Diabetes mellitus and Hypoglycaemia

Question 1

Symptoms:

Answer 1

Polyphagia (excessive hunger), polydipsia, polyuria, weight loss, fatigue, blurred vision, poor wound healing

Question 2

Type 1 diabetes occurs because

Answer 2

of a lack of insulin following autoimmune destruction of the pancreatic beta cells.

Question 3

Type 2 diabetes occurs because

Answer 3

of reduced insulin release or resistance to insulin or both.

Question 4

Alcohol can

Answer 4

mask symptoms of hypoglycaemia, so it should be consumed only in moderation and with food.

Question 5

Diagnose type 1 diabetes on

Answer 5

clinical grounds in adults presenting with hyperglycaemia, bearing in mind that people with type 1 diabetes typically (but not always) have one or more of:
• Ketosis, Rapid weight loss, Age of onset below 50 years, BMI below 25 kg/m2, Personal and/or family history of autoimmune disease.
Do not discount a diagnosis of type 1 diabetes if an adult presents with a BMI of >25 kg/m2 or is >50 years

Question 6

HbA1C targets

1) fasting blood glucose conc on waking
2) blood glucose before meals and throughout day
3) blood glucose 90 mins after eating
4) blood glucose when driving

Answer 6

• HbA1C gives an indication of glycaemic control over the past 2-3 months.

A target HbA1C concentration of 48mmol/mol (6.5%) is recommended for patients with type 1 diabetes. Blood-glucose concentration should be monitored atleast 4 times a day: including before each meal and before bed. Patients should aim for:

1. A fasting blood glucose concentration of 5-7mmol/L on waking
2. A blood glucose concentration of 4-7mmol/L before meals and throughout the day
3. A blood glucose concentration of 5-9mmol/L atleast 90 minutes after eating
4. A blood glucose concentration of atleast 5mmol/L when driving.

Question 7

treatment of type 1 diabetes

Answer 7

Insulin

Question 8

Types of insulin

Answer 8

1. Short-acting insulins are used shortly before meals, they include NovoRapid and Humalog
2. Intermediate insulins are usually given twice daily, they include Humulin I, Levemir + Detemir
3. Long-acting insulins are usually given just once daily, they include Lantus
4. Biphasic insulins combine more than one of the above, they include NovoMix30, Humalog Mix25 and Humulin M3.

Question 9

1st line in type 1 diabetes

Answer 9

 1st line in type 1 diabetes: Patients are usually started on a short-acting insulin before meals, PLUS an intermediate or long acting insulin to use once or twice a day (Insulin detemir).
 If this is not practical, they are switched to a biphasic insulin preparation to be used once or twice a day before meal.
 Alternatively, an insulin pump containing short-acting or rapid acting insulin can be used. The pump infuses the insulin into the patient s/c slowly, this provides basal control. When patient is about to eat, they press the button and get bolus dose of soluble insulin as well. NOTE: This is only used for adults who suffer disabling hypoglycaemia or have high HbA1C concentrations. Not in Type 2.

Question 10

Insulin requirements may increase if

Answer 10

the patient is affected by infection, stress, trauma, puberty + pregnancy (2nd + 3rd trimester). In contrast, they may decrease in certain endocrine disorders (e.g. Addison’s disease, hypopituitarism), hepatic impairment and renal impairment, coeliac disease.

Question 11

Insulin should be injected into

Answer 11

• a body area with plenty of SC fat usually the abdomen (fastest absorption rate) or outer thighs/buttocks (slower absorption rate).
• Lipohypertrophy can occur due to repeatedly injecting the same area and can cause erratic absorption of insulin resulting in poor glycaemic control.
• Lipohypertrophy can be minimised by using different injection sites in rotation.

