Endocrine JC034: Deterioration Of Eyesight In A Diabetic Patient: Diabetic Complications

Question 1

Ocular complications of DM

Answer 1

1. Lacrimal system: ↓ Tear production
2. Extraocular muscles: ***Mononeuritis multiplex —> CN3, 4, 6 palsies —> Diplopia
3. Refraction: Fluctuating refractive errors (∵ fluctuating glucose level within lens, solved when glucose level settled)
4. Glaucoma: ↑ Incidence in DM
5. Iris: ***Neovascular glaucoma (∵ new blood vessels in iris —> impairment of flow of aqueous humour)
6. Lens: ***Cataract (early development)
7. Retina: ***Diabetic retinopathy / papillopathy (ischaemia of optic nerve)
8. Others: ↑ Eye infections, ↑ Inflammation after ocular operations

Question 2

Diabetic retinopathy (DR)

Answer 2

If Maculopathy —> Impaired vision

Non-proliferative:
- Microaneurysm
- Dot + Blot haemorrhages
- Exudates: Soft / Hard
- Macular edema

Proliferative:
- Neovascularistion —> Retinal haemorrhage, **Vitreous haemorrhage, **Neovascular glaucoma
- Fibrous proliferation —> ***Tractional retinal detachment

Question 3

Complications

Answer 3

Abnormal angiogenesis (neovascularisation) —> **Retinal haemorrhage, Vitreous haemorrhage, **Neovascular glaucoma

Abnormal fibrous proliferation —> ***Tractional retinal detachment —> sudden vision loss (like a curtain coming down)

Question 4

Treatment

Answer 4

Prevention always the best cure
- diabetic retinopathy can be prevented if blood glucose level well controlled + other risk factors controlled (e.g. HT)

1. Proliferative diabetic retinopathy
   - New blood vessel: **Panretinal photocoagulation (Laser therapy), Cryotherapy, **Anti-VEGF monoclonal Ab (Bevacizumab)
   - Vitreous haemorrhage / Retinal detachment: Vitrectomy + Laser therapy to readhere retina
2. Clinically significant macular edema
   - Focal / Grid laser
   - ***Anti-VEGF monoclonal Ab (very effective, ↑ in use)

Question 5

***Microvascular + Macrovascular complications

Answer 5

DM associated with ↑ mortality / morbidity due to Micro/Macrovascular complications

Microvascular (Small vessel disease)
1. Retinopathy

2. Nephropathy (***Glomerulosclerosis)
   —> Microalbuminuria (<0.5g protein, <0.3g albumin)
   —> Albuminuria (significant proteinuria)
   —> ↑ Serum creatinine
   —> End-stage renal failure
3. Neuropathy
   - Peripheral
   - Autonomic
   - Acute mononeuropathy (Mononeuritis multiplex)
   - Motor
   - ***Diabetic amyotrophy (acute / subacute)

Macrovascular (Large vessel disease): ***Acelerated atherosclerosis
1. Stroke (CVA)
2. Coronary artery disease (IHD)
3. Peripheral artery disease

Question 6

Diabetic Nephropathy

Answer 6

Clinical features:
1. **Proteinuria
2. Nephrotic edema (ankle edema)
3. Nephrotic syndrome
4. **Hypertension
5. ***Renal failure

Natural history and progression of Diabetic nephropathy (From GIS + MSS + HNS + HIS + ERS PBL)
First changes
- **Microalbuminuria
- **Glomerular BM thickening —> Microangiopathy
- Accumulation of matrix material in mesangium

Subsequent changes
- **Heavy proteinuria
- Nodular deposits
- **Glomerulosclerosis

Pathogenesis:
1. Chronic hyperglycaemia
—> ***↑ Mesangial Cell matrix production + apoptosis —> Mesangial cell expansion + injury

2. Glomerular hypertrophy (↑ Renal size)
   —> ↑ shear stress on glomerular capillary wall
3. Glomerular hyperfiltration (↑ GFR)
   —> dilatation of afferent arteriole by ***AGEs, Sorbitol, IGF-1
   —> ↑ Renal blood flow
   —> ↑ Intra-glomerular pressure (Intra-glomerular hypertension)
4. Glomerulosclerosis
   —> ∵ Intra-glomerular hypertension
   —> ∵ Hyaline narrowing of vessels supplying the glomeruli (Hyaline deposition induced by ischaemic injury)

