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Oral Treatments for Type 2 Diabetes Prescribing Support Pharmacist Learning Outcomes • Recognise the different oral agents used in controlling blood glucose levels • Describe the pharmacological effects of the agents • Explain the side effects of the agents • Understand the rationale for clinical guidelines 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 Type 2 Diabetes is a Progressive Disease: UKPDS1 Cross-sectional median values Treatment (n=1138) Intensive Treatment (n=2729) Median A1C (%) Conventional 9 8 ADA action suggested 7 ADA target 6 0 0 3 Time 6 9 12 From Randomisation (years) 15 2 Control BP 3 Add statin 4 Add metformin 5 consider tight glucose control 1 Lifestyle (exercise, diet, stop smoking) Don’t Let’s give our diabetic patients a hand! turn the hand around 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 Why is good glycaemic control important? Microvascular Complications Macrovascular Complications Stroke Diabetic Retinopathy Leading cause of blindness in working-age adults1 Diabetic Nephropathy Leading cause of end-stage renal disease2 2- to 4-fold increase in cardiovascular mortality and stroke4,5 Heart Disease6 Diabetic Neuropathy Leading cause of nontraumatic lower extremity amputations3 All Peripheral Vascular Disease6 references last accessed April 2012: 1. IDF. Fact Sheet Diabetes and Eye Disease. Available at: http://www.idf.org/node/1186?unode=C1CCADE9-4A03-4D17-A662-155B3ED59FDB. 2. The Renal Association. UK Renal Registry. Twelfth Annual Report. December 2009. Available at http://www.renalreg.com/Reports/2009.html. 3. Dang, CN., Boulton, AJ., International Journal of Lower Extremity Wounds. 2003; 2(1):4-12. 4. Jeerakathil, T., et al. Stroke. 2007;38(6):1739-43. 5. Kaul, S., et al. Circulation. 2010;121:186877. 6. IDF. Fact sheet: Diabetes and Cardiovascular Disease (CVD). Available at: http://www.idf.org/fact-sheets/diabetes-cvd. Glucose Homeostasis Biguanides - Metformin Metformin • 1st choice in obese patients - helps weight loss and rarely causes hypoglycaemia, as it does not stimulate insulin secretion • Side-effects: GI upset (anorexia, nausea, vomiting, diarrhoea), B12 malabsorption, and very rarely lactic acidosis • Renal impairment – dose should be reduced • Can be used alone or in combination with any other oral hypoglycaemic agent or insulin Metformin • If HbA1c remains at or below 53mmol/mol on Metformin continue to review the patient 6 monthly • Metformin has been shown to reduce CVD events (UK Prospective Diabetes Study: http://www.dtu.ox.ac.uk/ukpds/) • Has favourable effects on lipid metabolism – it reduces total cholesterol, LDL cholesterol and triglyceride levels 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 Options for second line drug therapy • • • • Sulphonylurea Pioglitazone Gliptin (DPP-4 inhibitor) SGLT-2 ▲ • Consider individual patient factors and contraindications Sulphonylureas Sulphonylureas • Side-effects: GI, weight gain, hypoglycaemia • Caution in hepatic/renal impairment (increased chance of hypos). If hepatic/renal impairment is severe - Avoid • Contra-indicated: Pregnancy, breastfeeding, acute porphyria, ketoacidosis Sulphonylureas • Pros – – – – Confidence and experience in using Cheap (generic: £6 per month) Effective (mean 1% reduction HbA1c) Minimal responder variability • Cons – Significant hypoglycaemia risk – BGM may be appropriate for 1st three months – Weight gain – Poor durability Thiazolidinediones (Glitazones) Pioglitazone • Side-effects GI, weight gain, hypoglycaemia (rarely). It is associated with fluid retention and has precipitated heart failure and pulmonary oedema in patients at risk • Cautions – Monitor liver function: Check LFT’s before use and periodically thereafter • Contra-indications – Hepatic impairment – Pregnancy and breast-feeding – Previous or active bladder cancer Pioglitazone and Heart Failure • PROactive Study • Cardiac failure risk 39% higher in Pioglitazone group compared to placebo. (5.7% v 4.1%) • Of those with serious heart failure mortality due to heart failure similar in both groups • And all cause mortality lower in Pio group (26.8% v 34.3%) Pioglitazone & bladder cancer Risk of Bladder Cancer July 2011: • The European Medicines Agency has advised that there is a small increased risk of bladder cancer associated with pioglitazone use • However, in patients who respond adequately to treatment, the benefits of pioglitazone continue to outweigh the risks Pioglitazone and bone fractures • 39% increased incidence of fractures in men and women on TZDs. • Increased incidence in all women and in men > 50 years. DPP-4 inhibitors (Gliptins) DPP-4 inhibitors work by blocking the action of DPP4, an enzyme which destroys the hormone incretin. DPP-4 Inhibitors (Gliptins) Preferred List: • Sitagliptin (Januvia®) – 1st choice • Linagliptin (Trajenta®) ▲ Total Formulary: • Saxagliptin (Onglyza®) • Vildagliptin (Galvus®) • Alogliptin (Vipidia®) ▲ DPP-4 inhibitors (Gliptins) • Monotherapy – only if metformin or SU contraindicated or not tolerated • Combination with a sulphonylurea is restricted to