Diabetes medication Flashcards
1
Q
What are the main types of diabetes medication?
A
- Metformin
- Sulphonylureas
- Thiazolidinedione
- Incretin drugs
- SGLT2 inhibitors
- Insulin
2
Q
What is the first line medication used in treatment of T2DM?
A
Metformin
3
Q
Describe the history of metformin
A
The French lilac (Goat’s root) was found to contain substances known as guanidine and biguanides
This was shown to have therapeutic affects in diabetes management
Dimethylbiguanide was then synthesised in 1922, which became metformin
4
Q
What is the proposed mechanism of action of metformin?
A
- Inhibition of complex-1 of mitochondrial oxidative phosphorylation
- Fall in cellular ATP
- Activation of AMP kinase
- Reduction in gluconeogenesis
- Reduction of BGC
5
Q
How is metformin absorbed?
A
Organic cation transporters present in the intestines, liver and kidneys
6
Q
How is metformin excreted?
A
Kidneys
7
Q
What are some of the effects metformin has?
A
Increased GLP-1 secretion
Reduced gluconeogenesis
Reduced lipogenesis
Reduced inflammation
Suppression of macrophage formation
8
Q
How does metformin affect weight?
A
It is weight neutral, and in some cases can be weight decreasing, making it desirable alongside lifestyle changes
9
Q
How does metformin affect the cardiovascular system?
A
It may provide some cardiovascular benefit
10
Q
What is the normal dose of metformin?
A
500mg BD, with a maximum dose of 2g per day
11
Q
What are some side effects of of metformin?
A
- Diarrhoea
- Bloating
- Abdominal pain
- Dyspepsia
- Metallic taste in mouth
12
Q
Why does metformin cause GI upset?
A
It is highly concentrated in the intestines and is a metabolic poison
13
Q
What are ways in which metformin side effects can be minimised?
A
Build up dose
Use MR formulation
14
Q
What is a possible complication of metformin use in acute kidney injury?
A
Metformin associated lactic acidosis (MALA)
15
Q
How does metformin cause MALA?
A
Metformin increases lactate production which is normally cleared by the liver and kidneys
In acute kidney injury, sepsis or impaired liver clearance, lactate can build up, causing lactic acidosis
16
Q
At what eGFR is metformin contraindicated?
A
<30ml/min
17
Q
At what eGFR should maximum daily dose of metformin be dropped to 1g?
A
30-45ml/min
18
Q
What drug is most commonly used as 2nd line in T2DM?
A
Sulfonylureas
19
Q
Describe the history of sulfonylureas
A
These were discovered in the 1940s by French doctors treating war victims with sulphonamide antibiotics, which were shown to lower blood glucose
20
Q
What are some examples of 1st generation sulphonylureas (Rarely used)?
A
- Tolbutamide
- Chlorpropamide
21
Q
What are some examples of 2nd generation sulphonylureas?
A
- Gliclazide
- Glipizide
- Glimepiride
- Glibenclamide
22
Q
Describe the structure of the K-ATP channels in the ß-cells
A
Contains 4x Kir6.2 subunits surrounded by 4x SUR1 subunits
23
Q
Describe the MOA of sulfonylureas
A
- Bind to SUR1 of K-ATP channels in ß-cells
- Close K-ATP channels
- Cell depolarisation without ATP need
- Insulin release
24
Q
What is the normal dosing of sulfonylureas?
A
40-80mg OD
25
How do sulfonylureas affect weight?
Cause weight gain - increase anabolism from insulin, which causes increase in carbohydrate storage and increase in hunger
26
What is a possible complication of sulfonylureas?
Hypoglycaemia
27
What are some factors that increase risk of hypoglycaemia in sulphonylurea usage?
- Increased age
- Diabetes duration
- Creatinine
- Lower HbA1c
28
How do sulphonylureas affect the cardiovascular system?
No affect (Some theory that they do but not proven)
29
What is the MOA of thiazolidinedione?
1. Bind to PPAR-gamma ligands
2. Activates PPAR-gamma genes
3. Provides both beneficial and adverse effects, commonly in the liver epithelium and adipose tissue
30
What is the effect of thiazolidinediones on adipose tissue?
