Diabetes Flashcards
What is Diabetes Mellitus?
Diabetes mellitus is a metabolic disorder that causes hyperglycaemia but also affects the metabolism of fats and proteins. Diabetes leads to the development of long-term complications and associated morbidity.
What is the pathology of T1DM?
Type 1 diabetes mellitus is an autoimmune condition where there is total loss of insulin production from the pancreatic B-cells. Insulin is essential for the treatment of type 1 diabetes.
What is the pathology of T2DM
In type 2 diabetes mellitus the pancreas may be producing greater quantities of insulin but because of insulin resistance the body struggles to use it. In the long-term the pancreas’ ability to produce insulin may wear out.
Treatments are aimed at reducing insulin resistance (e.g. through weight reduction, exercise and with medication such as metformin), increasing insulin production (sulphonylureas) or by providing exogenous insulin by injection.
Type 2 diabetes is a progressive condition whereby good glycaemic control can be lost with time despite treatment which have worked in the past. Treatment of type 2 diabetes focused on reducing cardiovascular risk and improving glycaemic control, and can be either lifestyle changes or lifestyle changes and medication.
What are symptoms of diabetes?
How do these differ between T1DM and T2DM?
Common Symptoms:
* Polyuria (urine amount)
* Polydipsia (thirst)
* Raised glucose levels
* Tiredness
* Slower healing
* Blurred vision
* Genital infections
T1DM:
* Fast onset
* Ketoacidosis - sweet smell in breath
* Unexplained weight-loss
* Low/no insulin concentration
* Younger onset
* First degree relative increases likelihood
T2DM:
* Insulin high (normal), glucose high
* Overweight
* Slow onset
* Elder onset - increased risk with increase age
* Runs in family
What are diagnostic tests for diabetes and results?
Diagnostic test results indicative of diabetes mellitus:
- Fasting venous plasma glucose ≥7mmol/L
- Venous plasma glucose ≥11.1mmol/L two hours after 75g of oral glucose (glucose tolerance test)
- A random blood glucose >11.1mmol/L in someone who is symptomatic
Diagnostic tests can also be diagnosed from glycated haemoglobin (HbA1c) ≥48mmol/L. HbA1c is a measure of blood sugar control over the past 2-3 months. Although it can be used for diagnosis in some circumstances it is not suitable for various groups of patients including those suspected of having type 1 diabetes and in pregnant women where more immediate assessment is indicated). It is not recommended in patients with end-stage chronic kidney disease or HIV.
HbA1c is routinely used in the evaluation of control in patients known to have diabetes. The patient does not need to fast to measure an accurate HbA1c and it can be taken at any time of the day.
What diagnostic tests and results could indicate patients at risk of developing T2DM?
What are complications of diabetes?
Are these micro or macrovascular?
The long-term complications which develop from diabetes are often divided into microvascular (affecting the small blood vessels) and macrovascular (affecting the larger blood vessels) conditions. The complications of diabetes have a huge impact on quality of life and are leading causes of disability and mortality.
What are signs of diabetic ketoacidosis?
DKA develops when your body doesn’t have enough insulin to allow blood sugar into your cells for use as energy.
Signs and symptoms:
- Rapid weight loss
- Feeling sick or being sick
- Stomach pain
- Fast and deep breathing
- Sleepiness
- Sweet smell to breath
- Sweet or metalic taste in mouth
- Different odour to sweat or urine
What are HbA1c targets for diabetes?
* T1DM?
* T2DM (non-hypoglycaemics)
* T2DM (hypoglycaemic)
* T2DM (HbA1c >58mmol/mol)
For type 1 diabetes, an HbA1c is <58mmol/mol is recommended, although NICE guidelines suggest patients should be supported to aim for an HbA1c of 48mmol/mol or lower.
For type 2 diabetes, NICE recommends a target of 48mmol/mol for patients who manage their condition with diet and lifestyle or diet and lifestyle and a single drug that is not associated with hypoglycaemia. The recommended target rises to 53mmol/mol if the single drug is associated with hypoglycaemia. NICE suggests intensifying treatment when the HbA1c is >58mmol/mol and resetting the target HbA1c to 53mmol/mol when multiple drugs are used.
Describe monitoring in diabetes
HbA1C
* Every 3 months until stable. Then 6 monthly there after.