patients in whom metformin is contraindicated or not tolerated. • Combination with both metformin and a sulphonylurea (i.e triple therapy) restricted to patients who are inadequately controlled on max tolerated doses of metformin and sulphonylurea. • NB: dose of concomitant Sulphonylurea or insulin may need to be reduced DPP-4 inhibitors (Gliptins) • Pros – Very low hypo risk – Weight neutral – Low side-effect profile • Cons – Expensive (around £30 per month) – Less effective (mean 1% reduction HbA1c) – Responder variability – No long term safety information DPP-4 Inhibitors (Gliptins) • Side-effects-GI disturbance, peripheral oedema • Caution: elderly • Contra-Indications: Ketoacidosis, pregnancy, breast feeding. Doses may need adjusted in renal or hepatic impairment SGLT-2 inhibitors SGLT-2 Inhibitors All on NHSGGC total formulary • Canagliflozin (Ivokana ®) ▲ • Dapagliflozin (Forxiga ®) ▲ • Empagliflozin (Jardiance®) ▲ SGLT–2 Inhibitors • NOT recommended for monotherapy • Restricted to initiation by clinicians experienced in the management of diabetes for the indications • Side effects – constipation, genital infection, nausea, polyuria, thirst, urinary frequency, UTI SGLT–2 Inhibitors • Pros – Weight loss – Very low hypo rate – Effective at all stages of diabetes • Cons – – – – – High cost Urinary tract infections Genital thrush No long term safety information Not licensed in eGFR <60mls/min SGLT-2 inhibitors Hepatic and Renal Function MHRA advice on SGLT-2 inhibitors and Ketoacidosis • SGLT2 inhibitors are licensed for use in adults with type 2 diabetes to improve glycaemic control. • Serious, life-threatening, and fatal cases of DKA have been reported in patients taking an SGLT2 inhibitor. 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 Two Infrequently used Oral Type 2 Hypoglycaemic Drugs • Alpha-Glucosidase Inhibitors (Acarbose) • Meglitinides (Repaglinide & Nateglinide) Acarbose (Glucobay®) • The largest evidence base for the alpha glucosidase inhibitors is with Acarbose and its in the GG&C Formulary restricted to patients who cant tolerate Metformin • Acarbose works by slowing down the absorption of starchy foods from the intestine. This means that 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 What next? DEPENDS ENTIRELY ON YOUR PATIENT... 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 This type of medication works by increasing the levels of hormones called ‘incretins’. These hormones help the body produce more insulin only when needed and reduce the amount of glucose being produced by the liver when it’s not needed. They reduce the rate at which the stomach digests food and empties, and can also reduce appetite. 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 The Introduction of Insulin • If there is suboptimal control with two (or three) oral hypoglycaemic agents or if dual therapy is contraindicated then insulin should be introduced with one oral hypoglycaemic agent, preferably metformin 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 1 Mr Smith is a 52 year old man who drives long distances in lorries for a living. Mr Smith is a smoker and was diagnosed with Type 2 diabetes 5 years ago. HbA1c last week was 70mmol/mol Current medication: Metformin 500mg at a dose of 1g twice daily • Do you want to change or add to Mr Smiths medication regimen? • Discuss the options available and what medications you might add to his current regimen. What to do with Mr Smith • Move to second line based on HbA1c being >53mmol/mol – Gliclazide not selected based on occupational hazards with hypoglycaemia risk Suitable options remaining: – Glitazone – Gliptin – SGLT-2 Case 2 Mrs Mackie is a 78 year old lady with Type 2 diabetes. She has been prescribed her current medications for the last 7 years and her HbA1c has been stable under 53mmol/mol. Current Medication: – Metformin 1000mg twice daily – Gliclazide 80mg twice daily – Pioglitazone 30mg daily Mrs Mackie has developed osteoporosis and has also suffered from an MI with resulting Heart Failure NYHA Class 2 in the past 3 years. You are carrying out her annual diabetes review. Are there any considerations you may need to make when reviewing her current medication regimen? What to do with Mrs Mackie • Pioglitazone – Contra-indicated in Heart Failure – Caution in osteoporosis as can increase the risk of fractures • Stop Pioglitazone • Consider commencing Gliptin or SGLT2 Case 3 Miss Carter is a 84 year old lady who has had Type 2 diabetes since she was 72. • Current Medication: – – – – Metformin 1g twice daily Gliclazide 40mg twice daily Empagliflozin 25mg once daily Renal Function is being monitored by the practice nurse and has noted to be falling. Most recently it is 53ml/min What else would you want to know? What do you do? What to do with Miss Carter Consider reduced renal function: • If falling persistently below 60ml/min reduce dose to 10mg once daily. Stop if eGFR reduces below 45ml/min Review patients HbA1c – does she need all this medication for type 2 diabetes, often patients lose weight as they get older and more frail therefore her HbA1c may be reducing based on this.