Criteria for diagnosis of diabetes ( CCP Guidelines 2018) - venous plasma glucose
Fasting PG > 126 mg/dl 2 separate occasions
After ingestion of 75 g glucose - at 2 hours >200mg/dl
Glycosylated Hb > 6.5
Criteria for diagnosis of pre-diabetes ( CCP Guidelines 2018) - venous plasma glucose
FPG 100- 125 mg/dl
HbA1c 5.6 – 6.4 %
After ingestion of 75 g glucose at 2 hours BS 140 – 200
Classification
Primary
>>Â Insulin dependent diabetes mellitus (IDDM,type I)
>>Â Non insulin dependent diabetes ( NIDDM, Type II)
(Insulin dependency referes to development of ketoaciodosis in the in the absence of insulin therapy.)
Secondary
Pancreatic disease
Homornal abnormalities
Drug or chemical induced
Genetic syndromes
others
NIDDM (type 2)
- Resistance to insulin
- Abnormal insulin secretion
Clinical characteristics of Type 2 diabetes
Body habitus –obese
Age -T2DM often present after the 4th decade
Insulin resistance –Patients with T2DM frequently have acanthosis nigricans (a sign of insulin resistance), hypertension, dyslipidemia, and polycystic ovary syndrome (in girls)
Family history –T2DM 75 – 90 %
Mechanism of beta-cell loss in Type 2 diabetes
Natural history of type 2 DM
3 phases
—Elevated insulin levels -normoglycemia
—insulin resistance
—Elevated insulin levels -post prandial hyperglycaemia
—worsening insulin resistance
—Declining insulin levels - fasting hyperglycaemia
—fall in insulin secretion
Prevalence
- NIDDM 75%
- IDDM 25%
Risk factors for DM type II
- Overweight or Obesity ( BMI > 23 kg/m2)
- First degree relative with type 2 disbetes
- H/o Gestational diabetes
- H/o pre diabetes
- Hypertension
- HDL Cholesterol <35 mg/dl
- Polycystic ovary syndrome
- Metabolic syndrome
Management of risk factors
Blood pressure control
- Target BP < 140/90 , 130/80 , 130 /70
- Drug of choise ACEI / ARB
Manage dyslipidemia
- Moderate / low intensity statin therapy
Anti platelet therapy
- If 10 year CV risk > 10%
Why treat diabetes?
- It is a life long illness
- Good control will delay the onset of complications and lengthen productive life
- A wide ranging therapeutic armamentarium is available
Interventions?
- Â there is a trend to use basal insulin even with monotherapy
Multisystem involvement with complications
NEUROPATHY
Diabetic neuropathy
Mononeuritis (common peroneal nerve, third cranial nerve, sixth cranial nerve, wrist drop)
- Mononeuritis multiplex
- Peripheral neuropathy (distal, symmetrical, predominantly sensory) usually axonal (glove and stocking - gradually ascends upwards)
- Diabetic autonomic neuropathy
- Diabetic amyotrophy (pain affecting the quadriceps muscle)
Diabetic foot
(punched out appearance, foot arch is lost, pressure ulcers)
Check with monofilament vibratory and JPS(Joint position sensation)Â to detect diabetic neuropathy.
- If Normal re-examine in 1 year
- If loss of sensation only re examine in 6 months
- Loss of sensation
- --+ PAD ( ankle- brachial index < 0.9 )
- --Structural foot deformities
- --Onychomycosis (Onychomycosis increase risk of foot ulceration and gangrene 3 fold)
THEN Custom insoles to off load pressure on at risk areas (custom design footwear)
Foot care advice
â–Ş Use of appropriate footwear
â–Ş Avoid walking barefoot
â–Ş Keeping feet clean and dry. Application of moisturizer to prevent cracked soles
â–Ş Trimming toe nails appropriately
▪ Inspection of feet for early detection of complications such as infection, blisters and callus
Diabetic autonomic neuropathy
- -
Gastrointestinal autonomic neuropathy
Dysphagia
Abdominal pain
Nausea/vomiting
Malabsorption
Fecal incontinence
Diarrhea (early morning)
Constipation
- -Cardiovascular autonomic neuropathy may produce the following symptoms
- Persistent sinus tachycardia
- Orthostatic hypotension (usually present in elderly)
- Sinus arrhythmia
- Decreased heart variability in response to deep breathing
- Near syncope upon changing positions from recumbent to standing
Bladder neuropathy
D/diagnosis - prostate or spine disorders
- Poor urinary stream
- Feeling of incomplete bladder emptying
- Straining to void
Erectile dysfuction
Sudomotor neuropathy may produce the following symptoms
=
Heat intolerance
=Â Heavy sweating of head, neck, and trunk with
anhidrosis of lower trunk and extremities
=Â Gustatory sweating
Staging of diabetic neuropathy
—NO - No neuropathy
—N1a - Signs but no symptoms of neuropathy
—N2a - Symptomatic mild diabetic polyneuropathy; sensory, motor, or autonomic symptoms; patient is able to heel-walk
—N2b - Severe symptomatic diabetic polyneuropathy; patient is unable to heel-walk)
—N3 - Disabling diabetic polyneuropathy
Investigation - cause for polyneuropathy
- Vitamin B-12 and folate levels
- Thyroid function tests
- Erythrocyte sedimentation rate
- C-reactive protein
- Serum protein electrophoresis (amyloidosis?)