Each patient should be seen at least annually. Monitoring which should be done is:
HbA1c
Urea and electrolytes
Lipids
LFTs
RFTs (eGFR)
Albumin creatinine ratio (ACR) - to detect microalbuminium
Blood pressure
Height, Wt, BMI
Diet
Smoking
Exercise
Erectile dysfunction
Basic feet check
Retinal screening
Monitoring in T2DM Is not routinely reccomended for patients who are managed with lifestyle and/or oral agents (except sulphonylureas).
What Lifestyle advice could be given to patients with diabetes?
- Exercise- moderate-vigourous aerobic exercise 2.5h each week plus muslce strengthening
- Smoking - stop
- Weight - loosing weight to achieve healthy BMI can reduce HbA1c
- Alcohol - in moderation and consider sugar/caloris
Diet:
* Choose low GI carbohydrates
* If over weight reduce portionsizes
* Salt in take less than 6g a day
* Reduce sugar and saturated fat
* Replace refined carbohydrate with wholegrain foods.
* Increasing foods, including veg that are high in fibre.
What are examples of drug classes used in T2DM?
- Bigunites (e.g. metformin)
- Sulphonylureas
- DPP-4 Inhibitors
- SGLT2 inhibitors
- Pioglitazone
- Non-insulin injectables (GLP-1 agonists)
MOA of metformin
Metformin reduces hepatic glucose production, increases insulin sensitivity by improving peripheral glucose uptake and use by the muscles and by delaying intestinal glucose absorption.
Where is Metformin place in treatment for T2DM?
first choice for initial treatment for all patients, due to its positive effect on weight loss, reduced risk of hypoglycaemic events and the additional long-term cardiovascular benefits associated with its use
T or F
Metformin causes hypoglycaemia?
F - alone it does not. Combined with other antidiabetic agents it may.
What is the dosing regimen of metformin (both IR and MR)
Metformin should be given with or after meals. Metformin should be introduced slowly to improve tolerance:
IR:
- 500mg OD in week 1
- 500mg BD in week 2
- 500mg TD in week 3
- 1g BD in week 4 (or slower)
- 500 mg with breakfast for at least 1 week, then 500 mg with breakfast and evening meal for at least 1 week, then 500 mg with breakfast, lunch, and evening meal thereafter; maximum dose 2 g daily (in divided doses).
MR:
- Initially 500 mg once daily, then increased if necessary up to 2 g once daily, dose increased gradually, every 10–15 days, dose to be taken with evening meal.
- Alternatively, dose increased to 1 g twice daily, dose to be taken with meals, alternative dose only to be used if control not achieved with once daily dose regimen. If control is still not achieved, then change to standard-release tablets.
Although metformin is licensed up to a maximum daily dose of 3g daily, the usual maximum is 1g BD as there is little benefit above this dose.
Metformin has a moderate effect on HbA1c and is licensed for use with other antidiabetic medications as dual or triple therapy.
Why is it important to monitor renal function in patients on metformin?
What are the limits for GFR?
- Renal function should be checked before prescribing and at least annually thereafter. Metformin is contraindicated if GFR <30mL/min. The maximum recommended dose is 1g per day if GFR is 30-44mL/min and 2g per day if 45-59mL/min.
- AKI and reduced renal function are amongst the risk factors for lactic acidosis – a rare side effect of metformin.
- Patients taking metformin should be counselled on the sick day rules and provided with the wallet size reminder card.
Why is it important to monitor renal function in patients on metformin?
What are the limits for GFR?
- Renal function should be checked before prescribing and at least annually thereafter. Metformin is contraindicated if GFR <30mL/min. The maximum recommended dose is 1g per day if GFR is 30-44mL/min and 2g per day if 45-59mL/min.
- Avoid if <30mL/min
- AKI and reduced renal function are amongst the risk factors for lactic acidosis – a rare side effect of metformin.
- Patients taking metformin should be counselled on the sick day rules and provided with the wallet size reminder card.
- Determine renal function before treatment and at least annually (at least twice a year in patients with additional risk factors for renal impairment, or if deterioration suspected).
What are common side-effects of metformin?
How can side-effects be minimised?
Common side-effects include nausea, diarrhoea and abdominal pain. These generally improve as treatment continues. Some patients however will need a dose reduction, but where possible treatment should be continued. Slow titration can help minimise GI side-effects.
Metformin has been showed to result in neutral or small weight-loss.
Can also cause vitamin B12 deficency
What are examples of sulphonylureas?
Examples include: gliclazide, glipizide, glimepiride
Where do sulphonylureas fit in the treatment of T2DM?
