Oral Treatments for Type 2 Diabetes. Prescribing Support Pharmacist

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

Take a moment to think.. You have been diagnosed with diabetes... You have been told you need to go on medication... WHAT WOULD YOU LIKE YOUR MEDICATION TO DO? WHAT WOULD BE YOUR CONCERNS?

A brief history of diabetes medication...

Type 2 Diabetes is a Progressive Disease: UKPDS1 Cross-sectional sectional median values Median A1C (%) 9 8 7 6 0 Time From Randomisation (years) Conventional Treatment (n=1138) Intensive Treatment (n=2729) ADA action suggested ADA target 0 3 6 9 12 15

3 Add statin 2 Control BP 4 Add metformin 1 Lifestyle (exercise, diet, stop smoking) Let s give our diabetic patients a hand! 5 consider tight glucose control Don t t turn the hand 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

When would you start treatment?

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 1 st intensification: HBA1C > 58mmol/mol (7.5%) Target 53mmol/mol (7%) 2nd intensification: HBA1C > 58mmol/mol, target 53mmol/mol

Legacy Effect Holman 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. Macro-and microvascular benefits remained 10 years later

UKPDS: A 1% decrease in HbA 1c is associated with a reduction in complications HbA 1 C 1% 43 % 37 % 21 % Amputation or fatal peripheral blood vessel disease* Microvascular complications e.g. kidney disease and blindness * Deaths related to diabetes* 14 % Heart attack* * p<0.0001 ** p=0.035 12 % Stroke** Stratton IM, et al. BMJ 2000; 321: 405 412.

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?

What would you use as first line treatment? WHY?

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 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

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 MR prep could be considered (non-formulary) 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?

NO WRONG ANSWER Remember to 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 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 1 st three months Can t be used in severe renal /liver impairment or if breast feeding 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 important to career? Groups at increased risk of hypo elderly, mild renal or liver impairment

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

Pioglitazone Experience, low cost, CVD event reduction in PROactive Weight gain, fluid retention, fractures, uncertain safety (bladder cancer?)

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 DPP4 inhibitors (gliptins) Alogliptin, Linagliptin 1 st line in NHSGGC. Other available DDP4s include sitagliptin, vildagliptin & saxagliptin Second line therapy in combination with metformin Triple therapy in combination with other OHA

DPP-4 inhibitors -pros Very low hypo risk 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 linagliptin most suitable in renal impairment

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. Advise patient to return for HbA1c review in 3-6 months and that drug will be stopped if no therapeutic response.

SGLT-2 Inhibitors Newest class of oral hypoglycaemic agent All on NHSGGC total formulary Canagliflozin (Ivokana ) Dapagliflozin (Forxiga ) Empagliflozin (Jardiance )

SGLT-2 inhibitors 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

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 ( HbA 1c, body weight, BP and an HDL chol) CV benefits due to hemodynamic effects, - BP and in extracellular volume.

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 comorbidities CANVAS trial expected 2018 DECLARE trial expected 2019

SGLT2 renal benefits 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 renal function before initiation, before initiation on other drugs which may reduce renal function and annually thereafter. DKA at near normal blood glucose levels Stop before surgery, sick day rules Caution elderly risk of volume depletion More adverse effects >75yrs

SGLT-2 inhibitors Hepatic and Renal Function

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 Advice for HCPs and Ketoacidosis 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

SGLT2 inhibitors Cost, genital fungal infections, risk of DKA, long term safety uncertain Weight loss, hypoglycaema rare, reduced CV events

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 Rules - SGLTs

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 foodor 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

WHAT NEXT? Consider adding a third oral medication? Consider adding a injectable GPL1-agonist? Only if BMI >30kg/m2 Consider starting insulin therapy? Can cause weight gain and requires more intensive BGM

Unpicking Polypharmacy SCI Diabetes

First line Metformin In summary 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

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

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

Would you choose anything different now?

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?