no benefit and possible harm from tight BG control -target< 6.5mmol/l

• Achieving good BG control, while addressing lifestyle, BP, and lipids will prevent more complications, than a narrower approach focused on intensive BG control

• Individualise treatment

• Agree targets with patient

NICE • Hba1c rises to > 48mmol/mol on lifestyle start tx

• Target 48mmol/mol (6.5%)- on diet plus one drug

not associated with hypoglycaemia

– If drug associated with hypos target 53mmol/mol

• 1st intensification: HBA1C > 58mmol/mol (7.5%)

• Target 53mmol/mol (7%)

• 2nd intensification: HBA1C > 58mmol/mol ,

• target 53mmol/mol

Legacy EffectHolman RR et al. 10 year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med

2008: Oct 9; 359: 1577

• In type 2 diabetes, early intervention with intensive glucose control has long-lasting effects still evident at 10 years

• UKPDS Study - 5000 randomly assigned to

• conventional tx or tight control (median HBA1C 7 ) (Metformin if overweight, su or insulin )

• Differences in HBA1C disappeared 1yr after the trial. Benefits remain 10 years later

�After median 8.5 years post-trial follow-up

�Aggregate Endpoint 1997 2007

�Any diabetes related endpoint RRR: 12% 9%

� P: 0.029 0.040

�Microvascular disease RRR: 25% 24%

� P: 0.0099 0.001

�Myocardial infarction RRR: 16% 15%

� P: 0.052 0.014

�All-cause mortality RRR: 6% 13%

� P: 0.44 0.007�RRR = Relative Risk Reduction, P = Log Rank

UKPDS- Legacy Effect of Earlier Glucose Control

UKPDS: A 1% decrease in HbA1c is associated

with a reduction in complications

�Stratton IM, et al. BMJ 2000; 321: 405–412.

�43

%

�37%

�21%

�14%

�12%

�HbA1

C

�1%

�* p<0.0001

�** p=0.035 �Stroke**

�Microvascular complications e.g.

kidney disease and blindness *

�Amputation or

fatal peripheral blood vessel

disease*

�Deaths related

to diabetes*

�Heart attack*

Individualise targets

• 45yr old male, young family, works, T2D 1 yr, takes

metformin HBA1C 62mmol/mol

• Any comments on HBA1C and target?

• 80 year old male, T2D 10yr, takes metformin and

gliclazide, HBA1C 48mmol/mol,

• any comments on HBA1C and target?

Metformin –

• First line in combination with lifestyle

• Meformin mechanism of action:

– It helps to stop the liver producing new

glucose

– It helps to overcome insulin resistance by

making insulin carry glucose into muscle

cells more effectively.

Benefits of Metformin

• Cardiovascular benefits • UK Prospective Diabetes Study: http://www.dtu.ox.ac.uk/ukpds/)

• Can cause weight loss

• Does not cause hypos

• Reduces total cholesterol, LDL chol and trigs

• Use in combination with any OHA

• On the market a long time

• inexpensive

Contra-indications and cautions

• Avoid if Egfr < 30mls/min - Risk lactic acidosis (rare)

– Other conditions that increase risk of lactic acidosis

– Dehydration – diarrhoea,

– NSAIDs, ACE, diuretics – can all affect renal fn

– Iodinated contrast media – can cause acute renal

impairment, stop metformin for 48hours, renal fn

checked ......

• Avoid in severe liver disease

https://www.medicines.org.uk/emc/medicine/26762

Advice for patients

• Gastro-intestinal problems are common.

• Occur more than 1 in 10 people

• Let us know. We can try and help!

• Minimise - start on a low dose and increase slowly

take with food or after food,

– spread the dose – take twice daily

– usually go away after a few days

– reducing the dose

• Other side effects -taste disturbance, low Vit B 12

When to intensify treatment?

• If HbA1c is still <53mmol/mol or if

individualised target is not met

• The addition of a second oral agent is likely to

improve HbA1c by no more than 9.0 – 16mmol/mol

• Withdraw treatment after 6 months if HbA1c has

decreased by less than 6mmol/mol

Case 1

Mr Smith is a 52 year old teacher. Mr Smith was diagnosed with Type 2

diabetes 2 years ago. He is a car driver.

HbA1c last week was 70mmol/mol

Weight is 80kg, height 5’ 8”, BMI 31.8

Current medication:

� Metformin 500mg at a dose of 1g twice daily.

�What second line OHA would you choose?