- Antinuclear antibody (connective tissue disorders like SLE)
- Anti-SSA and SSB antibodies
- Rheumatoid factor
- Paraneoplastic antibodies
- heavy metals (lead) and agrochemicals (pesticides)
- toxins other
- medications (chemotherapic agents, INH)
>> in exams describe the peripheral neuropathy and look for possible cause (SHORT CASE)
Pharmacotherapy of neuropathy
- Tricyclic antidepresents
amitriptytline 25 75 mg day
nortriptyline
- gabapentin
- carbamazepine 200 – 800 mg /day
- phenytoin
- capsaicin cream for L.A.
Diabetic nephropathy
a clinical syndrome characterized by the following
- Persistent albuminuria (>300 mg/d or >200 ÎĽg/min) that is confirmed on at least 2 occasions, 3-6 months apart
- Progressive decline in the glomerular filtration rate (GFR)
- Elevated arterial blood pressure (see Workup)
FACTS
leading cause of chronic kidney disease
- 30-40% of all end-stage renal disease
If no proteinuria- risk after 20-25 years
- overt renal disease 1 % per year.
With proteinuria incidence of ESRD in patients
- type 1 DM is 50% 10 years
- type 2 DM 3-11% 10 years
Clinical presentation
—Passing of foamy urine
—Otherwise unexplained proteinuria
—Diabetic retinopathy (close association_
—Fatigue and foot edema secondary to hypoalbuminemia (if nephrotic syndrome is present)
Natural history
Histological findings (renal biopsy)
- Class I - Mesangial expansion
- Class II - Thickening of the glomerular basement membrane (GBM)
- Class III – Glomerular sclerosis ( Nodular ) (Kimmelstiel–Wilson lesions
- Class IV - advanced diabetic glomerulosclerosis
Management of nephropathy
- Monitor GFR
- Monitor weight Electrolytes Haemoglobin, Calcium, and PTH. Albumin
- Correct as necessary
- When e GFR < 30 ( stage 4 ) refer to nephrologist
Therapy
- Meta-analysis has shown that ACE inhibitors in reduce urinary albumin excretion in
- Both type 1 and type 2 DM patients
- whether they are normotensive or hypertensive
- and that they are superior to beta-blockers, diuretics, and calcium channel blockers in reducing progression of nephropathy
Diabetic retinopathy
>> try to learn and acquire skill of using opthalmoscope
—Microaneurysms:
—Dot and blot hemorrhages
—Retinal edema and hard exudates
—Neovascularization
Imaging studies
- Fluorescein angiography: Microaneurysms appear as pinpoint, hyperfluorescent lesions in early phases of the angiogram and typically leak in the later phases of the test
- Optical coherence tomography scanning: Administered to determine the thickness of the retina and the presence of swelling within the retina, as well as vitreomacular traction
Pharmacologic therapy
Intravitreal administration of
- Triamcinolone - diabetic macular edema
- Bevacizumab: to prevent neovascularization of the disc or retina
- Ranibizumab: to reduce neovascularization of the disc or retina
Risk factors for diabetes
—Overweight or Obesity ( BMI > 23 kg/m2)
—Physical inactivity
—First degree relative with type 2 diabetes
—H/o Gestational diabetes
—H/o pre diabetes
—Hypertension
—HDL Cholesterol <35 mg/dl
—Polycystic ovary syndrome
—Metabolic syndrome
Modifiable, traditional risk factors
Physical inactivity
- dyslipidemia,
- obesity
- hypertension
- smoking
Un-modifiable’ risk factors
high levels of Lp(a) lipoprotein
- high levels of homocysteine
- plasminogen activator inhibitor (PAI-1), fibrinogen,
- High levels C-reactive protein
Primary prevention
Life style and dietary modification will reduce the incidence of the illness
- BMI – 18.5 – 23
- Saturated and trans fat intake should be reduced
- Salt intake reduced to 2.4 g ( 1 tea spoon )
- Increase physical activity
- Stop smoking and alcohol
Glycaemic target
- more stringent for younger people
Glycaemic recommendations for older adults
Pharmacotherapy of Diabetes
Step 1
- Life style modification
Step 2
- Life style modification + Metformin
Step 3
- Life style modification + Metformin + Any one of the foll.
