Drugs And Trials Etc

Question 1

Diabetes criteria

Answer 1

> 7mmol/l glucose
11.1mmol/l 2hrs after 75g oral glucose
HbA1c > 6.5%

Gestational diabetes
>5.6mmol/l glucose
>7.8mmol/l 2hrs after 75g OGTT load
Usually occurs in 5% of pregnancies and associated with 7-fold increase in risk of developing Type II

Aim to keep HbA1c under 48mmol/mol in diabetics

Question 2

Metformin

Answer 2

Down gluconeogenesis, up glucose uptake in muscle, up fatty acid oxidation, down lipogensis
Associated with improved CV endpoint as determined by reduced incidence of MI
May cause ketone acidosis
Commonly paired with sulphonylureas or in recent times incretins
Resistance may develop over a few years
Has GI side effects such as irritation, may have effect through microbiota
low risk of hypoglycaemia in T2DM

Question 3

UKPDS

Answer 3

Type 2 trial
Intense therapy induced a HbA1c reduction of around 1% compared to metformin monotherapy
Down 25% in retinopathy, nephropathy and neuropathy
Better CV endpoint
No improvement in QoL survey

Question 4

DCTT Trial

Answer 4

Type 1 trial
Intense anti hyperglycaemic therapy associated with better CV endpoint
Better health
Down 75% retinopathy
Down 50% neuropathy and nephropathy

Question 5

DKA

Answer 5

Diabetic ketoacidosis

Hyperglycaemia, ketonaemia, blood acidosis

Question 6

Type I Diabetes Mellitus

Answer 6

Autoantibodies to GAD67, IA-2 IA-beta, ZN-T8
2-6% heritability
50% of genetic predisposition explained by HLA genes on chromosome 6, encodes MHC class II
Over 40 genes have been associated through GWAS
Glucosuria, thirst, dehydration, weight loss, DKA, ketone breath
Can lead to hypoglycaemic coma
5-10% of diabetes
Treated with insulin

Question 7

Insulin mimietcs for T1DM

Answer 7

Aspart, lispro, glulisine are rapid acting with short half-lives
Glargine and detemir are slow acting and have long half lives
Eg glargine in morning and before bed to maintain basal levels, and lispro after meals to mimic endogenous release times.
NPH is in the middle, medium pace and medium metabolis - often given in combination with a fast acting such as lispro; patients would have in morning and before dinner

Question 8

Sulphonylureas

Answer 8

eg glibenclamide, tolbutamide
Insulin secretagogues (promote insulin secretion)
Block K+ATP channel, causes depolarisation, Ca2+v channel opening and thus insulin vesicle release. Relatively small decrease in HbA1c of about 1-2%.
Causes weight gain as insulin stimulates lipogenesis, whereas metformin does not.
Often used as adjunct to metformin.
Only works if beta-cells are functional and may enhance beta-cell failure due to exacerbated insulin synthesis.
Has risk of hypoglycaemia.
Usually taken orally after a meal.

Question 9

Meglitinides

Answer 9

Same as sulphonylureas, however bind to different site to cause K+ATP closure.
Appear to have lower risk of hypoglycaemia and less weight gain compared to sulphonylureas.

Question 10

Thizolidinediones

Answer 10

Eg pioglitazone, rosaglitazone
PPARy (peroxisome proliferator-activated factor gamma) ligand. Binds to PPARy and regulates transcription of lipogenesis genes, stimulates glucose uptake in fat, liver, muscle.
Has some reduction in hepatic glucose production.
High rate of hepatotoxicity (25% of patients discontinued on this drug).
Increased incidence of cardiovascular events in chronically treated patients has led to it not being used often.
Very expensive, not used as a first line.
Causes weight gain.

Question 11

Acarbose

Answer 11

alpha-glucosidase inhibitor. Reduces the rate of digestion of polysaccharides in proximal small intestine. Reduction of about 0.5-0.5% in HbA1c.
Weight neutral, however, has GI aide effects such as irritation, flatulence, pain, nausea etc.
Required 3 doses daily, with meals.
Small effects in combination with inconvenient side effects mean that it is only really used in patients who have trouble reducing calorific intake.

Question 12

SGLT2 inhibitors

Answer 12

inhibit sodium-glucose co-transporter 2 in the nephron to prevent reuptake of glucose from urine.
Thus reduces blood glucose levels, excretes around 200-300cal a day in glucose urine.
Works independently of insulin and has low risk of hypoglycaemia
Increased risk of UTIs
Significantly reduced cardiovascular events by about 14% - may exert this through haemodynamic effects, specifically reduced blood pressure and decreased extracellular volume.
First-line therapy if metformin contraindicated or cannot be tolerated

Question 13

DPP-4 inhibitors

Answer 13

dipeptidy peptidase-4 inhibitors.
DPP-4 catalyses the rapid breakdown of incretins such as GIP and GLP-1.
Small HbA1c reduction (0.5-1.5%)
Very low risk of hypoglycaemia as incretins only spike in release during feeding to enhance insulin release, therefore only enhanced insulin release in the presence of food.

Question 14

Insulin for T2DM

Answer 14

Only if all oral agents lose efficacy, absolute last option.

Question 15

Extreme lifestyle modification in T2DM

Answer 15

clinical trial of 600cal/day diet caused remission in 7/10 patients with T2DM

Question 16

Exercise

Answer 16

Simulates AMPK to enhance GLUT4 translocation and thus increase glucose uptake in muscle.
Is not insulin dependant! can always work!

Question 17

Incretins

Answer 17

e.g. exendin-4 from glia monster, GLP-1R agonist
Mimetics of endogenous peptides. Act on specific beta-cell receptors to increase only glucose-dependant insulin release - near no hypoglycaemia risk.
Suppress postprandial glucagon secretion also
Down in gluconeogenesis, slows gastric emptying, promotes satiety - likely through action in hypothalamus.

Question 18

CAMERA trial

Answer 18

In patients receiving metformin had 25% higher GLP-1 levels vs placebo