Options --

• A – Add a sulphonylurea?

• B - Add pioglitazone?

• C – Add Gliptin?

• D – SGLT2?

• A – Reinforce Lifestyle advice

• B - Add a statin

Sulphonylurea eg Gliclazide

• Can use 1st line if intolerant to metformin

• Can use in combination with all other OHAs

• CI- severe renal /liver impairment, breast feeding

• Mechanism of action

– Stimulate pancreatic cells to make insulin.

• Reduction in hepatic glucose production

• Improvement in clearance of glucose.

Sulphonylureas

• Pros

– Confidence and experience in using

– Cheap (generic: £6 per month)

– Effective (mean 11mmol/mol reduction HbA1c)

– Minimal responder variability

• Cons

– Significant hypoglycaemia risk – BGM may be appropriate for 1st three months

– Weight gain

– Poor durability

What to advise the patient

• Take with meals - Regular meals are important

• Alcohol – increased risk prolonged hypo

• Weight gain – average 1 – 2 kg

• Hypo – recognise, how to treat

• Blood Glucose Meter – when to monitor?

• Driving

• Groups at increased risk of hypo – elderly, mild

renal or liver impairment

Timeline of Gliclazide

• Onset 1-2 hours

• Peak 4-6 hours

• Half-life 8-12 hours

Pioglitazone – Thiazolidinediones

• Second line therapy – add to metformin

• Triple therapy - combination with other OHA

• Contra-indicated

– Heart failure

– Hepatic impairment

– History bladder cancer, uninvestigated haematurea

• Mechanism of action - Reduces insulin resistance

Pioglitazone - benefits

• Reduce insulin resistance – unique mechanism

of action and durable effect

• Proactive study - all cause mortality lower in

Piogliazone group group (26.8% v 34.3%)

• Iris study -Pioglitazone may reduce CV events

after a CVA

Pioglitazone – adverse effects

• Fluid retention – can precipitate heart failure

– Avoid in patients with a MI, angina,? Elderly

• Bone fractures–increase in men and women > 50yrs

• Macular oedema – report blurred vision

• Bladder cancer – risk low however risk increased

with length of treatment and higher dose

• Liver – reports hepatic failure – test lfts periodically

Advice for Patient

• Once daily, can take at any time of day

• Report any fluid retention, blurred vision

• Increased risk weight gain and fractures

• Bladder cancer – risk increased with duration

and larger dose

Follow up?

• Check HBA1C - has there been a 6mmol/mol

reduction?

• If not stop pioglitazone

• consider alternative strategies

DPP4 Inhibitors - Mechanism

• Incretins are a group of hormones produced by the

gut particularly when we eat –

• Incretins stimulate a decrease in blood glucose by

• causing an increase in insulin released from

pancreas after eating

• DPP-4 is an enzyme which destroys the hormone

incretin.

• DPP-4 inhibitors block the action of DPP-4,

DPP-4 Inhibitors (Gliptins)

• Sitagliptin (Januvia®)

• Linagliptin (Trajenta®)

• Saxagliptin (Onglyza®)

• Vildagliptin (Galvus®)

• Alogliptin (Vipidia®)

• Second line therapy – in combination with metformin

• Triple therapy in combination with other OHA

DPP-4 inhibitors - pros

– Very low hypo risk – hypo possible if with SU or insulin

– Weight neutral

– Low side-effect profile

– No major adverse cardiovascular outcomes / heart

failure (apart from saxagliptin – increased risk

hospitalisation for heart failure esp if renal impairment)

DPP4 inhibitors – Cons– Expensive (around £30 per month)

– Less effective (mean 5mmol/mol reduction HbA1c)

– Responder variability

– No long term safety information

– Risk Pancreatitis – small

– Adjust dose in renal impairment

– Serious hypersensitivity reaction – within first 3

months

Advice for Patient

• Take at any time of the day

• Risk of hypo if on gliclazide or insulin

• Pancreatitis – inform patients about the

symptoms of pancreatitis (ie, severe,

persistent abdominal pain sometimes

radiating to the back)

• seek medical advice if this is suspected.

SGLT2• Dual therapy with metformin

• Triple therapy

• Mechanism of action –

– inhibit SGLT2 protein – sodium-glucose transport

protein helps reabsorb glucose into blood in kidney.

