LT5 Second line drugs for T2D and obesity Flashcards
What are the established ORAL hypoglycaemic agents?
Sulphonylureas
Incretins
Meglitinides
TZD
Acarbose
What do SU end in?
-ide
What do SU structure have in common?
All sulphonylurea class of drugs contrain a central S-arylsulphonylurea structure with a p-substituent on the phenyl ring and alternative groups terminating the urea N end group
Gives a variety of pharmacological properties
What is the mechanism of action for sulphonylureas?
SUs bind to SUR1 subunit of the K_ATP channel
This binding inhibits K_ATP channel = allowing depolarization of the beta-cell
Causing Ca2+ influx and thus vesicle secretion
SUs mimck the action of ATP
How were sulphonylureas discovered?
People were looking for anti-bacterial drugs
SUs were a derivative but had little anti-bacterial efficacy
Reserachers notived animals that were dosed with them became hypoglycaemic
When will SUs not work?
SUs only work if there are functional beta-cells that can release insulin
They will not work in T1D
How are meglitinides different to sulphonylureas?
They have faster onset and shorter duration of action than SUs because they ahve a weaker binding efficiency and faster dissociation constant
Typically taken just before a meal to control postprandial (after meal) blood glucose spikes
What is the mechanism of action of Meglitinides?
Same mechanism to SUs
Binds to the allosteric site on SUR1 of the K_ATP channel
What are the problems with sulphonylureas?
Not very potent on their own = only small decrease in HbA1c
Cause weight gain (like insulin)
Risk of hypoglycaemia because not glucose-dependent
Only work if beta-cells are functioning (not in T1D)
May enhance beta-cell dailure due to extra strain of chronic insulin production
What are the problems with Meglitinides?
Similar side effects to SUs but seem to cause less weight gain and have lower risk fo hypoglycaemia compared to SUs
Weaker side effects probably due to fast acting response and their rapid degradation
Why would Meglitinides need to be used if they are almost the same as SUs?
Used in patients with allergy to sulphur contianing drugs
Or that have side effects with SUs
What is another name for TZD?
Thiazolidinediones
or Glitazones
What do TZD/glitazones do?
Induce glucose and fatty acid uptake into fat cells
While in obese mice they promoted dramatic glucose lowering
What is the mechanism of action of TZD/glitazones?
TZD bind PPAR-Υ (transcription factor)
Regulates the transcriptio nof may genes involved in lipid and carbohydrate metabolism
Results in increased lipogenesis and glucose uptake in fat, liver and muscle
With some reduction in glucose production in liver
Why is it good that TZD/glitazones cause adipose proliferation?
Helps store nutrients in adipose, instead of elsewhere
Where is PPAR-Y predominantly found?
Adipose
But some expression in liver and muscle
What other mechanism have been propsed for TZD/glitazones?
Activation of AMPK and modulation of mitochondria (like Metformin)
What are the problems with TZD/glitazones?
First TZD ws withdrawn due to heptaotoxicity (LIVER issues)
Often used in combination with SUs so hypoglycaemia risk is increased
Increased incidence of heart failure in chronically treated patients
5% of patients experience oedema
Very EXPENSIVE
Name the two TZD/glitazones being used?
Tosiglitazone is being phased out
Pioglitazone is only one used in UK in new patients
What is Acarbose?
alpha-glucosidase inhibitor
alpha-glucosidase = a membrane-bound enzyme primarily found in the small intestine’s brush border, responsible for breaking down complex carbohydrates (like starch and disaccharides) into simpler sugars like glucose for absorption
Inhibiting this enzyme reduces glucose absorption and postprandial blood sugar spikes, used in the treatment of diabetes.
What is the mechanism of action of Acarbose?
Competitive inhibition of alpha-glucosidase
Stops enzyme form breaking down copmlex carbs = less glucose released
Slows carbohydrate digestion and absorption
What is the problem with Acarbose?
Reduced rate of digestion of polysaccharides in proximal small intesine
Reduced HbA1c very small
No weight alteraitons though!
