Management of Type 2 Diabetes

Management of Type 2 Diabetes

Pathophysiology Insulin resistance and relative insulin deficiency/ defective secretion Not immune mediated No evidence of β cell destruction Increased risk with age, obesity and physical activity Strong genetic predisposition

The pathophysiology of type 2 diabetes Insulin deficiency Islet Excess glucagon Pancreas Alpha cell produces excess glucagon Diminished insulin Beta cell produces less insulin Diminished insulin Hyperglycaemia Muscle and fat Liver Excess glucose output Insulin resistance (decreased glucose uptake)) Adapted from 2. Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427 1483; 3. Buchanan TA Clin Ther 2003;25(suppl B):B32 B46; 4. Powers AC. In: Harrison s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152 2180; 5. Rhodes CJ Science 2005;307:380 384.

Presentation Insidious onset (asymptomatic many yrs) generally not ketosis Tendency to be obese Macrovascular/microvascular complications at presentation Not insulin dependent but may be insulin requiring

Current Treatment Type 2 Diabetes Diet, Lifestyle change and Metformin Metformin Intolerant Add New Therapy Sulphonlyurea Or Poglitazone HbA 1C 7 % On Triple Therapy Insulin Regimens New Therapy

Problems With Existing Therapies Sulphonlyurea Therapy Glitazone Therapy Insulin combinations Weight gain 2.6kg (UKPDS 1998) Weight gain 4.5 kg (obesity review 2007) 43 % Myocardial Infarction (NEJM 2007) Weight Gain 4 kg (UKPDS 1998)

Treatment of Type 2 Diabetes First line Diet and lifestyle changes and Metformin Second line Sulphonlyura Gliptins Glitazone Third line Add on any of above Basal Insulin BD Insulin

Metformin First line drug in all patients regardless of weight Mechanism of action is reduction in hepatic glucose output and increased insulin sensitivity Not associated with hypoglycaemia Start small dose (500mg) and titrate upwards With or after food to reduce side effects Slow release metformin Sulphonlyurea, Glitazone, Gliptins and Insulin can be added to metformin therapy Renal failure

Sulphonlyurea Therapy Add on to Metformin Lowers blood glucose by stimulating insulin release Can induce hypoglycaemia Timing of dose not crucial but consider 30 min before breakfast ( plasma levels) Role of sulphonlyureas in management is changing

Glitazone Therapy New class of drug Decreases glucose output by liver and decreases peripheral insulin resistance Two licensed at present which is restricted Rosiglitazine Pioglitazone Time to effect 8 weeks Contraindicated in liver disease and CCF

Rosiglitazone vs Pioglitazone Recent evidence rosiglitazone is associated with significant increase risk of MI and death from cardiovascular causes No such effect with Pioglitazone Pioglitazone lower risk of deaths from MI, stroke Position statement risk vs benefits

Insulin Secretagogues Post prandial glucose regulators Second line drugs Rapid onset of action and short duration Avoidance of hypoglycaemia Nateglinide or Repaglinide

α Glucosidase Inhibitors Inhibit glucose absorption in small bowel Effective in control of post prandial hypoglycaemia Cause GI upset

GLP-1 effects in humans GLP-1 secreted upon the ingestion of food 5.Brain: promotes satiety and reduces appetite 4,5 2.α-cell: suppresses postprandial glucagon secretion 1 1.β-cell: enhances glucose-dependent insulin secretion in the pancreas 1 3.Liver: reduces hepatic glucose output 2 4.Stomach: slows the rate of gastric emptying 3 Adapted from 1 Nauck MA, et al. Diabetologia 1993;36:741 744; 2 Larsson H, et al. Acta Physiol Scand 1997;160:413 422; 3 Nauck MA, et al. Diabetologia 1996;39:1546 1553; 4 Flint A, et al. J Clin Invest 1998;101:515 520; 5 Zander et al. Lancet 2002;359:824 830.

