Drugs for Diabetes

1. Drugs for Diabetes

2. Diabetes • TYPE 1- absolute insufficiency of insulin- treatment involves giving exogenous insulin • TYPE 2- Relative deficiency of insulin. Reduced sensitivity to insulin. Treatment aims at increasing sensitivity to insulin and sometimes exogenous insulin • TYPE 3- Combination of both. Patient has chronic pancreatitis (causing insufficient insulin) as well as type 2 diabetes. If patient is given exogenous insulin temporarily it gives the pancreas chance to regenerate and begin to produce insulin again. Patient will need drugs to increase insulin sensitivity.

3. Insulin • Secreted naturally from the b cells in the islet of Langerhans in response to high blood glucose. It is stored with C-peptide Therefore C-peptide levels are checked in urine when looking for an insulinoma as it is co-released so will be markedley raised, there is no c-peptide in exogenous insulin so it will not be raised if someone has taken an insulin overdose. • Glucagon opposes insulin and is secreted from the A cells in the islets of Langerhans

4. Hormonal Control • Hormones that stimulate insulin release through eating: gastrin, secretin, cholecystokinin, glucagon like peptide (GLP), gastic inhibitor peptide (GIP) • Hormones that inhibit insulin release: adrenaline and somatostatin

5. Effects of insulin glycogen synthesis glucose uptake into muscle and fat decrease gluconeogenesis decrease glycogen breakdown

6. Pharmacokinetics and insulin preparations • It is destroyed in the GI tract so must be given subcut • It is inactivated in the liver and 10% is excreted through the kidneys • Can be given short acting or long acting • Longer acting are often given at night and short acting given at meals • Insulin pumps can be given in special circumstances

7. AMK Question John, 25, is a type 1 diabetic. He is currently controlled with long-acting SC insulin taken at night and short acting insulin given before meal times. He has recently been having high glucose readings when he checks first thing in the morning. What should you do to his insulin therapy? a. Increase long acting insulin at night b. Increase short acting insulin before evening meal time c. Advise him to eat evening meal earlier d. Decrease long acting insulin at night e. Increase morning short acting insulin f. Don’t Know

8. Answer • D- decrease long acting insulin before bed Due to rebound hyperglycaemia- bodies own hormonal mechanisms of treating a hypoglycaemic attack he has had at night

9. BIGUANIDES • METFORMIN- 1st line Increase glucose uptake and utilisation in skeletal muscle Reduce hepatic gluconeogenesis Patients lose weight which can be beneficial to T2DM Give at maximum tolerated dose Side effects: GI disturbance (common), lactic acidosis (rare but potentially fatal) Contraindications: liver disease, renal disease, CHF, shock (all situations that predispose to lactic acidosis as reduced tissue perfusion or drug elimination) Pregnancy

10. Sulfonylureas • Chlorpropamide, glibenclamide, tolbutamide • Second line- add to metformin Stimulate insulin release from pancreas Side Effects: weight gain, hypoglycaemia, GI disturbance Contraindications: pregnancy Drug interactions: drugs that augment action and may cause hypoglycaemic attack: NSAIDS, alcohol, monoamine oxidase inhibitors

11. Postprandial glucose regulators • Repaglinide and nateglinide • stimulate a rapid, short duration release of insulin from the pancreas. Postprandial glucose regulators are particularly effective for patients with: •Erratic lifestyles •Recurrent hypoglycaemia with sulphonylureas •Postprandial hyperglycaemia. Side effects- weight gain and hypoglycaemia. Contraindications- impaired renal and hepatic function.

12. Acarbose • Decreases absorption of carbohydrate in the gut Acarbose may be considered as an alternative glucose lowering treatment in people unable to use other oral drugs Side effects: GI, flatulence, bloating Contraindications: IBD, malabsorption

13. Thiazolidinediones • Pioglitazone • Thiazolidinediones reduce insulin resistance in adipose, skeletal, and hepatic tissues by increasing transcription of insulin sensitive genes in these cells. • Side effects: oedema and anaemia • Hepatotoxicity has been reported rarely. Liver enzymes should be monitored before the drugs are started and periodically thereafter.