Frequent GI side effects = increased gas production
3 times a day dosing = after every meal
EXPENSIVE
Is Acabose a good drug?
Minimal health benefits
Major GI side effects
Really only used if patients have serious difficulty in reducing calorie intake
What are the two more recent hypoglycaemia agents?
Incretins (incretin modulating drugs)
SGLT2 inhibitors
Name the two incretins
Gastric inhibitory polypeptide (GIP)
Glucagon-like peptide-1 (GLP-1)
Why are the half-lives of incretins too short for clinical use?
Because these peptides are normally rapidly degraded in blood by DPP4
So used DPP4 inhibitors and more stable GLP-1 peptide mimetics
What are the advantages of incretins?
Beneficial effects on satiety and gastric emptying (not just pancreas targeting)
Only act in the presence of glucose = so lower risk of hypoglycaemia
When is GLP-1 secretion triggered?
When food is ingested GLP-1 is secreted from intestinal L-cells
Where does GLP-1 act in humans?
Beta-cells = enhances glucose-dependent insulin secretion in pancreas
Alpha-cells = suppresses post-prandial glucagon secretion
Liver = reduces HGP
Stomach = slows rate of gatric emptying
Brain = promotes satiety and reduces appetite
Where are the two SGLT found?
SGLT2 is located in segment1 of proximal tubule
SLGT1 is located in distal segment 2/3 of primal tubuil (decending into Loop of Henlee)
What is the mechanism of action of SGLT2 inhibitors?
Glucose pass from bloodstream into nephron
SGLT2 normall reabsorbs glucose from nephron back into bloodstream
Inhibitors block SGLT2 reabsorbing glucose
Glucose is excreted in the urine ad blood glucose decreases
What are the (dis)advantages of SGLT2 inhibitors?
Result in more glucose being excreted in urine (weight control)
Lowers blod glucose = independent of insulin so low risk of hypoglycaemia
Only a few issues of UTI in the clinical trials = good
What are the names of SGLT2 inhibitors?
-flozins
What other systems can SGLT2 inhibitors impact?
More than just glucose transport
Reduced adverse cardiac event end point by 14%
Thi sis unlikely to be due to simple glucose lowering (as metformin does not have same effect with same glucose lower)
Haemodynamic effects = specifically reduced blood pressure and decreased extracellular volume
Potential to benefit kidneys as well
Hearing about this SGLT2 inhibitors beneficial effect on CV death, what did NICE say?
SGLT2 inhibitors can now be considered a first like therapy option if Metformin is contraindicated or cannot be tolerated
BUT increased reptorts of diabetic ketoacidosis in people taking any of currently available SGLT2 inhibitors
What are the last resort drugs?
Insulin because it has such a narrow therapeutic window (only used if oral agents lose efficacy)
Acarbose because it has such bad side effects for so little benefit
What needs future research?
Develop drugs to replace, improve or mimic insulin action
Need to bypass the issue of INSULIN RESISTANCE
What is always consdiere a first option in treatment and prevention of T2D?
LIFESTYLE changes
Why is targeting obesity important for T2D prevention?*** [potential essay question]
How can we prevent/trat obesity-diabetes?
Lifestyle changes = total diet replacement
Psychological therapies = cognitive behavioural therapy (not able to deliver on mass scale bc expensive)
Bariatric surgery = effective but risk (limited to surgeon/theatre availability)
Therapeutic agents to reduce body weight = decrease consumption/absorption of food and/or increase energy expenditure
What do noradrenergics do?
Appetite supressant
Inhibit noradrenaline uptake
CV side effects = short term use
What do serotonergics do?
Appretite supresant
Act on Serotonin uptake and release
Induced heart disease = no longer prescribed in US and UK
What is fen-phen?
Combination of a noradrenergic and a serotonergic appetite supressant
Very effective BUT causes potentialy fatal pulmonary hypertension and heart valve problems
FDA withdrew it in 1997
What do sibutramines do?
