Management of T2DM

Question 1

describe the insulin curve and the purpose of management

Answer 1

T2DM can be described as falling off the curve - aim to get one back on

Question 2

what are the ideal treatment aims for T2DM

Answer 2

alleviate hyperglycaemic symptoms and improve glycaemic control

minimise hypoglycaemia

minimise weight gain/cause weight loss

reduce micro and macro vascular complications

Question 3

what benefit has maintaining a lower HbA1c been show to have

Answer 3

reduce risk of microvascular endpoints, MI, cataract extraction, retinopathy and albuminuria

Question 4

HbA1c targets

Answer 4

48 mmol/L in younger patients

53 mmol/L in others

Question 5

what does HbA1c relate to

Answer 5

mean glucose level over past 8 weeks

Question 6

when would one consider less tight HbA1c control

Answer 6

if patient is at risk of hypoglycaemia

eg elderly patients prone to falls

Question 7

what can the failure to reach glycaemic targets be influenced by

Answer 7

youner, female, obese

not at BP or lipid targets

more complex glucose lowering therapies - several drugs

poor adherence to meds and lifestyle

reluctance to intensify treatment

Question 8

outline of T2DM treatment

Answer 8

information

diet and lifestyle

weight target

exercise target

metformin

statin

ACE

review (foot care)

Question 9

what is the foundation of treatment

Answer 9

diet, exercise and education

Question 10

is it better to add on drugs or increase the dose of a drug

Answer 10

far better to add on - efficacy can be decreased at higher dosages

Question 11

SIGN guidelines for pharmacological treatment

Answer 11

metformin

sulphonylurea

TZD (eg Pioglitazone) or DDP-4 or SGLT2

insulin

Question 12

outline the criteria to add on a second drug from metformin

Answer 12

HbA1c ≥53 mmol/L 16 weeks later

Question 13

when is sulphonyurea first line

Answer 13

• intolerance to Metformin or contraindications (renal failure etc)
• patients with osmotic symptoms - quicker onest of action

Question 14

outline the criteria to add a drug on from sulphonylurea

Answer 14

HbA1c ≥57 mmol/L 6 months later

Question 15

what type of drug is Metformin

Answer 15

Biguanide

insulin sensitiser

Question 16

what is Metformin derived from

Answer 16

guanidine

Question 17

describe how Metformin must be started

Answer 17

gradually increased (from around 500mg to 1000mg BD)

otherwise the patient will have diarrhoea and vomiting

Question 18

Metformin mechanism

Answer 18

decrease hepatic gluconeogenesis and increase peripheral glucose uptake

suppress appetite- of particular use in overweight patients

Question 19

is hypoglycaemia a risk in Metformin treatment

Answer 19

not in monotherapy

Question 20

does Metformin have an effect on complications

Answer 20

reduce micro and macro complications

• reduce triglycerides and LDL
• minor reduction in BP

Question 21

what is metformin also used to treat

Answer 21

PCOS and NAFLD

Question 22

is Metformin safe in pregnancy

Answer 22

yes

Question 23

GI adverse effects of Metformin

Answer 23

nausea, vomiting, anorexia, abdominal pain, taste disturbance

up to 25% patients

this is why start low and go slow

Question 24

when should Metformin be avoided

Answer 24

• renal impairement - significant risk of lactic acidosis as adequate renal function is required to excrete Metformin
  
  • do not give if eGFR <30ml/min
• also have caution in patients with pre-existing risk eg acute heart failure, sepsis, acute MI, respiratory failure, hypotension
• temporarily withhold if IV contrast being used eg angiography or CT scan

Question 25

other adverse affects of Metformin

Answer 25

interference with vitamin B12 and folic acid absorption liver failure - discontinue use if there is advanced cirrhosis/liver failure. rash renal toxicity

Question 26

what eGFR values indicate that Metformin should be stopped due to renal toxicity

Answer 26

eGFR \<30 ml/min or serum creatinine \>150 half dose if eGFR 30/45 ml/min

Question 27

what should happen to Metformin dose if IV contrast eg angiography/CT scan being usd

Answer 27

temporarily withheld

Question 28

Sulphonylurea examples

Answer 28

2nd generation - Glicazide, Glibenclamide, Glimeparide

Question 29

patients with which symptoms are recommended a sulphonylurea as first line

Answer 29

those with osmotic symptoms

Question 30

which generation of Sulphonylurea drugs are used

Answer 30

2nd generation

Question 31

Sulphonylurea mechanism of action

Answer 31

Mimic the action of ATP on K_ATP to depolarize ß cells, and stimulate insulin release.