•

– By blocking these proteins, less glucose reabsorbed

excess glucose is passed out in the urine

SGLT-2 Inhibitors

All on NHSGGC total formulary -

• Canagliflozin (Ivokana ®) ▲

• Dapagliflozin (Forxiga ®) ▲

• Empagliflozin (Jardiance®) ▲

Benefits SGLTS

• Can help with weight loss

• Can be used at all stages of Type 2 Diabetes

• Low hypo incidence (risk if on SU or insulin)

• EMPA-REG OUTCOME

– Cardiovascular benefits –

– Diabetic kidney disease – reduced risk – EMPA-REG

OUTCOME the placebo group.

CV benefits – EMPA-REG• Patients studied - T2DM pts high CVD risk

• Empagliflozin ↓ 1y end point (CV death, nonfatal

MI and stroke) by 14%

– driven by a 38% ↓ in CV mortality

– 35% ↓ in hospitalization for heart failure

• SGLT2 inhibitors - many metabolic benefits

– (↓ HbA1c, body weight, BP and an↑ HDL chol)

• CB benefits due to hemodynamic effects, - ↓ BP

and ↓ in extracellular volume.

SGLT2 – renal benefits

• EMPA-REG – T2D at high risk for CVE,

• Empagliflozin group had a significantly lower

risk of microvascular outcome events

– driven by a lower risk of progression of kidney

disease.

• Empagliflozin group had a significantly lower

risk of progression to macroalbuminuria

• More work needs to be done

SGLT2s - cons• Increase frequency – one extra voiding per day

• Increased risk infections – eg thrush, utis

• Renal impairment – don’t start if Egfr < 60

• Less effective in impaired renal fn

• Can cause acute renal failure - monitor

• DKA – at near normal blood glucose levels

• New drug -

• Stop before surgery, sick day rules

• Caution elderly – risk of volume depletion

– More adverse effects >75yrs

SGLT-2 inhibitors

Hepatic and Renal Function

Cardiovascular Outcome Trials

• Empa-reg trial - published 2016

– Evidence of improved CV outcomes with this drug,

significantly lower rate of mortality

– Trial in patients with exisiting cardiovascular co-

morbidities

• CANVAS trial – expected 2018

• DECLARE trial – expected 2019

MHRA advice on SGLT-2 inhibitors

and Ketoacidosis

• Serious, life-threatening, fatal cases of DKA

reported

• Test ketones if signs DKA regardless of Glucose conc

• Risk factors identified include

– a low beta cell function reserve, off label use T1D

– Restricted food intake or severe dehydration

– Change in insulin requirements

– surgery

– alcohol abuse

MHRA advice on SGLT-2 inhibitors

and Ketoacidosis

• Advice for HCPs

– Educate patients on symptoms of DKA and what

to do if experiencing symptoms.

– Test for raised ketones in patients with

ketoacidosis symptoms, even if plasma glucose

levels are near-normal.

– Report suspected side effects to SGLT2 inhibitors

or any other medicines on a Yellow Card

SGLT2s – Advice for patients

• Report any symptoms of DKA - rapid weight loss,

feeling or being sick, stomach pain, fast and deep

breathing, sleepiness, sweet smelling breath…

• Increase urinary frequency

• Increased risk of infection

• Risk of hypo if on SU or insulin

Sick Day Sick Day

Rules Rules --

SGLTsSGLTs

Case 1

Mr Smith is a 52 year old teacher. Mr Smith was diagnosed with Type 2

diabetes 2 years ago. He is a car driver.

HbA1c last week was 70mmol/mol

Weight is 80kg, height 5’ 8”, BMI 31.8

Current medication:

� Metformin 500mg at a dose of 1g twice daily.

�What second line OHA would you choose?

DEPENDS ENTIRELY ON YOUR

PATIENT...

What next?

Two Infrequently used Oral

Type 2 Hypoglycaemic Drugs

• Alpha-Glucosidase Inhibitors (Acarbose)

• Meglitinides (Repaglinide & Nateglinide)

Acarbose (Glucobay®)

• alpha glucosidase inhibitors – Acarbose

• GG&C Formulary restricted to patients who cant tolerate Metformin

• Acarbose - slows absorption of starchy foods from the intestine.

• blood glucose levels rise more slowly after meals.

• Acarbose should always be chewed with the first mouthful of food or swallowed whole with a little liquid immediately before the meal.

• Main side-effects are flatulence and diarrhoea

Meglitinides (Repaglinide &

Nateglinide)

• Like the sulphonylureas, these stimulate the cells in the

pancreas to produce more insulin.

• However, unlike the sulphonylureas, they work very quickly

but only last for a short time and are given within half an hour

before each meal.