Histology:
1. Diabetic **Glomerulosclerosis —> ECM deposition in glomeruli
2. **Mesangial expansion
3. **GBM thickening
4. **Arteriolar Hyalinosis / Arteriolosclerosis

Consequence:
Microalbuminuria

Management:
1. Protein restriction (controversial KCB Tan)
2. **Antihypertensive
3. **Glycaemic control

Question 7

Diabetic Neuropathy

Answer 7

Chronic Diabetic Neuropathy:
1. **Sensory disturbance
- **Glove and sock sensory peripheral neuropathy

2. **Motor disturbance
   - **Peripheral weakness, less common
3. **Autonomic disturbance
   - **Bladder dysfunction
   - Postural hypotension
   - Erectile dysfunction

Acute (**Diabetic Mononeuropathy):
1. CN3 palsy
- Ptosis + Divergent squint with **sparing of pupil (medical CN3 palsy)

2. CN6 palsy
   - Lateral rectus palsy —> Diplopia when looking laterally
3. Common peroneal nerve palsy
   - Foot drop
4. Upper facial + eye pain

***Diabetic amyotrophy (acute / subacute):
- Weakness and pain over proximal muscles of Pectoral girdle / Pelvic girdle

Question 8

Macrovascular diabetic complications

Answer 8

1. Stroke (Cerebral thrombosis)
   - Ischaemic stroke
2. MI / Angina
3. Peripheral vascular disease
   - Intermittent claudication

Question 9

Diabetic gangrene

Answer 9

Causes:
1. Peripheral sensory neuropathy
2. Peripheral vascular disease
3. Poor glycaemic control —> impaired healing

Question 10

Pathogenesis of Chronic Diabetic Complications

Answer 10

**Prolonged hyperglycaemia + Genetic predisposition + **Accelerating factors (HT, smoking, hyperlipidaemia etc.)
—> Chronic diabetic complications

Question 11

Treatment of Chronic complications

Answer 11

1. Prevention
   - Good glycaemic control
2. Insipient (Subclinical) stage: ***Reversible (e.g. microalbuminuria)
   - Improve glycaemic control
   - Treat other risk factors: BP, smoking
   - Pharmacological intervention:
   —> ACE-I
   —> ARB
   —> SGLT2 inhibitors (e.g. Dapagliflozin), some GLP-1 receptor agonists (Incretin mimetics e.g. Exenatide, Liraglutide)
3. Overt (Clinical) stage (e.g. albuminuria, moderately severe retinopathy, clinical neuropathy) —> **Retard (but cannot reverse) progression
   - General: ↑ Glycaemic control, Risk factor management (HT, HL, smoking)
   - Specific (e.g. Nephropathy): ACE-1, ARB, SGLT2 inhibitors, some GLP-1 receptor agonists
   - Symptomatic: **Dialysis / Transplantation (e.g. End stage renal failure), **Pain relief (e.g. Painful neuropathy by Gabapentin)
   - Prevention of drastic consequences: **Laser therapy (for severe retinopathy), ***Foot care (for severe neuropathy + PVD: ↓ risk of amputation)

Question 12

Glycaemic control

Answer 12

1. Lifestyle measures (ALL diabetic patients)
   - diet
   - exercise
   - optimise body weight
2. Lifestyle measures + Oral hypoglycaemic agents (Type 2 DM)
3. Lifestyle measure + Insulin (Type 1 + Type 2 DM)

Question 13

Dietary management

Answer 13

Integral part of therapy for ALL patients with DM

General guidelines:
- **30 kcal/kg ideal body weight per day (adjustments depending on lifestyle, body weight)
- Aim at achieving normal body weight, supplying enough calories for physical activities / growth
- Composition:
—> **40-50% Carbohydrates (↓ in overweight)
—> **30% Fat (<7% saturated fat)
—> **20-30% Protein
—> Fibre intake ***20-35g / day

Dietary advice:
1. Personalised according to individual preference and culture
2. **Consistency of meal timings + quantity (esp. if requiring insulin) —> prevent hypoglycaemia
3. Healthy foods consistent with prevailing population-wide dietary recommendations
4. Emphasise on **high fibre food (vegetables, fruits, wholegrains, legumes), **low-fat dairy products, fresh fish
5. Minimise high energy foods (high saturated fats, sweet desserts, snacks)
6. **Hypocaloric diet for obese type 2 DM