14. GLP-1 Analogues • exenatide and liraglutide • GLP-1 analogues work through the incretin effect. Incretin hormones were first identified when it was found that glucose given orally produced a greater stimulation of insulin release than when an equivalent glucose level was achieved by IV infusion. • GLP-1 is secreted from the ileum when food is ingested. It has multiple sites of action with the following effects: Beta cells - enhances glucose dependent insulin secretion Stomach - helps slow gastric emptying Liver - ↓ glucagon, which reduces hepatic glucose output Alpha cells - ↓ postprandial glucagon secretion Promotes satiety and reduces appetite. • Side effects- nausea and vomiting. There is some evidence to suggest GLP-1 analogue therapy may increase the risk of pancreatitis. In patients at high risk of developing pancreatitis (gallstones, alcohol dependency, hypertriglyceridaemia) VERY EXPENSIVE

15. DPP-4 inhibitors • sitagliptin, vildagliptin, saxagliptin, and linagliptin • An alternative strategy to improve insulin output from the pancreas via the incretin system is to block the action of DPP-4. DPP-4 inhibitors bind to the active site of the DPP-4 enzyme so that it cannot bind to and degrade GLP-1. This increases the availability of endogenous GLP-1. Consider adding a DPP-4 inhibitor as second or third line therapy to sulphonylurea or metformin when control of blood glucose is inadequate if: •The person is at significant risk of hypoglycaemia or its consequences •Further weight gain would cause or exacerbate significant problems associated with a high body weight •When control of blood glucose is inadequate and insulin is unacceptable or inappropriate. Very few side effects but very expensive

16. Insulin in type 2 The reasons for needing to consider insulin include: •Poor glycaemic control despite maximal treatment with oral anti-diabetes agents •Weight loss without dieting in someone of low or normal weight •Contraindications to oral hypoglycaemic agents, for example renal or hepatic failure •Pregnancy •Post-myocardial infarct •Marked thirst and polyuria with high blood glucose.

17. AMK Question • 2.Four months later Mr White returns to your clinic. He has made a significant effort to improve his lifestyle. He has lost weight and his BMI is now 22.7. His fasting blood glucose readings range between 6 mmol/l and 12 mmol/l and his most recent HbA1c has improved to 60.7 mmol/mol (7.7%). He is taking metformin 500 mg twice daily without side effects. What is next logical step in treatment? • a. Increase metformin to 1 g twice daily • b. Continue with more intensive lifestyle changes • c. Start glipizide (sulphonylurea) • d. Continue as he is

18. ANSWER • Increase metformin to 1 g twice daily • Metformin, lifestyle changes, and dietary modification have not adequately controlled Mr White's diabetes (his HbA1c is greater than 53 mmol/mol (7%)), so increasing his metformin dose is the next step in management. Metformin at the maximum tolerated dose is recommended as first line drug therapy for all patients with type 2 diabetes unless there is a specific contraindication.

19. AMK Question • One month later Mrs Johnson is reviewed. Blood glucose has improved with morning readings between 6-9 mmol/l. Her main complaint is nausea and she is vomiting at least once every day. These symptoms do not appear to be improving and she is not keen to continue treatment. Her weight has reduced by 3 kg in four weeks. How should you proceed? • a. Continue exenatide 5 µg twice daily • b. Increase exenatide to 10 µg twice daily • c. Stop exenatide and start a DPP-4 inhibitor

20. Answer • Stop exenatide and start a DPP-4 inhibitor • Mrs Johnson is experiencing significant nausea and vomiting which is most likely a side effect of the exenatide. Although these symptoms usually settle within a week or two of starting treatment she continues to vomit regularly. Both sulphonylurea and thiazolodinedione therapies are associated with further weight gain and a DPP-4 inhibitor would be an appropriate option for this obese woman. Liraglutide could be considered as an alternative GLP-1 therapy since it has a lower incidence of nausea and vomiting side effects.