Appetite suppresants
Selectively inhibit re-uptake or NorA, serotonin and dopamine
Decreases food intake and may also increase themogenesis
Modest weight loss (4.5kg in 1 year)
Major side effects = cardiovascular events and strokes
Withdrawn
What do Rimonabants do?
Appretite suppresant
Antagonist of CB1 receptors = high levels in the hypothalamus
Useful to counteract obesity and potential effectiveness against addition (smoking, drugs, etc)
Improve short-term memory
Serious psychiatric side effects = severe depresion and anxiety
Withdrawn
What does Lorcaserin do?
Appetite suppressants
Agonist at 5HT2c receptors (serotonergics act on 5HT2b)
Inferior weight loss efficacy compared to Rimoonabant or subutramine
Heart valve problems and increased cancer = withdrawn
What does Qsymia do?
Appretite suppresant
Combination therapy
Weight loss in obese rats = better than sibutramine or rimonabant
Rejected by EMA
What does Contrave do?
Appreitite suppressant
Bupropion = dopamine reuptake inhibitor also activates POMC neurones
Naltrexone = opiod antagonist acts to usppress POMC inhibition
Together = may reduce cravings via reward pathway
CV side effects
What was the first drug for obesity treatment that was aproved?
Liraglutaide = GLP-1 RA
GLP-1 = satiety peptide
Higher doses than used for diabetes produces significant weight loss
2014 = approved by FDA
Mechanism for anti-obesity action unclear
Some concerns remain regarding increased risk of thyroid and pancreatic cancer
What is the name of the dual incretin agonist?
Mounjaro/Tirsepatide
What is GIP responsible for?
Main incretin hormone in HEALTHY people = responsible for most incretin effects
Insulin response after GIP secretion in T2D = strongly REDUCED
So GIP nor as good as diabetes target
Who is Mounjaro (GLP1-RA) given to?
High BMI people with weight-related health problems such as,
Pre diabetes
High bp
High cholesterol
Heart problems
Why is it an issue to give GLP-1 receptor agonists?
This medicine is meant to be used together with a reduced-calorie diet and increase physical actiivity
If they come off the drug and don’t change lifestyle habits = then will just put the weight back on
OR will have to take the drug forever, not being able to enjoy food because of the reduced appetite
What is the target weight loss where health benefits are seen?
Health benefits are seen starting at 5% body weight reduction
What are the current issues with GLP-1 receptor agonists?
They are still very expensive = could bankrupt the NHS
Evidence suggets when stop treatment = weight comes back
Side effects still unclear = evidence of MALNUTRITION if sustained treatment but not proper nutrition
They are injections = self-administraiton is more difficult
What paradox was seen with GIP?
BOTH GIPR agonists and antagonists worked on the receptor to reduce hyperglycaemia, when combined with GLP-1RA = could be T2D treatment
Both enhanced GLP-1 action on glucose control and weight loss
What does Orlistat do?
Inhibits pancreatic lipase = decreases triglyceride absorption
Reduction efficiency of fat adsorption in small intestine
Side effects = cramping, bloating, flatulence, abdominal pain an ddiarrhoea
What do you need to take alongside Orlistat?
Vitamine supplements because losing fat soluble vitamins
Why is Orlistat not really worth it?
Because not very effective over long-term = 3kg in 1 year
And then tend to reboud weight after
What are the 3 type of bariatric surgery?
Adjustable gastric band = band limits food entry to stomach
Roux-en-Y gastric bypass = (accelerates GI transit of food) re-route, bypassing most of stomach an dpart of small intestine
Vertical sleeve gastrectomy = reduces size of stromach (lowering food intake and gastric emptying increases)
Overall effect of bariatric surgery?
Substantial weight loss in 1 year = 50%-60%
Increased satiety and reduced hunger
So very effective against obesity and T2D
Improves glucose homeostasis and insulin sensitivity before wieght loss occurs
What are potential mechanisms happen in bariatric surgery to cause glucose control (happens before weight loss)?
Altered GI physiology
Marked increase in GLP-1 after most surgeries
Pancreatic beta-cell function improves (possibly because of GLP-1)
Changes in adipokine levels
Change on gut microbiota in rodents and human
What is the “thrifty genotype”?
