Drugs for Type 2 Diabetes – where next after metformin ? Dr Emily McMurray Western General Hospital

Overview What are the drug options? What do the guidelines say? Gliclizide, glipizide (SU) Pioglitazone (TZDs) Sitagliptin (DPP4 inhibitor) Dulaglutide (GLP-1 receptor agonist) Empagliflozin (SGLT2 inhibitor) What do the guidelines say? What about in our everyday practice?

A lot has changed! 1993 guidelines were simple Start with metformin – unless fasting sugar >13 If that’s not enough add SU If that’s not enough, stop them both and start insulin Easy to remember, but not very patient- centred

Not everything has changed Metformin is still first line Stop if eGFR <30 Ask patient to stop it if at risk of dehydration, ongoing D+V – “sick day rules”

Sulphonylurea Increase insulin secretion, regardless of blood glucose level Pros: Effective Symptomatic relief Extensive experience Cheap

The downsides Weight gain Glucose monitoring Hypoglycaemia Reduce dose in renal impairment Avoid in hepatic failure

Pioglitazone Was the first of the “new” drugs Reduces insulin resistance Pros: Effective Rare hypoglycaemia Sustained improvements in HbA1c Cardiovascular benefits? If HbA1c > 48mmol/mol after dietary input

The downsides Heart failure Fracture risk Bladder cancer Hepatic impairment Weight gain

sitagliptin Blocks the enzyme which breaks down GLP1 Increases insulin and decreases glucagon relative to plasma glucose Moderate efficacy Pros Safe in renal impairment Weight neutral Little hypo risk ??CV event reduction Cons GI side effects cost

dulaglutide GLP1 receptor agonist More effective than sitagliptin Pros Increases insulin and decreases glucagon relative to blood glucose More effective than sitagliptin Pros Weight loss often seen Not associated with hypos Study with liraglutide (daily) showed reduction in CV event rate and mortality

The downside Injectable medication Major hurdle for some patients Extra training requirements GI side effects ? pancreatitis

Empagliflozin SGTL2 inhibitor Acts at kidney to prevent glucose resorption Glycosuria and polyuria Moderately effective (~7mmol/mol) Pros: Weight loss BP reduction Not associated with hypos CV mortality improved

Empagliflozin EMPA-REG Published Nov 2015 (7000 pts, 3 years) T2DM with established cardiovascular disease Added to standard care 38% reduction in cardiovascular outcomes (death) 35% reduction in hospitilisation due to heart failure 32% reduction in death by any cause

SGLT2 inhibitors – the downside Polyuria Care with hypovolaemia / loop diuretics / pioglitazone Genital infections Cannot be given to >85 years Cannot be used if eGFR<45 Cannot be initiated if eGFR<60 Risk of DKA with normal blood sugars – patients require to be counselled on symptoms to be aware of Cost

What do the guidelines say? SIGN, NICE, joint ADA/European society All recognise that combination therapy is often required No hard and fast rules as to which drug and when

Ideal Algorithm Reality

Choosing a 2nd or 3rd line agent If HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions: · Offer standard–release metformin · Support the person to aim for an HbA1c level of 48 mmol/ mol (6.5%) FIRST INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): · Consider dual therapy with: - metformin and a DPP-4i – metformin and pioglitazone metformin and an SU metformin and an SGLT-2ib · Support the person to aim for an HbA1c level of 53 mmol/ mol (7.0%)

There’s more! SECOND INTENSIFICATION If HbA1c rises to 58 mmol/mol (7.5%): · Consider: - triple therapy with: metformin, a DPP4 and an SU metformin, pioglitazone and an SU metformin, pioglitazone or an SU, and an SGLT-2 insulin-based treatment · Support the person to aim for an HbA1c level of 53 mmol/ mol (7.0%) If standard-release metformin is not tolerated, consider a trial of modified–release metformin If triple therapy is not effective, not tolerated or contraindicated, consider combination therapy with metformin, an SU and a GLP-1 mimeticc for adults with type 2 diabetes who: - have a BMI of 35 kg/m2 or higher (adjust accordingly for people from black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or - have a BMI lower than 35 kg/m2, and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity- related comorbidities

