The therapeutics of diabetes

1. The therapeutics of diabetes Simon Heller

2. Outline • Treating Type 1 diabetes • Type 2 diabetes • Role of current oral agents and new injectables • Approaches to insulin treatment • Treating DKA

3. Current insulins • Short acting insulins • Conventional human soluble • Actrapid, Humulin S • Rapid Acting insulin analogues • Insulin aspart, insulin lispro, insulin glulisine • Medium acting insulins • Conventional human isophane (NPH) • Human insulatard, Humulin I • Long acting insulin analogues • Insulin glargine, insulin detemir • Pre-mixed insulins • Conventional human insulin • Mixtard, Humulin M3 (30% sol, 70% NPH) • Insulin analogues • Humalog Mix25 (25% humalog 75% NPH), Novomix 30 (30% aspart, 70% NPH)

4. 16 100 Hypoglycaemia Retinopathy 14 80 12 10 60 8 Severe hypoglycaemia per 100 patient years Intensive group 40 Retinopathy per 100 patient years 6 4 20 2 0 0 Benefits and risks of tight glucose control 5 6 7 8 9 10 11 12 13 14 Haemoglobin A1c DCCT Group, Diabetes 1996

5. Estimated s.c. injected soluble human insulin + NPH 0900 1200 1500 1800 2100 2400 0300 0600 0600 Breakfast Lunch Dinner NPH Conventional plasma insulin profile 450 Normal free insulin levels (Mean) 300 Plasma insulin (pmol/l) Meals 150 0 Time of day Adapted from Rizza 1981, Polonsky et al. 1988

6. Treatment of Type 1 diabetes First choice for everyone is to “restore” the physiology of the beta cell • Insulin treatment • Separate basal insulin secretion and meal related insulin by giving: Meal related insulin-pre meal quick acting insulin)Background-twice daily medium acting insulin (NPH) or once or twice daily long acting analogues (glargine or detemir) • Measure CHO intake (CHO counting) • Eat freely and flexibly with pre-meal monitoring to decide correct dose of quick acting insulin • Awareness of blood glucose lowering effect of exercise All combined to keep blood glucose close to normal (and so prevent diabetic complications) For those who are unable to cope with this intensive therapy, then twice daily pre-mixed insulin with occasional monitoring is a less good but common option

7. Most people with Type 1 diabetes fail to achieve tight glycaemic control • Risk of hypoglycaemia • Too arduous a treatment • Risk of weight gain • Interference with lifestyle New educational approaches encouraging effective self-management by intensive skills training are now standard treatment across the UK

8. Type 2 diabetes • Perhaps the greatest non-infective threat to global health • 4% prevalence in Sheffield • 15-20% prevalence in many developing countries • Currently affects 150 million (set to double by 2020) • A disease of ‘western industrialised lifestyle’ • Obesity • Lack of physical exercise

9. Increasing Prevalence of T2D Globally 140 120 100 2000 80 Prevalence (millions) 60 2030 40 20 0 Africa Europe SE Asia Americas Eastern Med Western Pacific WHO database, 2003

10. Type 2 diabetes-pathophysiology • Metabolic defects • Insulin resistance • Impaired insulin secretion and progressive -cell damage • Excessive hepatic glucose output • Increased counterregulatory hormones including glucagon On the background of excessive energy intake

11. Principles of treatment • Control of symptoms • Identification and prevention of long-term microvascular complications • No evidence yet that glucose control reduces cardiovascular events (confirmed by 2 recent clinical trials, ACCORD, ADVANCE) in the short-term • But longterm follow-up indicates a modest reduction in MI from tight glucose control if started at diagnosis • HbA1c <7.5% (as low as possible in those not on insulin or sulphonylureas) • Negative urine tests • Fasting blood glucose <7mM

12. Treatment in Type 2 diabetesin reality • Ideally consists of weight loss and exercise which if substantial will reverse hyperglycaemia but most of those with Type 2 diabetes have been making the ‘wrong’ lifestyle choices all their lives and rarely respond to std approaches • At present, management usually consists of medication to control BP, blood glucose and lipids

13. Metformin a biguanide,the drug of choice in the obese with NIDDM • modest improvement in control (around 1-1.5% in HbA1c) • opposes insulin resistance • no weight gain • may improve lipids • reduces cardiovascular risk (UKPDS) risk of lactic acidosis if renal function impaired • (don’t prescribe if creatinine >150mcmol/l) • s/e of diarrhoea reduced by gradual increase in dose and taking tablets with food.