- Sulfonylurea (Preferred)
- DPP4 Inhibitor
- Alpha glucosidase inhibitors
- GLP-1 RA
- SGLT2 inhibitor
- TZD
- Glitanides
- Basal Insulin
Step 4
>> check compliance
>> other medications and health effects?
- Life style modification + Metformin + Any 2 of the foll.
- Sulfonylurea (Preferred)
- DPP4 Inhibitor
- Alpha glucosidase inhibitors
- GLP-1 RA
- SGLT2 inhibitor
- TZD
- Glitanides
- Basal Insulin
Step 5
- Life style modification
- Complex insulin regimen +/- Metformin
FROM GUIDELINES
THIS IS A CARD SO READ AND REVISE
SECONDARY PREVENTION OF DM THROUGH DRUGS
REFER PHARM TUTES ON THE SUBJECT
Range of drugs available :
—Biguanides - Metformin
—Sulfonylurea
—Prandial glucose regulators
—Thiazolidinedione - insulin sensitizers
—Glycosidase inhibitors
—DDP 4 Inhibitors
—Insulin therapy
—Incretin analogues
—SGLT2 inhibitors
- ------------------------------------------------------
BIGUANIDES
—Guanidine
—
—Phenformin (not used because of lactic acidosis)
—
—Metformin
Mode of action
—Reduces insulin resistance – increases insulin sensitivity
—metformin has an antihyperglycemic action
(cf. hypoglycaemic action of sufonylurea)
—Increases peripheral uptake and utilization of glucose
—Reduces hepatic out put of glucose
Uses:
—Hypoglycaemic activity similar to sulfonylurea
—As single agent or as add on therapy to either sulfornyluria / thiazolidenediones
—Induces anorexia - useful in the Obese diabetic patient
—In other insulin resistant states
—Polycystic ovary syndrome
—In gestational diabetes
C.I
- Renal impairment
>use cautiously if Cr. Cl is 50 -30 Avoid if < 30
- Cardiac or respiratory insufficiency
- History of lactic acidosis
- Tissue hypoxia,- MI, sepsis, dehydration,
- Liver diseases
- Alcohol abuse
- Use of contrast media
AE
- Lactic acidosis
- more common If dose > 2.5 g/24h
- Decreased absorption of vit B12 and folate Anorexia, N&V and intolerance
- -------------------------------------------------------------------------SulfonylureaOld
—clopropamide
—glibeclamide
—tolbutamide
NEW
—glipizide
—gliclazide
—glimepiride
—glyburide
Mode of Action
—The primary action of sulfonylurea drugs is to increase insulin secretion,
—thereby decreasing hepatic glucose production
—and indirect improvement of insulin sensitivity.
Clinical uses
1As a first line drug in NIDDM
2As drug to be used in combination with other agents
Only first line is metformin has C/I
Some choose newer drugs as second line but this is tried and tested
Some introduce basal insulin as well
AE
—Weght gain
—Hypoycaemia if given in excess
- Reductions greater with marked hyperglycemia
- --------------------------------------------Prandial gulcose regulators (not used anymore that much)
1Repaglinide ( Combination with metformin or monotherapy)
2
Netaglinide (Used in combination with metformin)
—Stimulates release of insulin from islet cells
—Rapid onset and short duration of action
—Should be given shortly before each meal
Weak hypolglycaemic action compared to others
- ----------------------------------------Insulin sensitizers -ThiazolidinedionesMechanism
—Selective agonists of PPARg
—PPARg - Member of a family of nuclear receptors
—Binds to peroxisome prolifrator-activated gamma
—Most abundant in adipocytes
—Improves uptake of fatty acids and promotes lipogenesis
—Increases insulin sensitivity
Examples
1Rosilglitazone (used but not that much)
2Pioglitazone
Reduces peripheral insulin resistance
Licensed for used in combination with metformin or sulphonylurea
Effects
—Lowers HbA1 C levels by 0.5 to 1.5 %
—Increase peripheral glucose up
—increases the high-density lipoprotein (HDL) levels by approximately 5% to 15%,
—reduction of approximately 10% to 20% in the plasma triglyceride levels ( by increasd uptake of FFA and triglycerides into adipocytes)
—Reduction in microalbuminuria
—Reduction in the progression of atheroma
—reduction in the blood levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen
—Redistribution of body Fat
—Reduction of FFA content in liver
AE
—Lipid Effects
Increase LDL
Increase Apo a
—Fluid Retention/Edema
—Weight Gain/Obesity ( 4- 6 %)
—Hepatic Toxicity ( Troglitazone only not a class effect )
—Cardiac Toxicity
Other uses
—Non alcoholic fatty liver disease
—polycystic ovary syndrome
—lipodystrophies
Whats NAFLD?