Incretins and glycaemic control Ingestion of food GI tract Release of incretin gut hormones Active GLP-1 and GIP Pancreas Beta cells Alpha cells Glucose dependent Insulin from beta cells (GLP-1 and GIP) Insulin increases peripheral glucose uptake Blood glucose control DPP-4 enzyme rapidly degrades incretins Glucagon from alpha cells (GLP-1) Glucose dependent Increased insulin and decreased glucagon reduce hepatic glucose output Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153 165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Therapeutic Agents using the GLP-I Pathway GLP-1 receptor agonists Exenatide (naturally occurring but bioengineered) Liraglutide (GLP-1 analogue) DPP-IV Inhibitors Sitagliptin Vidagliptin Saxagliptin

GLP-1 BYETTA was authorised by the European Medicines Evaluation Agency (EMEA) in November 2006 BYETTA is indicated for the treatment of type 2 diabetes mellitus in combination with metformin, and/or sulphonylurea in patients who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies Exenatide Summary of Product Characteristics 2006 Fixed dose, pre-filled pens

Adverse events Results of 30-week exenatide studies Overall incidence 5% and incidence of Exenatide > placebo BYETTA (exenatide) US Prescribing Information, February 2007, data on file. Placebo (N = 483) Exenatide 5 µg and 10 µg BD (N = 963) Nausea 18% 44% Vomiting 4% 13% Diarrhoea 6% 13% Feeling jittery 4% 9% Dizziness 6% 9% Headache 6% 9% Dyspepsia 3% 6%

Sitagliptin (DPP-4 inhibitor) Sitagliptin is an orally administered DPP-4 inhibitor Improvement in glycaemic control is mediated by increasing the levels of active incretin hormones (GLP-1, GIP) leading to Decreased glucagon Increased insulin Sitagliptin improves glycaemic control as monotherapy or add on therapy to metformin or pioglitazone

Adverse Events Hypoglycaemia Sitagliptin and Metformin Uncommon Sitagliptin and Pioglitazone common Nausea Common Abdominal Pain Uncommon Diarrhoea Uncommon Vomiting Uncommon

Diagnosis DIAGNOSIS LIFESTYLE INTERVENTION Life style change ANDand Metformin METFORMIN METFORMIN INTOLERANT HbA1C 7% YES SITAGLIPTIN SULPHONLYUREA Or PIOGLITAZONE And/ Or Add to METFORMIN or Or PIOGLITAZONE Or SULPHONLYUREA HbA1C 7% HbA1C 7% HbA1C 7% Add Add Add BASAL INSULIN PIOGLITAZONE Add Exenatide to Sulphonlyurea and or M etform in Stop SITAGLIPTIN consider triple therapy Or Addition of sulphonlyurea and/or basal insulin Or Intensifed insulin regim en eg basal plus

Summary Type 1 diabetes requires diet and insulin treatment Type 2 requires diet, oral hypoglycaemic agents and or insulin Choice is agent depends on many factors weight, co morbidities and ability to tolerate drug

Male Age 50 Years Presented with symptoms confirmed diagnoses of type 2 diabetes BMs 10-17mmol/l HbA1c 10 % What treatment, if any would you choose? Diet Role of Metformin Role of Glitazone Would you give a sulphonlyurea? Why/why not?

Female Age 56 Years Type 2 diabetes for 10 years HbA1c 9% Diet, metformin and sulphonlyurea BMI 35 Previous MI What options are available to you? How would you proceed? Review diet/ exercise Review treatments

Male Age 35 Years Type 2 Diabetes 3 years BMI 40 HbA1c 10% On sulphonlyurea and pioglitazone HGV License egfr 40 mls/min How would you proceed with this patient? Would you use Metformin??? What are your treatment options?

75 Year Old Man Type 2 diabetes 10 yrs Metformin, sulphonlyurea and exenatide HbA1c 12% Admitted with MI noted to have abnormal liver function How would you manage this patient?