These are an alternative first-line choice, particularly if there are osmotic symptoms or if the patient is intolerant of, or has CI to metformin.
MOA Sulphonylureas
These stimulate insulin secretion from the pancreatic beta cells and therefore rely on some residual beta cell function.
Side-effects of sulphonylureas
- HYPOGLYCAEMIA
- WEIGHT GAIN (1-5kg) - probably due to increased plasma-insulin concentrations
- abdominal pain, diarrhoea, nausea
Which sulphonylureas are at higher risk of hypoglycaemia?
All SU’s are associated with the risk of hypoglycaemia. Longer acting SU’s (e.g. glibenclamide) have a greater risk than short acting (e.g. gliclazide). Patients should have access to self-blood glucose monitoring and should test at times relevant to driving.
T o F
Sulphonylureas should be reviewed in elderly patients?
The use of SU’s in the frail elderly should be reviewed. Episodes of hypoglycaemia can worsen dementia and confusion and increase the risk of falls and cardiac arrythmias.
Renal impairment and hepatic impairment effects on sulphonylureas
- Hepatic - avoid in severe. Caution in mild to moderate (consider reducing inital dose/maintanince) - risk of hypo
- Renal - Avoid in severe. Caution in mild-mod. Gliclazide can be used in severe impairment as primarily metabolised in liver but care should be taken.
T or F
Gliclizde MR = Gliclizide IR dose
Gliclazide IR and MR are not equipotent (I.e. 80mg IR = 30mg MR).
What are examples of DPP-4 inhibitors
Examples include: alogliptin, sitagliptin, linagliptin
MOA DPP-4 inhibitors
Dipeptidyl peptidase-4 is an enzyme released by the gut to rapidly breakdown the incretin hormone, glucagon like peptide-1 (GLP-1) and glucose dependant insulinotropic polypeptide (GIP).
GLP-1 and GIP levels normally increase in response to food. By inhibiting DPP-4 the gliptins increase the time that GLP-1 and GIP are circulating and enhances their ability to increase insulin production and secretion.
GLP-1 is also responsible for inhibiting glucagon secretion and glucose production in the liver.
Dosing with DPP-4 inhibitors
DPP-4 inhibitors are prescribed as a single dose to be taken once daily. There is no dose titration but many of the gliptins needs to be prescribed at a reduced dose in renal impairment.
Side-effects of DPP-4 inhibitors
The gliptins are fairly well tolerated. The most commonly reported adverse effect with alogliptin therapy was headache.
They may increase the risk of hypoglycaemia when taken in combination with insulin or SU’s which may necessitate a reduction in the insulin or SU’s but are in themselves considered to be a low hypoglycaemic risk option.
Patients should be warned of the symptoms of acute pancreatitis (persistent, severe abdominal pain which may radiate to the back) although the incidence of this is low.
Caution (not-reccomended) in mod-severe HF (little evidence)
True or false
DPP-4 inhibitors cause weight gain?
F - weight neutral
How effective are DPP4-inhibitors?
They have a low to moderate efficacy, typically reducing HbA1c by 0.5%. Treatment with these should only be continued if HbA1c falls by more than 0.5% (5.5 mmol/mol) in 3-6 months.
What are examples of SGLT2 inhibitors?
Dapaglafozin, empaglaflozin, canagliflozin
MOA SGLT inhibitors?
Summarised:
These increase urinary excretoin of glucose. They do not rely on endogenous insulin being present as they work entirely in the kidney to reduce the uptake of glucose from the glomerular filtrate. The amount of glucose lost depends on the blood glucose levels and the glomerular filtration rate.
SGLT’s also reduce the reasorption of Na+, produce diuresis and a small reduction in blood pressure. Seen to have CV benefits.
**
Detailed:**
SGLT2 inhibitors aim to increase urinary glucose excretion to lower glucose levels in diabetic patients.
In a healthy individual, the kidneys are able to filter through approximately 180 grams of glucose per day. All of that glucose is reabsorbed into the bloodstream through two sodium-glucose transporters, SGLT1 and SGLT2.
In healthy subjects, the amount of glucose re-absorbed by SGLT1 and SGLT2 and equal to the amount of glucose filtered by the glomerulus. Hence there will be no glucose in the urine when you are not diabetic.
In diabetic patients, the kidneys become saturated with more glucose than it can reabsorb. At a certain glucose concentration, the glucose flux becomes too high and the glucose transport system, SGLT 1 and SGLT 2, become saturated and cannot reabsorb the glucose back into the bloodstream.