Certain genetic traits were beneficial for survival in ancient human populations have become deterimental in modern society
Specifically genes promoting efficient storage of fat and glucose = helped humans survive during periods of food scarcity
These same genetic traits may predispose individuals to metabolic disorders
What are variants in the FTO gene associated with?
FTO (fat mass and obesity-associated) gene
Genetic variants in the FTO gene have been strongly associated with increased body mass index (BMI) and a higher risk of obesity.
What are adipokines?
Signalling proteins/peptides secretd by adipose tissue
Regulate funciton i nmost major organs = metbolism, satiety and nutrient homeostasis
What are some of the best studied adipokines?
Apelin
RBP4
Leptin
Adiponectin
TNF-a
IL-6
PAI-1
What occurs in obesity to adipokines?
Altered production of adipokines
Higher levels of leptin and leptin resistance in obesity = contributes to hunger pangs
Low levels of adiponectin in obesity = this molecule is anti-diabetic and anti-CVD
What drug was proposed to reverse leptin resistance?
Celastrol
How does Celastrol potentially increase leptin sensitivity?
Celastrol enhances leptin sensitivity in the HYPOTHALAMUS
Inhibits leptin-negative regulators like PTP1B and TCPTP in the hypothalamus
Potentially stimulating fat consumption and reducing ER stress, which is a key factor in leptin resistance
Why does Celastrol have no effect in ob/ob and db/db mice?
Since ob/ob and db/db mice either lack leptin or cannot respond to it, their leptin signaling pathways are dysfunctional.
Celastrol is believed to work, in part, by activating leptin signaling and influencing the hypothalamus to reduce food intake and increase energy expenditure.
It also has anti-inflammatory properties and may modulate other metabolic pathways that help regulate body weight and inflammation.
What is wrong with Celastrol?
Toxicity is still an issue
What is an alternative to calorie restriction?
Targeting energy expenditure
Equation for energy expendiure
Energy expenditure = heat produced + work done
What 3 things cause energy expenditure?
Metabolism = obligatory energy expenditure
Physical activity
Adaptive thermogenesis
Define adaptive thermogenesis
Heat production by organism in response to change in the environmental temperature or diet
Where does adaptive thermogenesis occur?
Brown adipose tissue and skeletal muscle
What induces adaptive thermogenesis?
Cold-induced = shivering (skeletal muscle) or non-shivering (brown fat)
Diet-induced = feeding increases energy expenditure (brown fat)
What is the best described mechanism for adaptive thermogenesis?
In mammals = uncoupled ATP production
VIa uncoupling protein 1 (UCP1)
Why is ATP production not 100% efficient?
Because of proton leak = reduces amount of ATP produced and dissipates free energy as heat (e.g during exercise)
How does uncoupling work in brown adipose tissue (BAT)?
Regulated proton leak in BAT by UCP1 = inner mitochondrial transmembrane protein
Allows proton to re-enter mitochondrial matrix from intermembrane space = short circuit proton gradient
So no generate of ATP
Heat is generated by proton movement and there is increased flux through ETC
What activates UCP1 in brown adipose tissue?
Long chain fatty acids when broken down by beta-oxidation
Cold exposure or overfeeding → sympathetic nervous system activation → norepinephrine release.
This activates β3-adrenergic receptors in brown fat → lipolysis.
Lipolysis releases LCFAs from stored triglycerides, which:
Fuel β-oxidation for electron transport
Activate UCP1 to enable proton leak and heat production
What is the primary function of adaptive thermogenesis in BAT?
Generate body heat in animals or newborns that do not shiver
What happens when BAT and UCP1 are ‘removed’?
Induces obesity primarily because it impairs adaptive thermogenesis, reducing energy expenditure, especially in response to cold, high-fat diets, or overnutrition.
Can uncoupling be a therapeutic target?***
Yes, but DNP was not safe because produced hyperthermia
So perhaps lower DNP dose
Research these 3 drugs for uncoupling???
SkQ compounds
MitoQ
BAM15