• If a meal is missed, the dose must be omitted. These tablets

are taken up to three times daily.

• Not in GG&C Formulary

Consider adding a third oral medication?

– Only likely to be effective if HbA1c is < 86

mmol/mol

Consider adding a injectable GPL1-agonist?

– Only if BMI >30kg/m2

Consider starting insulin therapy?

– Can cause weight gain and requires more

intensive BGM

Glucagon-Like Peptide-1 (GLP-1)

analogues

• Mimic action of GLP1s (incretins)

• Incretins produced when we eat –

• Incretins cause a decrease in blood glucose by

• Stimulating the release of insulin by pancreas after eating.

• Inhibiting the release of glucagon by pancreas.

– Glucagon causes liver to release stored sugar into bloodstream.

• Slowing glucose absorption into the bloodstream

– reduces speed stomach empties after eating,

– making you feel more satisfied after a meal. – weight loss

Glucagon-Like Peptide-1 (GLP-1)

analogues

5 GLP-1 analogues which have been approved by SMC for use in NHSScotland -

Exenatide (Byetta®) - Twice daily s/c injections

Exenatide (Bydureon®) - Once weekly s/c injection

Liraglutide (Victoza®) - Once daily s/c injections

Lixisenatide (Lyxumia®) – Once daily s/c injections

Albiglutide (Eperzan®) – Once weekly s/c injection

Dulaglutide (Trulicity®) – Once weekly s/c injection

New study – Cardiovascular benefits

The Introduction of Insulin

• Suboptimal control with two (or three) OHA

• Consider insulin / injectable therapy

Unpicking Polypharmacy – SCI Diabetes

Black Triangle▲

• ▲Identifies preparations in the BNF that

require additional monitoring by the European

Medicines Agency

• All suspected adverse reactions should be

reported by the yellow card scheme to the

Commission on Human Medicines:

www.yellowcard.gov.uk

In summary

• First line Metformin

• Second line – individualise therapy

• Review efficacy of drug treatment

– Stop treatment if ineffective

• Targets – treat aggressively when first diagnosed

– Consider patient when setting targets

Taken from GG&C Diabetes Guideline available from http://www.nhsggc.org.uk

Taken from GG&C Diabetes Guideline available from http://www.nhsggc.org.uk

• GGC Formulary

http://www.ggcprescribing.org.uk/

• Clinical guidelines

http://www.staffnet.ggc.scot.nhs.uk

• SMC Advice

https://www.scottishmedicines.org.uk/SMC_Advice

/Advice_Directory/SMC_Advice_Directory

Driving and Type 2 Diabetes

• For further information see:

NHSGGC Self-monitoring of Blood Glucose

Guidelines

or

https://www.gov.uk/diabetes-driving

References

• GG&C Diabetes Guideline

Available at: http://www.ggcprescribing.org.uk

• SIGN 116 March 2010

Available at: www.sign.ac.uk

• Nice NG28 Dec 2015

Available at: www.nice.org.uk

• BNF 69 Sept 2015

Available at: www.bnf.org

• The Scottish Medicines Consortium

Available at: www. http://www.scottishmedicines.org.uk

• Diabetes and Driving:

Available at: https://www.gov.uk/diabetes-driving

Case 2

Mr Mackie is a 54 year old male with Type 2 diabetes. He has been

prescribed his current medications for the last 2 years and his HbA1c

has increased to 64mmol/mol.

Current Medication:

– Metformin 1000mg twice daily

Mr Mackie has a history of hypertension, MI, BMI 29, U/Es and lfts normal.

You are carrying out her annual diabetes review.

What would you suggest when reviewing his current

medication regimen?

Options --

• A – No change as well controlled

• B – Start new OHA and review in 3-6 months

• A – SU

• B – Pioglitazone

• C - DPP4 inhibitor

• D - SGLT2

Case 3

Miss Carter is a 84 year old lady who has had Type 2 diabetes since

she was 72. HBA1C 51mmol/mol, Egfr 40

• Current Medication:

– Metformin 1g twice daily

– Gliclazide 160mg twice daily

– Sitaglipin 100mg daily

What else would you want to know?

Any suggested changes?

What to do with Miss Carter

Review patients HbA1c – risk of hypos?

Altered hypo awareness

Reduced appetite, weight loss

Drive? Check blood glucose?

Consider reduced renal function:

• Reduce dose of sitagliptin and metformin?

Any questions?