All of the filtered glucose in excess of this threshold is excreted in the urine.
SGLT 2 inhibitors work by blocking the SGLT2 transporter and preventing the reabsorption of glucose, and allowing for more glucose excretion through the urine.
SGLT2 inhibition lowers the maximum re-absorptive capacity of the proximal tubule and lowers the renal threshold for glucose. Therefore, treated subjects will start to renally excrete glucose. The amount of excreted glucose is dependent on the glucose filtration and therefore dependent on the blood glucose values.
Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5,000 times more selective for SGLT2 compared with SGLT1, the major transporter responsible for glucose absorption in the digestive system. This is useful because unlike many current therapies, the mechanism of action of SGLT2 inhibition is independent of insulin secretion or insulin resistance. SGLT2 inhibition removes glucose directly.
It has been shown that there is a significant added benefit to cardiovascular risk reduction when using the SGLT2 inhibitor, Empagliflozin.
How does renal function impact use of SGLT2 inhibitors?
The efficacy of SGLT2s depends on renal function. SGLT2’s should not be initiated if CrCl <60mL/min.
Dose needs to be reduced and may need to be avoided. See individual monographs.
Renal function should be monitored before starting, if new meds which impact RF are started and at least annually.
What are possible side-effects for SLGT2’s?
Lower limb amputation (particularly toes) has been reported.
Hypoglycaemia can occur with SGLT2 inhibitors, but occurs more frequently if co-prescribed with another hypoglycaemic agent.
Vulvovaginitis and genital infections are a common side-effect, as are UTIs.
Fournier’s gangrene is a rare but serious and potentially life-threatening infection.
Diabetic ketoacidosis is also a risk.
What are risk factors for developing DKA while on SGLT2?
Risk factors for developing DKA while on this medicine include: alcohol abuse, little beta cell function, restricted food intake, severe dehydration, sudden reduction in insulin, increased insulin requirement in acute illness and surgery.
Stop SLGT2 if risk of dehydration (sick day rules)
What type of drug is Pioglitazeon?
Pioglitazone is the only thiazolidinedione with a marketing authorisation in the UK.
MOA pioglitazone
Pioglitazone makes cells in the liver, fat and skeletal muscle more sensitive to insulin reducing the glucose in the blood.
What patient group should pioglitazone not be used in?
Do not offer or continue to prescribe in patients with HF (or history of HF), hepatic impairment or ketoacidosis or active bladder cancer.
Side-effects of pioglitazone?
Causes dose-related weight gain (2-3kg in a year) and can cause fluid retention associated with an exacerbation or new onset HF. Oedema may be a higher risk when combined with insulin. Weight should be monitored.
There is a small increase in risk of developing bladder cancer. Those with current or history of bladder cancer should not be used in. Risk factors such as previous radiotherapy to the pelvic area, age and smoking should be considered.
Also, an increased fracture risk- initially higher in women – consider as risk in men and women.
hepatic impairment and pioglitazone
- Avoid in impairment
- Monitor liver function before treatment and periodically thereafter.
- Liver toxicity - Patients should be advised to seek immediate medical attention if symptoms such as nausea, vomiting, abdominal pain, fatigue and dark urine develop.
Examples of GLP-1 agonists
Examples: Exenatide (Byetta) (twice daily) Semaglutide (Ozempic) (weekly) Liraglutide (Victoza, Saxenda) (daily) Lixisenatide (Adlyxin) (daily)
Where are the place of GLP agonists?
GLP-1s are third line option for patients who are not at their HbA1c target and have a BMI >30.
What should be stopped if GLP-1 agonists
DPP-4 inhibitor
MOA GLP-1 agonist
GLP-1 agonists bind to GLP-1 receptors resulting in an increase in insulin secretion, supressing glucagon secretion and slowing gastric emptying. These have high efficiacy.
Where are GLP-1 agonists place in therapy?
GLP-1s are third line option for patients who are not at their HbA1c target and have a BMI >30.
What is the treatment of hypoglycaemia
Hypoglycaemia should be treated quickly by eating fast-acting sugary snack e.g. 4-5 jelly babies, 200mL orange juice or 4-6 glucose tablets. If blood sugars are improving then a medium acting carbohydrate e.g. a piece of toast or the nect meal should be eaten
Guidance for drug choice in those with T2DM.
Consider efficacy, CV benefit, Weight effect, main side-effect, risk of hypoglycaemia