14. Sulphonylureas (gliclazide, glibenclamide, gliquidone) • stimulate insulin release by binding to -cell receptors • Improve glycaemic control (1-2% in HbA1c) at the expense of significant weight gain. • Do not prevent the gradual failure of insulin secretion • Can cause hypoglycaemia (occasionally prolonged and fatal, particularly in the elderly) • Use gliclazide in most people and avoid glibenclamide in the over 60s • Warn and document the risks of hypoglycaemia

15. Thiazolidinediones (pioglitazone - ACTOS) • Bind to the nuclear receptor PPAR (peroxisome proliferator-activated receptor) • Activate genes concerned with glucose uptake and utilisation and lipid metabolism • Improve insulin sensitivity • Need insulin for a therapeutic effect • Glitazones are now less popular • Rosiglitazone increased cardiovascular events and is now withdrawn • Increase weight • Increase the risk of heart failure • Increase the risk of fractures

16. An ideal drug in Type 2 diabetes • Would: • Reduce appetite and induce weight loss • Preserve -cells and insulin secretion • Increase insulin secretion at meal time • Inhibit counterregulatory hormones which increase blood glucose such as glucagon • Not increase the risk of hypoglycaemia during treatment

17. ’Incretin’ concept • Enteral glucose (or food) causes greater secretion of insulin than glucose given IV • Many potential molecules • GIP/GLP-1 are the dominant peptides responsible for this effect Holst, 1999

18. Effects of GLP-1Summary

19. 7 9 37 Native GLP-1 is rapidly degraded by DPP-IV DPP-IV enzymatic cleavage T½ =1-2 minutes (i.v.) high clearance (renal)

20. Exendin 4(exenatide) • Naturally occurring 39AA GLP-1R agonist from salivary venom of Gila monster • 53% homology with GLP-1 • Resistant to DPP-IV

21. Extending the duration of action of GLP-1 • Exenatide(BYETTTA) • Liraglutide (VICTOZA) • DPP-IV inhibitors • Vildagliptin (GALVUS) • Sitagliptin (JANUVIA)

22. Therapeutic effect of GLP-1 in Type 2 diabetes • Reduces • energy intake • blood glucose • weight • HbA1c Is this the holy grail of therapy in Type 2 diabetes?

23. Comparing GLP1 with DPP-IV inhibitors

24. Oral agents - conclusions • Sulphonylureas are still the second line agents of choice • GLP1 analogues and DPP-IV inhibitors are starting to replace • Sales of glitazones are declining

25. Proportion of Type 2 patients eventually needing insulin 100 80 % 60 Insulin Oral Agents 40 20 0 0 5 10 Duration of diabetes (yr)

26. Choices of insulin therapy in Type 2 diabetes • Oral agent/insulin combinations • Bedtime long-acting (NPH or new long acting analogues (glargine or detemir)) • Twice daily pre-mixed insulin containing either soluble or rapid acting insulin analogue • Basal bolus-twice daily background (NPH) and pre-meal quick acting

27. Weight gain during insulin therapy occurs because: • the decrease in energy loss as glycosuria ceases is not compensated for by a comparable reduction in energy intake. • ? increase in appetite with an anabolic hormone • Combinations of bedtime background insulin(NPH) and oral agents seem to produce comparable improvement in glycaemic control but less weight gain.

28. Insulin in Type 2 diabetes • The best insulin combination in terms of long-term glycaemic control, hypoglycaemia, weight gain is probably basal overnight medium acting insulin (NPH, glargine, detemir) • Metformin and sulphonylureas should continue • Overnight insulin is simple, acceptable to patients who can contribute to dose adjustment

29. Bariatric Surgery • Can produce profound weight loss and may also alter secretion of incretin hormones • Two main operations • Gastric banding • Gastric bypass • Can ‘cure’ Type 2 diabetes in up to 70% even in those treated with insulin • Currently limited to those with BMI >40 • Will become more common

30. Type 2 diabetes - Conclusions • This is not ‘mild’ diabetes - high risk of premature vascular death and other vascular complications • The ‘best’ treatment, weight loss and increased exercise is rarely achieved • Needs multiple medications, many of which are probably not taken • The challenge is to engage the patient in the management of their own condition • Is only really treatable by changing the culture (health education and prevention)

31. Diabetic Ketoacidosis • Definition • Hyperglycaemia (use capillary sample but confirm with lab test) • Venous bicarbonate less than 15 mmol/l • Ketonaemia (if in doubt about cause of acidosis test urine or plasma with ketostix) • Causes • older age groups- infections • < 30y omission of insulin • Mortality • 5-10% ?lower in specialist centres • Causes • Elderly associated co-morbidity and late diagnosis • Young • severe DKA recognised late • a failure to monitor patients and follow guidelines • rare and poorly understood condition of cerebral oedema in children