1. Increased differentiation of pre-adipocytes to adipocytes to increase storage of free fatty acids, removing fats from the liver and muscle, therefore decreasing lipo-toxicity in these structures
2. Increased release of adiponectin, which activates AMP Kinase in the liver, therefore decreasing gluconeogenesis and lipogenesis
31
How do thiazolidinediones affect the cardiovascular system?
Decreased CVD risk
Decreased BP
32
How do thiazolidinediones affect weight?
Cause weight gain - Increased fat mass and fluid retention
33
What is the only available TZD?
Pioglitazone
34
What is the normal dose of pioglitazone?
15-30mg daily
35
What are some side effects of TZDs?
Weight gain
Fluid retention
Fracture risk
36
What causes fracture risk in TZD usage?
Fat accumulation in the bone marrow leads to reduced bone density
37
How were incretins discovered?
The oral glucose tolerance test is a test performed to test glucose levels and insulin levels, in which glucose is taken orally
Glucose levels in the body should rise slowly and then fall again, as will insulin levels
A week later, IV glucose is given at the exact same rate as glucose levels rose and fell in the body during the first test
It has been noticed that in this 2nd scenario, insulin levels do rise and fall, but to a much lower maximum level
This means there must be something changing between glucose taken orally and intravenously
This is known as the incretin response
38
How does diabetes affect the incretin response?
It impairs it
39
What does incretin stand for?
“Intestinal secretion of insulin”
40
What is the incretin response?
When glucose is absorbed in the intestines, incretins are also released which stimulates increased insulin production
41
What are the 2 main incretin hormones?
GIP
GLP-1
42
What cells produce GIP?
K cells
43
What cells produce GLP-1?
L cells
44
What breaks down incretins?
DPP4 (Dipeptidyl peptidase 4)
45
How do incretins increase insulin production?
1. Bind to recetors on ß-cell
2. Stimulate intra-cellular cAMP rise
3. Increases levels of secreted insulin, as long as the normal ATP pathway is stimulated
46
What are some other effects of incretins on the body?
Decreased glucagon secretion (Increased in T2)
Appetite suppression
Delayed gastric emptying
Increased heart rate
47
What are the 2 types of drugs that affect the incretin system?
DPP4 inhibitors
GLP-1 receptor agonists
GLP-1/GIP recepor agonists
48
How do DPP4 inhibitors (Gliptins) work?
They inactivate the peptides on DPP4, therefore increasing and prolonging the incretin effect
49
How do DPP4 inhibitors affect weight?
Weight neutral
50
What are some examples of DPP4 inhibitors?
- Sitagliptin
- Alogliptin
- Saxagliptin
51
What is the normal dose of sitagliptin?
100mg OD
52
What are some possible complications of DPP4 inhibitors?
- Increased risk of pancreatitis
- Increased of heart failure hospitalisation
53
Describe the history of GLP-1 receptor agonists
Gila monsters are able to regulate glucose despite long periods of fasting and high sugar intake
It was found that their saliva contains exendin-4, a GLP-1 receptor agonist
54
How do GLP-1 receptor agonists work?
They act as a GLP-1 molecule in up-regulating insulin production
They are also modified to avoid breakdown by DPP4 so can remain in the blood for longer periods of time
55
What are some of the effects of GLP-1 receptor agonists?
Increased insulin production
Lower glucagon
Reduce appetite in hypothalamus
Delay gastric emptying
56
What are some examples of GLP-1 receptor agonists?
- Liraglutide
- Semaglutide (Ozempic)
57
How is semaglutide given?
once weekly injection (1mg) or as a daily oral tablet
58
How do GLP-1 receptor agonists affect weight?
Cause weight loss
59
How do GLP-1 receptor agonists affect the cardiovascular system?
Reduced BP
Increased HR
Reduced cardiovascular mortality
Reduced heart failure hospitalisation
60
What are some side effects of GLP-1 receptor agonists?
- Nausea and vomiting
- Gallstone risk
- Possible pancreatitis
Nausea and vomiting may often improve after 6 weeks but if patients cannot tolerate it, it may need to be stopped
61
How can semaglutide be used outwith diabetes?