A spectrum ranging from
- Hepatic steatosis
- Elevated transaminases
- Statohepatitis
Cellular infiltrate
Necrosis
- Cirrhosis
Use with this drug:
—Recent studies have shown
—A reduction in liver cell fat content
—Reduction in elevated levels of tranaminases
—Reduction in inflammation and necrosis
------------------------------------
Apha-glucosidase inhibitors
—Acarbose
—
50 – 100 mg taken with food
—Inhibits alpha-glucosidase that converts polysaccharides to monosaccharides
—Slows the rate of glucose absorption
—Adverse effects – flatulence, abdominal distension diarrhoea
- -------------------------------DPP IV and GLP 1 (incretins) analogues Examples
Synthetic exendins ( Incretins)
—Exanatide – a 39 amino acid peptide similar to exendin 4 ( GLP 1 agonist )
—Liraglutide ( GLP 1 analogue )
Weight loss is key difMechanism
Incretins =>Â 1GIPÂ (glucose-dependent insulinotropic peptide /gastric inhibitory peptide)
2GLP-1Â (glucagon-like peptide-1).
Naturally occuring? —Similar to GLP 1 Exendin 4 – Found in the salava of Gila Monstor – a Poisonous Lizard
Actions of incretins
—Glucose dependent insulin secretion
—inhibits glucagon secretion.
—delays stomach emptying
—increase the number of beta cells,
—Causes weight loss
Many more in pharm tute
Potential to reduce loss of beta cells?
--------------------------------
SGLT2/T1 cotransporter
Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the
- intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the
- proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in PST).
- First approved by USFDA 2013
Examples
1
Dapagliflozin
2canagliflozin (160-fold more selective for SGLT2 than for SGLT1)
—in the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program
3empagliflozin
—in the EMPA-REG OUTCOME trial
Actions
—hypoglycemic effect
—Body weight reduction
—reduces GFR
lowers albuminuria
reduces the oxygen-consuming transport activity in renal tubules,
preserve the function (including GFR) and integrity of the remaining nephrons in the long term
—diuretic and natriuretic effects
Reduces
volume
blood pressure
body weight
AE
Genital and urinary tract infections
—dose dependent (2.1% in placebo group, 5.8% in 2.5 mg, 7.0% in 5 mg and 7.0% in 10 mg dapagliflozin group).[72]
—more common in females
—vulvovaginal mycotic infection
—Due to volume depletion postural hypotension
—?? Increase in euglycemic DKA (Fadini, Bonora, and Avogaro 2017; Monami et al. 2017; Rosenstock and Ferrannini 2015)
- --------------------------------------So summary of treatment in DM
—Step 1
—Life style modification
Step 2
—Life style modification + Metformin
Step 3
—Life style modification + Metformin + Any one of the foll.
—Sulfonylurea (Preferred)
—DPP4 Inhibitor
—Alpha glucosidase inhibitors
—GLP-1 RA
— SGLT2 inhibitor
— TZD
—Glitanides
—Basal Insulin
Step 4
—Life style modification + Metformin + Any 2 of the foll.
—Sulfonylurea (Preferred)
—DPP4 Inhibitor
—Alpha glucosidase inhibitors
—GLP-1 RA
— SGLT2 inhibitor
— TZD
—Glitanides
—Basal Insulin
Step 5
—Life style modification
—Complex insulin regimen +/- Metformin
Diabetic drugs in renal failure?
Â
Â
How DM leads to frequent UTI?
- Low immunity
- Polyuria
- Glycosuria
- SGLT 2 stuff
- Nephropathy
- Autonomic neuropathy ⇒ bladder control
To answer such questions think of all DM effects and pick and choose!!!
Â
Hospital most UTIs are male and the field most are female!
Â
Diabetic pts are given anti VeGF growth factors into the eye to stop diabetic retinopathy... Anti VeGF....
Laser damaging the damaged capillaries to stop leaking... Etc
Beta lockers and amiodarone blocks t4 to t3 conversion. So t4 to t3 ratio high..
Insulin stored in the middle compartment of fridge
Insulin can be kept at the room temp for 1 month. People come to the clinic every 2 months
Propioception and vibration lost first in DM
Corticosteroid injection into the sj for forzen sodier ... Sugar high but good for pain
DM outline management
Prevent complications..
For old no need to be that strict...
Protinuria drugs => ace, calcium channel blockers, SGLt2 blockers
If renal pathology don't use remap toxic drugs like nsaids etc. It's bad.