Question 14

***Major targeted sites of Oral drugs classes

Answer 14

兩組兩組咁記:

1. Sulfonylureas (Glipizide, Glimepiride)
   - Pancreatic β cells
   - ↑ insulin secretion
   - Weight gain, Hypoglycaemia
2. Meglitinide analogs (Repaglinide, Nateglinide)
   - Pancreatic β cells
   - ↑ insulin secretion
   - Weight gain, Hypoglycaemia (rare compared to SU)
3. Incretin mimetics (GLP analogs / agonists) (Exenatide, Liraglutide)
   - Pancreatic α + β cells
   - ↑ Insulin secretion + ↓ Glucagon secretion
   - ***Weight loss
   - GI disorder, dizziness, headache
4. DPP-4 (Dipeptidyl peptidase-4) inhibitors (Sitagliptin, Vidagliptin)
   - Gut, Pancreas
   - ↑ GLP-1 levels by inhibiting DPP4
   (- also ↓ Glucagon)
   - URT infections, sore throat, diarrhoea
5. Biguanides (Metformin)
   - Liver, Adipose tissue, Muscle, GI
   - ↓ Hepatic Glucose production —> ↓ Hyperglycaemia
   - ↓ Fatty acid synthesis, ↑ Fatty acid oxidation —> ↓ Hyperlipidaemia
   (- ↓ Insulin resistance in Adipose tissue, Muscle)
   (- ↓ Glucose absorption in GI)
   - ***Lactic acidosis, GI disturbance, B12 deficiency
6. Thiazolidinedione (Rosiglitazone, Pioglitazone)
   - Adipose tissue, Muscle, Liver
   - Bind to PPARγ to ↓ Insulin resistance + ↑ Fatty acid uptake + Anti-inflammatory
   - Weight gain, fluid retention, ***CVS risk
7. α-Glucosidase inhibitors (Acarbose, Miglitol)
   - Gut
   - ↓ Glucose absorption
   - Flatulence, diarrhoea, abdominal cramping
8. SGLT2 inhibitors (Dapagliflozin, Canagliflozin)
   - Kidney
   - ↑ Glucose excretion by inhibit glucose reabsorption
   - ***Weight loss
   - UTI

Question 15

Incretins

Answer 15

• Gut hormones GLP-1, GIP
• released from gut cells
• physiologically regulate Insulin / Glucagon in a glucose-dependent manner

Ingestion of food
—> GI tract
—> Release of Incretin Gut Hormones into bloodstream (Active GLP-1, GIP) (inactivated by DPP-4)
—> ***Pancreatic β + α cells

GLP-1, GIP:
β cells: ↑ Insulin secretion (glucose-dependent)
—> ↑ Glucose uptake + storage by muscles / other tissues

GLP-1:
α cells: ↓ Glucagon (glucose-dependent)
—> ↓ Glucose output from liver

Incretin effect is diminished in Type 2 DM: ***GIP effect on β cells diminished

Question 16

Incretin-based Antidiabetic therapy

Answer 16

Glucose-dependent stimulation of post-prandial insulin release + glucagon suppression: ***No hypoglycaemia if monotherapy

GLP-1 receptor agonist (GLP-1 RA) (**-Tides):
- GLP-1 analogue (resistant to DPP-4, longer t1/2)
- ALL are **injectable peptides (except Oral Semaglutide (QD) (not used in clinical setting yet))
- ↓ Appetite, ↓ Weight
- Potential **cardio-renal benefit (Liraglutide, **Dulaglutide, Semaglutide)
- SE: N+V (delays gastric emptying)
—> Exenatide (BD)
—> Liraglutide, Lixisenatide (QD)
—> **Exenatide XR, Dulaglutide (*Weekly)
—> Semaglutide

DPP-4 inhibitors (DPP-4i) (**-Gliptins):
- **Oral agents ↑ endogenous active incretins by inhibiting DPP-4
- Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin
- Fix-dose combinations with Metformin, Pioglitazone, SGLT2 inhibitor
- Saxagliptin: Heart failure

