New Treatments for Type 2 diabetes Nandini Seevaratnam April 2016 Rushcliffe Patient Forum
Overview Growing population of Type 2 diabetes Basic science on what goes wrong Current treatments Why there is a need for new treatments
Diabetes in the UK Estimates of diabetes Diagnosed Undiagnosed Around People in the UK have diabetes But have not been diagnosed Almost two in every three People in the UK are Overweight or obese M, million Diabetes UK News (More than 700 people a day diagnosed with diabetes; Friday 04 July 2014); Adapted from Diabetes: Facts and Stats. Version 3. Revised March 2014. Published by Diabetes UK, 2014.
Most common type of diabetes People with type 2 diabetes do not make enough insulin or the insulin they make does not work very well (insulin resistance)
The pathophysiology of type 2 diabetes: pancreatic dysfunction Insulin deficiency Islet Pancreas Alpha cell produces excess glucagon Beta cell produces less insulin Excess glucagon Diminished insulin Liver Diminished insulin High Glucose Muscle and fat Excess glucose output Insulin resistance (decreased glucose uptake)
Type 2 Diabetes Affects 6% of UK population Blood glucose control is only one aspect of care for Type 2 diabetes Good control is linked to a reduction in risk of complications eg heart attacks, kidney, eye and nerve problems Blood glucose control is measured by Hba1c
HbA1c Hba1c - longterm blood sugar control indicator, reflects average blood glucose level in the previous 2-3 months A high level means that blood glucose levels have been consistently high over recent weeks and treatment plan may need to be reviewed Ideal target (48-53 mmol/mol) but needs to be individualised Measured 3-6 monthly
Treatments for Type 2 diabetes Lifestyle diet, weight control and physical activity Tablets Insulin
Diet Healthy balanced diet Low in fat, high in fibre, fruit and vegetables If obese or overweight then losing weight will help to reduce blood glucose levels along with other health benefits VLCD (very low calorie diet)
Educational courses Education programme to adults and carers Diet and exercise Personalised plan to manage diabetes
Tablets Metformin Often first tablet advised Can take a few days to see effect (up to 2 weeks) Taken with food (1 to 3 times a day) Lowers blood glucose by decreasing the amount of glucose that your liver releases into the bloodstream Increases the sensitivity of your body s cells to insulin
Tablets Metformin Lowers risk of complications such as heart attacks or strokes Useful in those who are overweight as it does not cause weight gain Generally does not cause hypoglycaemia
Tablets Metformin Side effects digestive problems (1 in 10) Rare side effect lactic acidosis (1 in 10,000) particularly when dehydrated or prolonged fasting Need to stop when there is a decrease in kidney function Need to stop 3 days before scans eg. CT, MRI
Sulphonyurea eg. Gliclazide Increases the amount of insulin that the pancreas makes Often used if metformin is not tolerated Usually once to twice a day Can cause hypoglycaemia but can be avoided with regular meals/avoid missing meals Must home blood glucose monitor if driving
Hypoglycaemia Low blood sugars Shaky, sweaty, tremors, hungry, nausea and weak If very low brain runs out of fuel and can cause confusion Treat with glucotabs, 4-5 jelly babies followed by biscuits/toast/cereal Glucagon injection
Pioglitazone Lowers blood glucose by making the body more sensitive to insulin Usually used in combination with metformin and/or sulphonyureas Once a day dose Average weight gain 2-3kg over 12 months Should not cause hypoglycaemia
Pioglitazone Side effects Bone fracture 1-10 in every 1000 Cannot use in heart failure due to fluid retention Not to be used in those with a history of bladder cancer
The pathophysiology of type 2 diabetes: pancreatic dysfunction Insulin deficiency Sulphonylureas Insulin Pancreas Liver Excess glucose output Metformin Pioglitazone High Glucose Muscle and fat Insulin resistance (decreased glucose uptake) Metformin Pioglitazone
Effects of Anti-diabetic therapy HbA1c Weight Hypos Metformin / Sulphonylurea Pioglitazone Insulin
Barriers to Treatment Treatments are adding to the problem Weight gain Hypoglycaemia risk and fear leads to increased eating/snacking and poor control Adherence to treatment Difficulty in losing weight 80% overweight Newer treatments aid weight loss/neutral - reduce risk of hypoglycaemia
3 New Therapies GLP-1 peptides eg. Exenatide, Liraglutide, Lixisenatide Gliptins (DPP4 inhibitors) eg. Sitagliptin, Vildagliptin, Linagliptin SGLT2 inhibitors eg. dapagliflozin, canagliflozin, empagliflozin
GLP-1 Effects in Humans GLP-1 secreted upon the ingestion of food Reduces appetite and makes you feel fuller Stops liver from making too much glucose when your body does not need it Signals the pancreas to secrete the right amount of insulin after you eat Slows down how quickly food and glucose leaves the stomach Adapted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes. 1998;47:159-169.
GLP-1 mimetics Similar to hormones produced from the gut which stimulate insulin secretion in response to glucose Slows down stomach emptying encouraging fullness and reduces food intake Leads to modest weight loss Side effects nausea, vomiting, diarrhoea Not to be used in those with a history of pancreatitis or significant bowel surgery
GLP-1 mimetics Injectable therapy - once or twice daily - once weekly Often used with metformin /sulphonyurea / pioglitazone and/or insulin in those who are obese Reduced risk of hypoglycaemia Trial of 6 months need to show benefit in weight loss and improved sugar control to continue treatment
Gliptins (DPP4 inhibitors) DDP4 is an enzyme that breaks down GLP-1 hormone. Works by preventing the breakdown on naturally occurring hormone called GLP-1. GLP-1 helps the body to produce insulin in response to high blood glucose levels By preventing this breakdown help to prevent high blood sugars
Gliptins (DPP4 inhibitors) Increases insulin when blood sugars are high Reduces the amount of sugar made by the liver after you eat Improves fasting and after meal blood sugar No hypoglycaemia Not associated with weight gain
Gliptins (DPP4 inhibitors) Usually taken once a day Most common side effect runny nose, headache Rare acute pancreatitis (1-10 in 1000) Not to be used if a previous history of pancreatitis
SGLT2 inhibitors Increase the amount of glucose in your urine and so reduce blood glucose levels Can help to reduce weight On average 2-3kg over 6-12 months Should not cause hypoglycaemia
SGLT2 inhibitors Taken once a day Side effects increased risk of genital and urinary tract infections (1-10 in100) Low blood pressure Not to be used in >75 years old Not to be used in those on furosemide Rare diabetic ketoacidosis
Insulin Often if tablets not effective in lowering blood glucose levels Injections to lower blood glucose levels Type, dose and frequency varies from individual to individual Often used in conjunction with tablet therapy
Effects of Anti-diabetic therapy HbA1c Weight Hypos Metformin / Sulphonylurea Glitazone Insulin GLP-1 analogue Gliptin SGLT2- inhibitors
Decision Aid What HbA1c target is best for you? What medicine might help to try and achieve this target?
Other treatments Healthy Diet Keep active Stop smoking If any treatment that causes hypoglycaemia should be fingerprick testing for glucose levels with blood glucose meter if driving Anti-BP for high blood pressure Statin to reduce high cholesterol Screening eyes, kidneys and feet
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