Question 12

Rapid Acting

Answer 12

• Insulin Soluble  Examples: Actrapid, Humulin R, Humulin S, Bovine, Porcine
• Insulin Aspart  Examples: Novorapid
• Insulin Glulisine  Examples: Apidra
• Insulin Lispro  Examples: Humalog KwikPen
• NICE TA151: Continuous SC insulin infusion is recommended as an option in adults + children >12 years with Type 1 Diabetes:
o who suffer repeated or unpredictable hypoglycaemia, whilst attempting to achieve optimar glycaemic control with multiple injection regimens or
o whose glycaemic control remains inadequate (HbA1c over 8.5%  69mmol/mol) despite optimised multiple infection regimens or
o for whom multiple-injection regimens are impractical or inappropriate

Question 13

Intermediate Acting

Answer 13

• Biphasic Isophane Insulin  Examples: Humulin M3, Humulin M3 KwikPen, Hypurin Porcine, Insuman Comb 15/25/50
• Isophane (NPH) Insulin  Examples: Humulin I, Humulin I KwikPen, Hypurin Porcine Isophane, Insulatard. Never give Isophane IV due to thrombosis.

Question 14

Intermediate Acting COMBINED WITH Rapid Acting

Answer 14

• Biphasic Insulin Aspart  Examples: NovoMix 30

* Biphasic Insulin Lispro  Examples: Humalog Mix

Question 15

Long Acting

Answer 15

• Insulin Degludec  Examples: Tresiba
• Insulin Detemir  Examples: Levemir
• Insulin Glargine (Biological med - Must be prescribed by brand name)  Examples: Abasaglar, Lantus, Toujeo
• Insulin Zinc suspension  Examples: Hypurin Bovine Lente
• Protamine Zinc Insulin  Examples: Hypurin Bovine Protamine Zinc. Never give IV due to thrombosis. Protamine causes allergic reactions. Don’t mix with soluble – binds in syringe.

Question 16

Side effects of Insulin:

Answer 16

 Hypoglycaemia  Do not miss meals. Right insulin, Right dose, Right time, Right route.
 Lipodystrophy  rotate injection site (can be administered to buttocks, upper arm, abdomen + thigh)
 Local injection site reactions  check injection technique

Question 17

Insulin Interactions:

Answer 17

 Enhanced hypoglycaemic effect of insulin  ACEi (hyperkalemia +hypoglycaemia linked), B-Blockers (mask symptoms of hypoglycaemia), Alcohol
 Antagonised hypoglycaemic effect of insulin  Corticosteroids, Oral Contraceptives, Loop/Thiazide diuretics

Question 18

Insulin storage

Answer 18

Store insulin in fridge between 2 to 8c
 Once opened store at room temp + use by 28 days
 If left outside fridge at 15-30 c >48h then discard
 If frozen discard

Question 19

Type 2 –> What can help to reduce hyperglycaemia and reduce cardiovascular risk and should be encouraged.

Answer 19

• Weight loss, smoking cessation and regular exercise

Question 20

treatment of Type 2 diabetes

Answer 20

• Oral antidiabetics are used for the treatment of Type 2 diabetes. They should only be started following 3 months of attempted dietary control.

Question 21

Acarbose can cause + avoid … whilst on acarbose

Answer 21

• Acarbose can cause flatulence as a side effect + avoid sucrose as absorption of acarbose is affected

Question 22

Biguanide

Answer 22

• Metformin works by decreasing gluconeogenesis and increasing the body’s use of glucose. It does not stimulate insulin secretion so therefore, when given alone does not cause hypoglycaemia.
• GI side effects are common when initiating therapy, hence dose of standard-release regimens should be increased gradually. MR preparations are offered if standard treatment is not tolerated. It is taken TDS with meals.
• Risk of lactic acidosis (dyspnoea, muscle cramps, abdominal pain, hypothermia or asthenia)

Question 23

Sulfonylurea’s

Answer 23

(e.g. Gliclazide + Tolbutamide are short acting, Glimepiride + Glibenclamide are long acting)
 These work by augmenting insulin release and therefore may cause hypoglycaemia. Gliclazide is taken once daily in the morning, with breakfast. Avoid in pregnancy and breastfeeding (risk of neonatal hypoglycaemia)
 They may cause weight gain due to increased plasma-insulin concentrations so are used for patients who are not overweight or who cannot take metformin. Jaundice may occur.
 Side effects are GI disturbances, hyponatraemia, hypoglycaemia.
 Interactions: Warfarin + ACEi cause increased Hypo. NSAIDS cause reduced renal excretion

Question 24

Thiazolidinediones

Answer 24

(Pioglitazone)
• Pioglitazone reduces peripheral insulin resistance, leading to a reduction of blood glucose concentration.
• MHRA: Cardiovascular safety (increases incidence of heart failure when combined with insulin)
• Risk of bladder cancer: Report haematuria, dysuria and urgency
• Can cause hepatoxicity. Report signs of liver toxicity  nausea, vomiting, abdominal pain, fatigue, dark urine, itching. STOP if jaundice occurs
• However, as it increases appetite it can cause weight gain and is associated with several long-term risks.