Treatment considerations:
- Monotherapy / Combined used with other antidiabetic (including Insulin)
- NOT use GLP-1 RA, DPP-4i together (∵ target same pathway)
- Use in renal impairment: **dose adjustment for GLP-1 RA, DPP-4 inhibitors (except Linagliptin excreted via bile)
—> if eGFR <30, **not use Exenatide (∵ kidney excretion)

Question 17

SGLT2 inhibitor (Selective sodium-glucose co-transporter 2)

Answer 17

• ***-Gliflozin
• most recently introduced antidiabetic

MOA:
- ↓ hyperglycaemia by inhibiting proximal tubule reabsorption of glucose —> ↑ urine glucose loss

Advantages:
- **↓ weight, fat mass (∵ breakdown fat to supply energy), BP (∵ Na loss with glucose, H2O)
- no hypoglycaemia if monotherapy
- **potential cardio-renal protection, ↓ heart failure
- can be used with other antidiabetic

Disadvantage:
- ***↓ effectiveness if low eGFR (<45 ml/min)

Approved: Dapagliflozin, Canagliflozin, Empagliflozin, Ertagliflozin

Question 18

SE of oral antidiabetic drugs

Answer 18

1. Metformin
   - Dyspepsia
   - Diarrhoea
   - **Lactic acidosis (rare except in presence of conditions associated with ↑ production / ↓ clearance of lactate —> renal / hepatic / cardiac failure / alcoholism / MI / septicaemia)
   - **B12 deficiency (with long term high dose ∵ impaired absorption of B12)
   - **Not used if eGFR **<30 ml/min (∵ renal excretion)
   - Withhold before + 48 hours after contrast imaging
   —> if eGFR <60 ml/min, liver disease, heart failure, alcoholism (↑ development of lactic acidosis)
   —> if intra-arterial contrast (associated with ↑ risk of ***contrast-induced nephropathy)
2. Sulfonylurea, Meglitinides
   - **Weight gain + (∵ insulin stimulate appetite + fat buildup)
   - **Hypoglycaemia
   - Insulin preferred if renal insufficiency to avoid hypoglycaemia
3. α-Glucosidase inhibitor
   - **Flatulence
   - **Diarrhoea
   - Cannot use sugar (must use ***Glucose) to relieve hypoglycaemia
4. Thiazolidinedione (TZD) (only 1 used: Pioglitazone)
   - **Fluid retention (e.g. ankle edema) —> **CI in CHF
   - **Weight gain ++
   - **↑ Peripheral fractures
   - Anaemia (∵ haemodilution + fat infiltration of marrow)
   - ***↑ Ca bladder? —> CI in history of Ca bladder
5. DPP-4 inhibitors
   - ***Pancreatitis (very uncommon) —> CI in history of Pancreatitis
   - Joint pain (rarely)
6. SGLT2 inhibitors
   - Genital infection (fungal e.g. Candidiasis: 1-3%)
   - Lower UTI (<1%)
   - **Osmotic diuresis (↑ fluid intake recommended)
   - **Postural hypotension (esp. when taking anti-HT e.g. vasodilators, diuretics)
   - **DKA (rare, mainly insulin requiring patients) —> withhold if patient has decreased intake (risk of ketosis), stopped on day before an operation, not resumed until dietary intake resumed
   - **Dapagliflozin: avoid if active Ca bladder
   - ***Canagliflozin: may cause low bone mass / ↑ fracture risk

Question 19

Insulin

Answer 19

1. Maintenance treatment
   - SC injections 1-4 times / day
   - Needle + Syringe / Insulin pen
2. Acute / Temporary treatment of hyperglycaemia
   - IV infusion / IM injection
3. Continuous SC insulin infusion (Insulin pump)
   - needle inserted under abdominal skin
   - Insulin pump + CGMS (Artificial pancreas)
   —> Real-time insulin pump + Continuous glucose monitoring system (CGM (SpC Paed))
   (Indications of CGM:
   - Nocturnal hypoglycaemia
   - Hypoglycaemia unawareness
   - Brittle DM
   - Large discrepancy between HbA1c and HBGM)
4. Inhalation insulin
   - High cost
   - Low patient acceptance
   - ↑ lung cancer? (insulin stays in lungs)
   - only 1 in clinical use (not available in HK)

Source of insulin:
- Recombinant human (HM) / Insulin analogs
- Bovine / Porcine insulin (replaced by HM insulin now)