Question 32

does Sulphonylurea prevent complications

Answer 32

only microvascular ones

Question 33

effects of Sulphonylureas

Answer 33

hyperglycaemia management: - redice HbA1c by about 15-20 mmol/L by increasing insulin secretion - reduces glucose more rapidly than insulin sensitisers

Question 34

what decreases glucose levels faster? insulin sensitisers or Sulphonylurea

Answer 34

Sulphonylurea

Question 35

adverse effects of Sulphonylureas

Answer 35

**weight gain** **hypoglycaemia** - take particular care in the frail/elderly, alcohol excess or liver disease GI upset, headache

Question 36

what stage in the path is Sulphonylurea

Answer 36

2nd as an add on to metformin 1st in underweight T2DM / if intolerant to Metformin

Question 37

when should Sulphonylureas be avoided

Answer 37

severe renal or hepatic failure

Question 38

what is the only available TZD

Answer 38

Pioglitazone

Question 39

TZD onset

Answer 39

slow onset, maximum effect is after 1-2 months of treatment

Question 40

TZD mechanism of action

Answer 40

* **PPAR****g****activator**. They are lipophilic so readily enter cells and bind to PPARg, which is a**nuclear receptor**found predominantly in**adipose tissue**, but also skeletal muscle and liver. It is combined with RXR. * PPARg causes differentiation of adipocytes (weight gain), increased lipogenesis and enhances uptake of fatty acids and glucose. It also promotes Sodium ion reabsorption in renal collecting ducts (fluid retention). * TZDs cause PPARg-RXR to bind to DNA, promoting transcription of several genes that are important in insulin signalling.

Question 41

LPL

Answer 41

hydrolyses the breakdown of lipids found in lipoproteins (eg chylomicrons and VLDL) into fatty acids and glycerol LPL deficiency is assoicated with hypertriglyercidaemia

Question 42

effects of TZD

Answer 42

hyperglycaemia managment: reduces bA1c by about 15-20 mmol/L by increasing **insulin sensitivity**

Question 43

adverse effects of TZD

Answer 43

* **Weight gain** is almost inevitable * Due to increased deposition of subcutaneous (not visceral) fat and fluid retention * 1-4kg usually stabilising in 6-12 months * Hypoglycaemia * Usually not if used without a SU * **Heart failure** * Fluid retention results in doubling risk * **Avoid in over 65s** * Doesn’t prevent micro or macro vascular complications * Risk of fracture with chronic use and hepatotoxicity (regular LFTs)

Question 44

do TZDs prevent complications

Answer 44

neither micro nor macro

Question 45

incretin pathway

Answer 45

* group of metabolic hormones that stimulate a decrease in blood glucose levels * are secreted after eating and augment the secretion of insulin from pancreatic ß cells * also inhibit glucagon release from alpha cells of islet of Langerhans * Drugs acting on this are used in combination with metformin/sulphonylurea/pioglitazone in patients who have not achieved adequate glycaemic control with these drugs alone/in combination.

Question 46

incretin hormone life

Answer 46

**very short half life** GIP (from K cells) and GLP-1(from L cells) are rapidly inactivated by the enzyme **DPP4** and then are cleared by the kidney

Question 47

GLP-1 analogues

Answer 47

* Exenatide – BD - subcutaenously * Exendin – once weekly * Liraglutide – OD * Lixisenatide – OD These mimic the action of GLP-1, but are longer lasting

Question 48

benefits of GLP analogues

Answer 48

* Lowers blood glucose after a meal by increasing insulin secretion, suppressing glucagon secretion and slowing gastric emptying * Promote insulin secretion from pancreas **without hypoglycaemia** – increase insulin in a glucosensitive manner * Reduces food intake (by an effect on satiety), hence causing **weight loss**

Question 49

cons of GLP analogues

Answer 49

injectable nausea pancreatitis/pancreatic cancer?

Question 50

DPP4 inhibitors

Answer 50

orally active less potent that GLP these **competitively inhibit DDP4, prolonging the actions of GLP-1 and GLP,**

Question 51

DPP4 inhibitors name

Answer 51

- gliptins

Question 52

DPP4 inhibitors effect on glucose

Answer 52

dont reduce HbA1c that much - useful in the elderly no hypos

Question 53

DPP4 inhibtors effect on weight

Answer 53

neutral

Question 54

do GLP inhibitors or DPP4 inhibitors have a lower incidence of hypos

Answer 54

DPP4 lower incidence - less potent drugs

Question 55

SGLT2 inhibitors name

Answer 55

-agliflozin

Question 56

SGLT2 inhibitors mechanism of action

Answer 56

* Glucose reabsorption occurs in the proximal tubule, normally 100% of glucose is reabsorbed. It crosses the apical membrane by a secondary active transporter (SGLT1 and 2 - Sodium), and then crosses the basolateral membrane down its concentration gradient by facilitated diffusion * 90% through SGLT2 * SGLT2 inhibitors decrease the uptake of glucose by about one quarter, all this comes out in the **urine**.

Question 57

which patients are SGLT2 inhibitors good for

Answer 57

CV risk - reduce CV events, death and hospitalization for heart failure also beneficial for most renal outcomes

Question 59

which drugs have a risk of hypos

Answer 59

sulphonylureas

Question 60

side effects of SGLT2 inhibitors

Answer 60

* These can cause **weight loss**: calorific loss and mild osmotic diuresis * However, loss of glucose in the urine can increase risk of **thrush** and **UTI**.