Question 25

SGLT2 Inhibitors

Answer 25

 Gliflozins (Canagliflozin, Dapagliflozin, Empagliflozin)
• MHRA: Risk of DKA with above SGLT2
o Inform patients to report  rapid weight loss, nausea or vomiting, abdominal pain, fast + deep breathing, sleepiness, sweet smell to breath, sweet/metallic taste in mouth, different odour to urine or sweat
o Risk factors of DKA  Low B-cell reserve, surgery, alcohol abuse, conditions leading to restricted food intake/severe dehydration, sudden insulin reduction, increased insulin requirements due to acute illness
o Discontinue treatment if DKA suspected or diagnosed
o Stop SGLT2 in patients undergoing major surgery or acute serious illness until patient’s condition stabilised
• MHRA: Risk of lower-limb amputation
o Mainly toes in type 2 diabetic patients taking Canagliflozin. Report skin ulceration, discolouration, new pain. Stay hydrated, preventative foot care, treat foot problems early
• MHRA: Reports of Fournier’s Gangrene
o Necrotising fasciitis of the genitalia or perineum with SGLT2 use
o Inform patients to report  severe pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise - Urogenital infection/perineal abscess may precede necrotising fasciitis

Question 26

SGLT2 Inhibitors SE

Answer 26

• SE: Volume depletion. Report postural hypotension, dizziness. Other SE: Constipation, thirst polyuria, UTIs

Question 27

Dipeptidylpeptidase-4 inhibitors (DPP4I)

Answer 27

 also called gliptins
• Examples include Sitagliptin, Alogliptin and Linagliptin which inhibit the breakdown of incretins (incretins increase insulin secretion + lower glucagon secretion). They do not cause weight gain and have less incidence of hypoglycaemia than sulfonylureas. Discontinue if symptoms of acute pancreatitis occur such as persistent severe abdominal pain.

Question 28

Vildagliptin may cause

Answer 28

• liver toxicity. Stop if N&V, abdominal pain, dark urine, fatigue, pruritus, jaundice

Question 29

Glucagon-like peptide-1 receptor agonist (GLP1-agonist)

Answer 29

 Dulaglutide, Exenatide, Liraglutide.
• They work by augmenting glucose-dependent insulin secretion, supress glucagon secretion + slow gastric emptying. Discontinue if acute pancreatitis occurs (persistent severe abdominal pain). Do not give after meal
• Missed dose: Inject Lixisenatide within 1h of next meal. Continue Exenatide with next schedule dose. Inject Dulaglutide/Albiglutide within 3 days of next weekly dose.
• Use contraception with MR Exenatide (12w after stopping), Lixisenatide, Albiglutide

Question 30

Meglitinides

Answer 30

(Glinides: Nateglinide, Repaglinide)
• Work by stimulating insulin secretion. Rapid onset and short duration of action. Side Effects: Hypersensitivity reactions, rashes, urticaria, pruritius. Nateglinide - GI disturbances. Repaglinide - Visual disturbances

Question 31

Acarbose

Answer 31

• Inhibits intestinal a-glucosidase enzymes + delays digestion/absorption of starch + sucrose
• SE: flatulence, diarrhoea. Reserved for use when other oral hypoglycaemics cannot be taken.

Question 32

First line Treatment of type 2 diabetes

Answer 32

• Metformin monotherapy is first line in ALL patients with type 2 diabetes… it does not stimulate the release of insulin therefore (when used alone) there is a low risk of hypoglycaemia. It does not cause weight gain- therefore choice for overweight patients (if metformin not suitable 1st line, initiate treatment with a DPP4i, Pioglitazone or Sulfonylurea).