32. Pathophysiology (1) • lack of insulin and/or rising levels of glucagon, adrenaline, cortisol leads to rising glucose levels from gluconeogenesis • lipolysis raises NEFA and glycerol. Liver oxidises NEFA to form acetyl coA and then ketone bodies • High glucose overcomes capacity of the kidney to reabsorb glucose, glycosuria inhibits water reabsorption and losses of potassium, sodium + other electrolytes • Compensation for urinary losses by drinking maintains circulating blood volume

33. Pathophysiology (2) • Rise in ketones and increasing acidaemia leads to anorexia and vomiting, a critical point • Circulating blood volume falls due to obligatory urinary losses from osmotic effect of urinary glucose • A viscious spiral follows with renal loss of water, electrolytes, increasing glucose and worsening acidosis • Death within hours from severe acidosis and circulatory collapse

34. Principles of DKA managementa potentially lethal condition, treatment should be started with 30 min of admission • Restore circulating blood volume • Replace lost electrolytes • Return blood glucose towards normal while giving sufficient insulin to inhibit hepatic production of ketones Acidosis will correct itself if the above treatment is delivered appropriately

35. Investigations Venous blood for: Urea and electrolytes Blood glucose Full blood count Venous bicarbonate Blood cultures • Consider: Arterial blood gases- only if you suspect hypoxia. Chest X-ray ECG (always do in anyone over 30)

36. EARLY MANAGEMENT • 1. IV Fluids • 1 litre of normal saline over the first hour. If there is hypotension give plasma volume expander (eg, haemaccel or blood) • Rate of fluid administration thereafter depends upon age and fitness of patient. • Typical rates are 1 litre in next 2h, then 1 litre in 4h and 1 litre every 6h from then on. Reduce rates in the elderly or in cardiac disease • Be guided by urine output (>60ml/h) • Rapid IV infusion rates increase the risk of serious complications especially respiratory distress syndrome.

37. Early Management • Potassium Serum potassium is often normal or high initially but total body potassium is low. Add potassium to the IV infusion only when first plasma potassium is known as follows: Serum potassium (mmol/l) Action over 5.5 omit and check in 2h below 5.5 use 40mmol/litre in pre-filled bag

38. Early management • Insulin Add 50 units of Actrapid insulin to 50 ml N saline in a syringe. Infuse intravenously, using a syringe driver and start rate at 6 units an hour. Check venous blood glucose after 2h-if blood glucose has not fallen, check pump is working and IV connections then increase rate to 12u/h.

39. Further management Measure blood glucose hourly Start 10% Glucose 1L 8 hourly once BG ≤ 14 mmol/L; continue sodium chloride 0.9% separately if still volume deplete Typical insulin infusion rate Blood glucose (mmol/l);Infusion rate (units/h) <4 stop pump, check IV fluid 4-7 1 >7-11 2 >11-17 4 >17 6 Target blood glucose is between 11 and 17 mmol/l at 4u/h insulin Insulin levels need to remain high to inhibit ketogenesis

40. Other measures 1.Measure venous glucose, K+. Na+, bicarbonate every 2h for 6h, thereafter frequency depends upon clinical state. 2.Monitor ECG for potassium changes. 3.Consider urinary catheter if no urine passed after 2h 4.Consider n/g tube and aspiration if patient is comatose (only after airway is supported) 5.Give antibiotics only if there is evidence of infection. 6.Give oxygen if arterial pO2 less than 11kPa (80mmHg) 7.Give 10 units of Actrapid insulin IM if there is a delay in starting intravenous insulin.

41. Other points Bicarbonate Generally not helpful and potentially dangerous. Consider only after discussion with senior colleagues  Abdominal pain and tenderness common in DKA and serum amylase often high in the absence of pancreatitis.  White cell counts as high as 30 x 109/L occur in the absence of infection.

42. Hyperosmolar Non-Ketotic Coma (HONK) Definition  Hyperglycaemia (blood glucose is usually over 50 mmol/l)  Hyperosmolality (usually over 350mosmoles/l)  Serum bicarbonate over 20mmol/l

43. Management Similar to DKA but : • Patients are usually elderly, have Type 2 diabetes and have decompensated slowly Mortality is high • Plasma sodium is usually over 150 mmol/l, but normal saline is still the fluid of choice • Give enoxaparin 40mg once daily unless C/I, as dehydration is usually severe and high risk of venous thrombosis 4. Most patients can eventually be managed with sulphonylureas or diet.

44. Final comments The commonest mistakes in treating hyperglycaemic emergencies: • Failure to chase biochemistry and act on the results, particularly K+ • Failure to appreciate its severity (especially in the elderly in whom the mortality rate is over 50%) • Trying to correct the abnormal metabolism too quickly.