Drug choice is patient centred Effectiveness Safety Impact on weight Hypoglycaemia risk Co-morbidities Polypharmacy Patient preference Combination products Cost

Some patient scenarios 82 year old man Tolerating metformin but HbA1c 82mmol/mol Target sugars 8-14mmol/l Still active – walks to the park via newsagents daily Renal dysfunction: eGFR 52

considerations Hypo risk in the elderly Renal impairment HbA1c target is not as low as 53mmol/mol Avoid osmotic symptoms and hypos

considerations Hypo risk in the elderly Renal impairment HbA1c target is not as low as 53mmol/mol Avoid osmotic symptoms and hypos 2nd line: Sitagliptin 3rd line if symptomatic: low dose SU

Lost 2kg following dietary advice Metformin 1g BD Man in his 30s BMI 23kg/m2 Lost 2kg following dietary advice Metformin 1g BD HbA1c 70mmol/mol

Lost 2kg following dietary advice Metformin 1g BD Man in his 30s BMI 23kg/m2 Lost 2kg following dietary advice Metformin 1g BD HbA1c 70mmol/mol

Lost 2kg following dietary advice Metformin 1g BD Man in his 30s BMI 23kg/m2 Lost 2kg following dietary advice Metformin 1g BD HbA1c 60mmol/mol 2nd line: SU 3rd line………insulin

Trying hard to lose weight – HbA1c 67mmol/mol Woman in her 40s BMI 37kg/m2 Trying hard to lose weight – managed 3Kg with great difficulty HbA1c 67mmol/mol

Trying hard to lose weight – HbA1c 67mmol/mol Woman in her 40s BMI 37kg/m2 Trying hard to lose weight – managed 3Kg with great difficulty HbA1c 67mmol/mol

Trying hard to lose weight – HbA1c 67mmol/mol Woman in her 40s BMI 37kg/m2 Trying hard to lose weight – managed 3Kg with great difficulty HbA1c 67mmol/mol Not keen on possible weight gain with SU or pio, but would be prepared to inject 2nd line by current guidelines: sitagliptin GLP-1 agonist would offer best HbA1c results with weight loss SGLT2 also good option

On met 1g BD, gliclazide 80mg BD HbA1c 62mmol/mol Wary of injections 68y old woman On met 1g BD, gliclazide 80mg BD Has had hypos on active days HbA1c 62mmol/mol Wary of injections Has hypertension on 2 agents

On met 1g BD, gliclazide 80mg BD HbA1c 66mmol/mol BMI 32kg/m2 68y old woman On met 1g BD, gliclazide 80mg BD Has had hypos on active days HbA1c 66mmol/mol BMI 32kg/m2 Wary of injections Has hypertension on 2 agents 3rd line empagliflozin CV benefits

3 year history of diabetes Couldn’t tolerate metformin 67year old man 3 year history of diabetes Couldn’t tolerate metformin Terrible diarrhoea On maximal dose SU, but HbA1c 63mmol/mol No Hx CCF Urine dip clear

3 year history of diabetes Couldn’t tolerate metformin 67year old man 3 year history of diabetes Couldn’t tolerate metformin Terrible diarrhoea On maximal dose SU, but HbA1c 63mmol/mol No Hx CCF Urine dip clear

3 year history of diabetes Couldn’t tolerate metformin 67year old man 3 year history of diabetes Couldn’t tolerate metformin Terrible diarrhoea On maximal dose SU, but HbA1c 82mmol/mol No Hx CCF Urine dip clear 2nd line pioglitizone without met no treatment targeting IR

Monitoring / Effectiveness At 6 months after change in therapy Check HbA1c / therapeutic response Check renal function Discuss sick day rules

Summary Our options for treatment in T2DM so much wider than before Metformin is first line Subsequent choices influenced by many factors HbA1c Hypos Weight Co-morbidity Side effects Age Duration of diabetes

SU TZDs DPP4 SGLT2 GLP1 insulin Efficacy High Intermed Highest Hypo risk Mod low Low Weight gain neutral loss Gain s/e hypo CCF, # Bladder Ca rare GU, dehydration GI hypos cost high