Question 33

• Metformin contra-indicated in

Answer 33

general anaesthesia + iodine containing contrast media

Question 34

• If a single agent at the optimal dose is not enough to produce adequate control + HbA1c rises to 58mmol/mol (7.5%). Consider dual therapy  First Intensification:

Answer 34

o	Metformin PLUS 
	Sulfonylurea (Gliclazide)
	Pioglitazone
	DPP4i (Sitagliptin)
	SGLT2 (Canagliflozin - significant risk of hypos)

Question 35

• If HbA1c rises to 58mmol/mol (7.5%). Consider triple therapy  Second Intensification:

Answer 35

o	Metformin PLUS
	DPP4i + sulfonylurea
	Pioglitazone + sulfonylurea
	Sulfonylurea + SGLT2
	Pioglitazone + SGLT2

Question 36

If 1st and 2nd intensification fails then give

Answer 36

• Alternatively, start insulin-based treatment (NPH insulin OD or BD NICE + short acting (soluble) insulin as a biphasic or multiple injection regimen)

Question 37

STOP metformin if

Answer 37

dehydrated (fever, vomiting, diarrhoea) due to increased risk of lactic acidosis

Question 38

Consider stopping gliflozins if

Answer 38

 dehydrated as they cause volume depletion

Question 39

Diabetes, diagnosis and monitoring

Answer 39

Diagnosis  HbA1c Blood test: >48mmol/mol (6.5%) to diagnose type 2 diabetes. Oral glucose tolerance test
 Self-monitoring of blood-glucose concentration is appropriate for patient with type 2 diabetes who are:
o treated with insulin or oral hypoglycaemic drugs e.g. SUs to provide info on hypoglycaemia
o To monitor changes in blood-glucose concentration during activities including driving
 If the patient is unwell + DKA is suspected, blood ketones should be measured ref. to local guidelines

Question 40

Cholesterol Targets in diabetes:

Answer 40

• Normal patients <5mmol/L. - High risk patient e.g. diabetes <4mmol/L

Question 41

Diabetes + Driving

Answer 41

Drivers with diabetes may need to inform the DVLA of their condition depending on various factors, but ALL drivers who are taking Insulin MUST inform the DVLA.

• The DVLA recommends that drivers with diabetes need to be particularly careful to avoid hypoglycaemia and must be aware of warning signs… and what action to take.
• Drivers treated with insulin must carry a glucose meter with blood-glucose strips when driving… and check their blood-glucose concentration 2 hours before driving and every 2 hours while driving.
• Blood-glucose levels should always be above 5mmol/litre while driving. But if blood-glucose falls to 5mmol/litre or below, a snack should be taken (fast-acting carbohydrate).
• If blood glucose <4mmol/L or symptoms of hypoglycaemia appear… do not drive. If driving then stop, eat/drink some sugar and wait until 45 minutes after blood-glucose return to normal, before continuing journey.

Question 42

Diabetic complications  Macrovascular

Answer 42

• CVD

- STATIN as primary prevention in: Type 1 diabetes + Type 2 diabetes with 10y CVD risk score >10%

Question 43

Diabetic complications  Microvascular

Answer 43

(Retinopathy, Nephropathy, Neuropathy)

Question 44

Retinopathy treatment

Answer 44

Treat HTN: protects visual activity

Question 45

1. Nephropathy

Answer 45

• Microalbuminuria is the earliest sign of nephropathy, so patients should have an annual test for urinary protein.
• (provided there are no contraindications) all patients with nephropathy causing proteinuria/microalbuminuria should be treated with an ACE inhibitor or an ARB even if the blood pressure is normal. HTN with complication target BP 130/80mmHG. w/o complications 140/80mmHG
• To minimise the risk of renal deterioration… blood pressure should be carefully controlled.
• Patients with diabetic nephropathy are susceptible to developing hyperkalaemia, so should not be given both an ACEi and ARB.

Question 46

ACEi can potentiate

Answer 46

the hypoglycaemic effect of insulin and PO anti-diabetic drugs particularly when initiating treatment and in those with renal impairment

Question 47

2. Neuropathy

Answer 47

• Paracetamol or an NSAID e.g. Ibuprofen may relieve mild to moderate pain.
• Use Duloxetine for painful diabetic neuropathy, if ineffective or unsuitable give TCA (Amitriptyline)
• If treatment with the above drugs is inadequate, then Pregabalin should be tried.
• Neuropathic pain may respond to opioid analgesics  Tramadol is the drug of choice. Morphine and Oxycodone can only be given under specialist supervision.