Question 20

Human insulin

Answer 20

Aggregate into **hexamer
—> require dissociation first in body before use by cells
—> **variable onset, duration
—> ↑ risk of hypoglycaemia

Short-acting insulin analogues (modified insulin molecules)
- Lispro (Humalog), Aspart (Novorapid)
- less self-association than human insulin after SC injection
- more physiological profile: **faster onset, **shorter duration, ***less pre-meal hypoglycaemia

Long-acting insulin analogues
- delayed onset + sustained action with steady, predictable plasma level:
1. Glargine (Lantus)
- shift in isoelectric point —> **precipitates in SC tissue —> forms a **slow-releasing depot —> slower absorption —> steady level —> less hypoglycaemia
- less nocturnal + symptomatic hypoglycaemia

2. Insulin Detemir (Levemir)
   - binds to ***albumin (in SC phase / in blood)
   - less nocturnal + symptomatic hypoglycaemia

Intermediate-acting
3. Insulin with ***Protamine as retardant
- Protaphane, Humulin N
- less long acting
- less reliable absorption —> more nocturnal + symptomatic hypoglycaemia

Question 21

***Insulin with different duration of actions

Answer 21

***Prandial insulins
Short-acting (Prandial Insulin):
1. Regular human insulin
- Actrapid
- Humulin R

2. Rapid-acting analogs
   - **Aspart
   - **Lispro
   - Glulisine

***Basal insulins
Intermediate-acting (Protamine as retardant):
1. Protaphane
2. Humulin N
3. Premixed human
- Mixtard 30 (protaphane/actrapid 70/30)
- Humulin 70/30
- Humalog-Mix (25/75; 50/50)
- Novo-Mix 30

Long-acting analogs:
1. **Glargine (Lantus)
2. **Detemir (Levemir)

Ultra-long acting analogs:
1. Glargine 300 unit/ml (t1/2: 19 hours vs 12.1 hours for Lantus) (more concentrated)
2. Degludec (t1/2: 25.4 hours)

Question 22

Insulin requiring diabetic patient

Answer 22

1. Marked recent weight loss
2. ***Marked ketosis
3. ***Underweight (i.e. severe insulin deficiency / clinically ill (dehydrated, infection, infarction))
4. ***Severe hyperglycaemia at diagnosis
   - HbA1c >10%
   - fasting glucose >16.7 mmol/L (300 mg/dL)
5. ***Pregnancy
   - if satisfactory glycaemia cannot be achieved by diet alone
6. Failed oral therapy
   - ***GLP-1 RA as preferred alternative if HbA1c <11%, esp. if obese, presence of CVD, CKD (∵ Cardio-renal benefits + help lose weight)

Question 23

***Treatment algorithm of Type 2 DM (2018 ADA / EASD)

Answer 23

1st line:
- Metformin (if no CI) + Lifestyle (weight management + physical activity)

2nd line:
- if HbA1c above target in 3-6 months; consider
1. CVD / CKD present:
- **SGLT2 inhibitors (esp. if HF +) (∵ potential cardio-renal protection, ↓ heart failure)
OR
- **GLP-1 RA
- ***avoid TZD, saxagliptin if HF

2. No CVD / CKD
   - compelling need to minimise hypoglycaemia: DPP-4i, SGLT2i, TZD, GLP-1 RA preferred
   - compelling need to promote weight loss: **SGLT2i / **GLP-1 RA preferred
   - cost a major issue: **Sulfonylureas/ **TZD

If severe hyperglycaemia: can start with 2 / 3 drugs or insulin

***5個Concern:
1. CVD / CKD —> GLP-1 RA, SGLT2 inhibitor
2. Weight loss —> GLP-1 RA, SGLT2 inhibitor
3. Hypoglycaemia —> avoid Sulfonylurea, Meglitinide
4. HF —> avoid TZD, Saxagliptin
5. Cost —> Sulfonylurea, TZD

Question 24

Summary

Answer 24

Comprehensive management of DM
1. Patient education
- team approach (doctors, diabetic nurse educators, dietitians, podiatrists)
- about disease, risks if uncontrolled DM, SE of medication

2. Treatment of DM
   - diet
   - oral drugs
   - insulin
3. Treatment of associated coronary risk factors
   - HT
   - ↑ lipids
   - smoking
   - physical inactivity
   - obesity
4. Individualised treatment targets / choices
5. Regular assessment for complications