Endocrine JC034: Deterioration Of Eyesight In A Diabetic Patient: Diabetic Complications Flashcards
Ocular complications of DM
- Lacrimal system: ↓ Tear production
- Extraocular muscles: ***Mononeuritis multiplex —> CN3, 4, 6 palsies —> Diplopia
- Refraction: Fluctuating refractive errors (∵ fluctuating glucose level within lens, solved when glucose level settled)
- Glaucoma: ↑ Incidence in DM
- Iris: ***Neovascular glaucoma (∵ new blood vessels in iris —> impairment of flow of aqueous humour)
- Lens: ***Cataract (early development)
- Retina: ***Diabetic retinopathy / papillopathy (ischaemia of optic nerve)
- Others: ↑ Eye infections, ↑ Inflammation after ocular operations
Diabetic retinopathy (DR)
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
Complications
Abnormal angiogenesis (neovascularisation) —> **Retinal haemorrhage, Vitreous haemorrhage, **Neovascular glaucoma
Abnormal fibrous proliferation —> ***Tractional retinal detachment —> sudden vision loss (like a curtain coming down)
Treatment
Prevention always the best cure
- diabetic retinopathy can be prevented if blood glucose level well controlled + other risk factors controlled (e.g. HT)
- 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 - Clinically significant macular edema
- Focal / Grid laser
- ***Anti-VEGF monoclonal Ab (very effective, ↑ in use)
***Microvascular + Macrovascular complications
DM associated with ↑ mortality / morbidity due to Micro/Macrovascular complications
Microvascular (Small vessel disease)
1. Retinopathy
- Nephropathy (***Glomerulosclerosis)
—> Microalbuminuria (<0.5g protein, <0.3g albumin)
—> Albuminuria (significant proteinuria)
—> ↑ Serum creatinine
—> End-stage renal failure - 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
Diabetic Nephropathy
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
- Glomerular hypertrophy (↑ Renal size)
—> ↑ shear stress on glomerular capillary wall - Glomerular hyperfiltration (↑ GFR)
—> dilatation of afferent arteriole by ***AGEs, Sorbitol, IGF-1
—> ↑ Renal blood flow
—> ↑ Intra-glomerular pressure (Intra-glomerular hypertension) - 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
Diabetic Neuropathy
Chronic Diabetic Neuropathy:
1. **Sensory disturbance
- **Glove and sock sensory peripheral neuropathy
-
**Motor disturbance
- **Peripheral weakness, less common -
**Autonomic disturbance
- **Bladder dysfunction
- Postural hypotension
- Erectile dysfunction
Acute (**Diabetic Mononeuropathy):
1. CN3 palsy
- Ptosis + Divergent squint with **sparing of pupil (medical CN3 palsy)
- CN6 palsy
- Lateral rectus palsy —> Diplopia when looking laterally - Common peroneal nerve palsy
- Foot drop - Upper facial + eye pain
***Diabetic amyotrophy (acute / subacute):
- Weakness and pain over proximal muscles of Pectoral girdle / Pelvic girdle
Macrovascular diabetic complications
- Stroke (Cerebral thrombosis)
- Ischaemic stroke - MI / Angina
- Peripheral vascular disease
- Intermittent claudication
Diabetic gangrene
Causes:
1. Peripheral sensory neuropathy
2. Peripheral vascular disease
3. Poor glycaemic control —> impaired healing
Pathogenesis of Chronic Diabetic Complications
**Prolonged hyperglycaemia + Genetic predisposition + **Accelerating factors (HT, smoking, hyperlipidaemia etc.)
—> Chronic diabetic complications
Treatment of Chronic complications
- Prevention
- Good glycaemic control - 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) - 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)
Glycaemic control
- Lifestyle measures (ALL diabetic patients)
- diet
- exercise
- optimise body weight - Lifestyle measures + Oral hypoglycaemic agents (Type 2 DM)
- Lifestyle measure + Insulin (Type 1 + Type 2 DM)
Dietary management
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
***Major targeted sites of Oral drugs classes
兩組兩組咁記:
- Sulfonylureas (Glipizide, Glimepiride)
- Pancreatic β cells
- ↑ insulin secretion
- Weight gain, Hypoglycaemia - Meglitinide analogs (Repaglinide, Nateglinide)
- Pancreatic β cells
- ↑ insulin secretion
- Weight gain, Hypoglycaemia (rare compared to SU) - Incretin mimetics (GLP analogs / agonists) (Exenatide, Liraglutide)
- Pancreatic α + β cells
- ↑ Insulin secretion + ↓ Glucagon secretion
- ***Weight loss
- GI disorder, dizziness, headache - DPP-4 (Dipeptidyl peptidase-4) inhibitors (Sitagliptin, Vidagliptin)
- Gut, Pancreas
- ↑ GLP-1 levels by inhibiting DPP4
(- also ↓ Glucagon)
- URT infections, sore throat, diarrhoea - 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 - Thiazolidinedione (Rosiglitazone, Pioglitazone)
- Adipose tissue, Muscle, Liver
- Bind to PPARγ to ↓ Insulin resistance + ↑ Fatty acid uptake + Anti-inflammatory
- Weight gain, fluid retention, ***CVS risk - α-Glucosidase inhibitors (Acarbose, Miglitol)
- Gut
- ↓ Glucose absorption
- Flatulence, diarrhoea, abdominal cramping - SGLT2 inhibitors (Dapagliflozin, Canagliflozin)
- Kidney
- ↑ Glucose excretion by inhibit glucose reabsorption
- ***Weight loss
- UTI
Incretins
- 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
Incretin-based Antidiabetic therapy
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)
SGLT2 inhibitor (Selective sodium-glucose co-transporter 2)
- ***-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
SE of oral antidiabetic drugs
- 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) - Sulfonylurea, Meglitinides
- **Weight gain + (∵ insulin stimulate appetite + fat buildup)
- **Hypoglycaemia
- Insulin preferred if renal insufficiency to avoid hypoglycaemia - α-Glucosidase inhibitor
- **Flatulence
- **Diarrhoea
- Cannot use sugar (must use ***Glucose) to relieve hypoglycaemia - 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 - DPP-4 inhibitors
- ***Pancreatitis (very uncommon) —> CI in history of Pancreatitis
- Joint pain (rarely) - 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
Insulin
- Maintenance treatment
- SC injections 1-4 times / day
- Needle + Syringe / Insulin pen - Acute / Temporary treatment of hyperglycaemia
- IV infusion / IM injection - 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) - 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)
Human insulin
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
- 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
***Insulin with different duration of actions
***Prandial insulins
Short-acting (Prandial Insulin):
1. Regular human insulin
- Actrapid
- Humulin R
- 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)
Insulin requiring diabetic patient
- Marked recent weight loss
- ***Marked ketosis
- ***Underweight (i.e. severe insulin deficiency / clinically ill (dehydrated, infection, infarction))
- ***Severe hyperglycaemia at diagnosis
- HbA1c >10%
- fasting glucose >16.7 mmol/L (300 mg/dL) - ***Pregnancy
- if satisfactory glycaemia cannot be achieved by diet alone - 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)
***Treatment algorithm of Type 2 DM (2018 ADA / EASD)
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
- 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
Summary
Comprehensive management of DM
1. Patient education
- team approach (doctors, diabetic nurse educators, dietitians, podiatrists)
- about disease, risks if uncontrolled DM, SE of medication
- Treatment of DM
- diet
- oral drugs
- insulin - Treatment of associated coronary risk factors
- HT
- ↑ lipids
- smoking
- physical inactivity
- obesity - Individualised treatment targets / choices
- Regular assessment for complications