Question 48

• Diabetic diarrhoea:

Answer 48

Give Codeine or Tetracycline. Gastroparesis: Erythromycin.

Question 49

Erectile dysfunction

Answer 49

Sildenafil.

Question 50

• Neuropathic postural hypotension:

Answer 50

Fludrocortisone + increased salt intake.

Question 51

3. Ketoacidosis

Answer 51

More commin in Type 1 diabetics. Caused be high glucose low insulin and body needing energy therefore it breakdown fat for energy and the by-
product is ketonic acid (ketones) which makes blood acidic.

This type of hyperglycaemia occurs very quickly (>20mM), ketones irritate the vomiting centre and vomiting will reduce potassium levels. If insulin is given, any potassium remaining in the blood will be taken up into cells worsening hypokalaemia

Question 52

Ketoacidosis management

Answer 52

1. If systolic BP <90 give 500ml of NaCl 0.9% containing KCl IV, over 10-15 minutes. Monitor at 60 minutes
   then every 2 hours until blood pressure is >90; then just give enough NaCl and KCl for maintenance.
2. At the same time start infusion of soluble insulin mixed with the NaCl at a rate of 0.1 units/kg/hour and
   add s.c long acting insulin.
3. Monitor blood ketones and glucose every hour. Ketones should fall by 0.5mmol/L/hour and glucose should
   fall by 3mmol/L/hour. Once glucose falls below 14mmol/L then start glucose 10% at a rate of 125ml/hour
   (into large vein). Continue for 1 hour after ketones are below 0.3mmol/L and blood pH is above 7.3. Then give SC fast-acting insulin and a meal and stop the insulin infusion 1 hour later.

Question 53

Diabetes and surgery - on the day before surgery

Answer 53

• On the day before surgery, the patient’s usual insulin should be given as normal. An exception is ONCE daily long-acting insulin analogues which should be given at a 20% reduced dose.

Question 54

Diabetes and surgery - on the day of the surgery

Answer 54

• On the day of surgery and throughout the intra-operative period, ONCE daily long-acting insulin analogues should be given at a 20% reduced dose. All other insulin should be stopped until the patient is eating and drinking again after surgery.

Question 55

When insulin is required and given during surgery,

Answer 55

• acarbose, meglitinides, sulfonylureas, pioglitazone, DPP4i and SGLT2i should be stopped once the insulin infusion is commenced and not restarted until the patient is eating + drinking normally.

Question 56

What can be taken as normal and what cant.

Answer 56

• Pioglitazone and DPP4i can be taken as normal during the whole peri-operative period. SGLT2i should be omitted on the day of surgery and not restarted until the patient is stable. Their use during periods of dehydration + acute illness is associated with an increased risk of ketoacidosis.
• Sulfonylureas are associated with hypoglycaemia in the fasted state so should be omitted on the day of surgery and not restarted until the patient is eating and drinking again.
• Metformin is renally excreted, renal impairment may lead to accumulation and lactic acidosis during surgery. If only one meal will be missed during surgery and the patient has an eGFR greater than 60mL/minute/1.73m2 and a low risk of AKI, it may possible to continue metformin during the peri-operative period – just the lunchtime dose should be omitted if the usual dose is TDS.
• If the patient will miss more than one meal or there is a significant risk of developing an AKI, Metformin should be stopped when the pre-operative fast begins. Metformin should not be recommenced until the patient is eating and drinking again + normal renal function is confirmed

Question 57

Diabetes, pregnancy and breast-feeding

Answer 57

Diabetes in pregnancy is associated with increased risks to the woman (e.g. pre-eclampsia) and to the developing fetus. Effective blood-glucose control before conception and throughout pregnancy reduces the risk of adverse outcomes e.g. stillbirth, miscarriage and neonatal death.