Semaglutide can work in people without diabetes, especially in high dose, for weight loss
Semaglutide in high dose can now be given under the brand name Wegovy for those who are overweight and are possibly pre-diabetic
62
What is an example of a dual GLP-1/GIP receptor agonist?
Tirzepatide (Mounjaro)
63
What is the effect of tirzepatide?
It is far superior to semaglutide at lowering both HbA1c and weight (11% loss)
64
What are the 2 channels that allow for full re-absorption of glucose by the kidneys?
SGLT1 & 2
65
What is the word for glucose in the urine?
Glycosuria
66
What causes glycosuria in diabetes?
Increased BGC means more glucose is filtered into the kidneys
This exceeds the threshold that SGLT channels can re-absorb, meaning that some is left over to be excreted
67
Describe the history of SGLT2 inhibitors
Phlorizin is extracted from the bark of apple trees, which causes glycosuria and weight loss
Phlorizin was found to inhibit both SGLT1 and 2
Phlorizin is non-specific, and because SGLT1 is found in the gut as well for glucose absorption, so if SGLT1 is also inhibited, an osmotic diarrhoea and malabsorption of glucose will occur
SGLT2 specific inhibitors were then created from this
68
Describe the MOA of SGLT2 inhibitors
1. Inhibition of SGLT2 channels
2. Reduced uptake of glucose from the renal tubules by 25%
3. Decreased blood glucose concentration and reduced calories resulting in weight loss
69
What are some direct effects of SGLT2 inhibition on the body?
1. Osmotic diuresis (Increased urine output due to high glucose levels) and reduction of Na reabsorption can result in reduction of heart failure risk
2. Increased urate excretion is increased so there is a reduction in plasma urate concentrations
3. Increased Na+ deliver to DCT causes increased Na+ uptake at the macula densa, causing an increase in adenosine secretion, therefore causing a reduction in renal afferent vasodilation, so there is a reduced filtration pressure and thus protecting the kidneys
70
What are some indirect effects of SGLT2 inhibitors on the body?
1. Reduced glucose means raised insulin and increased glucagon
2. Raised insulin means increase of lipolysis
3. Increased lipolysis means increased ketone body production
4. This provides a fuel for cardiac myocyte contraction, providing cardiac benefit
5. This can however increase risk of ketosis and ketoacidosis
71
What are some effects of SGLT2 inhibitors on the cardiovascular system?
Decreased blood pressure
Increased LDL and HDL
38% reduction in death from CVD
72
Who are SGLT2 inhibitors less effective in?
Those with reduced eGFR such as in kidney disease, as they rely on excretion of glucose
73
What are some examples of SGLT2 inhibitors?
- Dapagliflozin
- Canagliflozin
- Empagliflozin
74
What are some possible side effects on SGLT2 inhibitors?
- Genetic mycotic infection (thrush)
- Fournier gangrene (Rare)
- Hypovolaemia and hypotension
- Euglycaemic ketoacidosis
75
How do SGLT2 inhibitors increase risk of thrush?
Glycolysis means more sugar passing through the area, providing energy for mycotic growth
76
What is Fournier gangrene?
A forminent necrotic infection of the perineum
77
What is euglycaemic ketoacidosis?
Diabetic ketoacidosis occurring despite normal glucose, caused by increased ketone body production
This is why SGLT2 inhibitors should be omitted in prolonged fasting
78
T2 diabetic patient
High risk of atherosclerotic CVD
What drug?
Metformin 1st line
Then
GLP-1 or SGLT2
79
T2 diabetic patient
High risk of heart failure
What drug?
Metformin 1st line
Then
SGLT2
80
T2 diabetic patient
No risk of atherosclerotic CVD
Compelling need to minimise hypoglycaemia
What drugs?
Metformin 1st line
Then
DPP1 or GLP-1 or SGLT2 or TZD
81
T2 diabetic patient
No risk of atherosclerotic CVD
Compelling need to promote weight loss
What drug?
Metformin 1st line
Then
GLP-1 or SGLT2
82
T2 diabetic patient
No risk of atherosclerotic CVD
Cost is a major risk
What drug?
Metformin 1st line
Then
Sulphonylurea or TZD
83