• Women with pre-existing diabetes planning to become pregnant should aim to keep their HbA1c level below 48mmol/mol (6.5%), which reduces the risk of congenital malformations in the new-born.
• These women should take Folic acid at the dose (5mg daily) for women who are at high-risk of conceiving a child with a neural tube defects.
• All oral antidiabetic drugs should be discontinued before pregnancy… EXCEPT Metformin…. And substituted with Insulin therapy.
• Avoid all anti-diabetic drugs while breast-feeding… EXCEPT Metformin or Glibenclamide post birth.

Question 58

Treatment of diabetes in pregnancy - 1st line

Answer 58

1. Isophane Insulin is the first choice for long-acting insulin during pregnancy. However, in women that have had good blood-glucose control before pregnancy with long-acting insulin analogues (e.g. Detemir/Glargine), it may be appropriate to continue using them during pregnancy.
2. All women treated with Insulin should be aware of the risk of hypoglycaemia and should always carry a fast-acting form of glucose such as dextrose tablets or a glucose-containing drink. Pregnant women with Type 1 diabetes, should also be prescribed glucagon if needed.
3. There is an increased risk of hypoglycaemia in the post-natal period, so the dose of insulin should be reduced immediately after birth.

Question 59

Gestational Diabetes

Answer 59

(woman without diabetes whom develop high blood-sugar levels during pregnancy).
• If the fasting blood glucose is <7mmol/L, firstly change diet and exercise to reduce blood-glucose levels
• If blood-glucose target is not met after 1-2 weeks, then start Metformin (or Insulin if contraindicated)
• If the fasting blood glucose is >7mmol/L, treat with Insulin immediately with/without Metformin
• Discontinue hypoglycaemic treatment immediately after giving birth.

Question 60

If pregnant women do not want insulin and are intolerant to metformin then

Answer 60

Give Glibenclamide (from 11 weeks gestation; after organogenesis)

Question 61

Hypoglycaemia

Answer 61

is a clinical state where the blood glucose levels fall below 3.5mmol/L.

Question 62

Hypoglycaemia - medical emergency treatment

Answer 62

 Initially, 10-20g of oral glucose is given (e.g. as 100mL cola, 2tsp of sugar, 110mL Lucozade). If necessary, this may be repeated after 10-15 minutes. After initial treatment, a sustained carbohydrate (e.g. sandwich, fruit, milk or biscuits) can prevent blood-glucose concentration from falling again.
 Hypoglycaemia which causes unconsciousness is an EMERGENCY. Glucagon increases plasma-glucose concentration by releasing glycogen from the liver. It is given by injection. If not effective after 10 minutes, give I.V. glucose.
 Alternatively, I.V. glucose 20% can be given into a large vein through a large-gauge needle.

Question 63

managing chronic hypoglycaemia

Answer 63

Diazoxide administered by mouth is useful for managing chronic hypoglycaemia only. Monitor BP.

Question 64

KEY WARNING: Sodium-glucose co-transporter 2 inhibitors

Answer 64

(promote excretion of glucose in the urine) e.g. Dapagliflozin
Cautions: correct hypovolaemia (decreased blood volume) before starting treatment.

Question 65

KEY WARNING: Exenatide

Answer 65

(binds to glucagon-like-peptide-1 receptor to increase insulin secretion + slow gastric emptying)
Side effects: severe pancreatitis has been reported rarely, discontinue permanently if diagnosed.
Patient and carer advice on missed doses: if a dose of the immediate release medicine is missed, continue with the next scheduled dose – do not administer after a meal.

Question 66

KEY WARNING: Pioglitazone

Answer 66

(reduces insulin resistance leading to a reduction in blood-glucose concentration)
MHRA: incidence of heart failure is increased when pioglitazone is taken with insulin, especially in patients with predisposing factors. Patients should be closely monitored for signs of heart failure, and treatment stopped if any cardiac deterioration occurs. It should not be used in patients with heart failure or with a history of heart failure.
There is a small increased risk of bladder cancer, but if patients respond adequately (after 3-6 months), the benefit outweighs the risks. It should not be used in patients with active bladder cancer or a history of bladder cancer. It should be used in caution with the elderly as the risk of bladder cancer increases with age. Patients should be advised to report any haematuria, dysuria or urinary urgency during treatment.
Side effects - Liver toxicity: Rare reports of liver dysfunction. Discontinue if jaundice occurs.