Download DIABETES MELLITUS AND METABOLIC SYNDROME

DIABETES MELLITUS AND METABOLIC SYNDROME
PATHOPHYSIOLOGY:
 Insulin is secreted by β-cells (also called B-cells) of the islets of Langerhans
 In type 1 diabetes there is an absolute deficiency of insulin (such patients are usually
young and non-obese at presentation)
 In type 2 diabetes there is a relative lack of insulin secretion, coupled with marked
resistance to its action (such patients are usually middle-aged or older and obese at
presentation)
DIAGNOSIS:
 Normal fasting blood glucose: 70- 99 mg/dl ( 3,9-5,5 mmol/l)
 Criteria for hypoglycemia: < 70 mg/dl, regardless of the clinical symptoms
CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS:
 Symptoms of diabetes plus random blood glucose concentration >=200 mg/dl ( 11,1
mmol/L) or
 Fasting plasma glucose >=126 mg/dl ( 7,0 mmol/L)- double confirmation or
 2-h plasma glucose>=200 mg/dl ( 11,1 mmol/L) during an oral glucose tolerance test
ORAL ANTIDIABETIC AGENTS:
 Biguanides (metformin)
 Sulphonylureas
 Thiazolidinediones (glitazones)
 α-glucosidase inhibitors (acarbose)
 Incretin mimetics ( GLP-1 receptor agonists, DPP-4 inhibitors)
 SGLT-2 inhibitors
BIGUANIDES: METFORMIN
 It is used in type 2 diabetic patients inadequately controlled by diet
 Biguanides are recommended as first-line therapy for type 2 diabetes (recommended
especially in obese patients)
 Metformin does not increase body weight or provoke hypoglycemia
 Primary effect is to:
 reduce hepatic glucose production through activation of the enzyme AMP-activated
protein kinase (AMPK)
 impairment of renal gluconeogenesis,
 slowing of glucose absorption from the gastrointestinal tract, with increased glucose
to lactate conversion by enterocytes,
 direct stimulation of glycolysis in tissues,
 increased glucose removal from blood
 reduction of plasma glucagon levels
 Hypoglycemia during metformin therapy is essentially unknown
METFORMIN-ADVERSE EFFECTS:
 Metformin causes nausea, a metallic taste, anorexia, vomiting and diarrhoea
 Lactic acidosis, which has a reported mortality in excess of 60%, is uncommon
provided that the above contraindications are respected
METFORMIN- CONTRAINDICATIONS:
 Renal disease ( GFR< 30 ml/min/1,73m2- do not use, GFR 30-44 ml/min/1,73 m2- do
not start therapy, you can continue but the dose should be reduced >50%, renal
function should be monitored every 3 months
 Liver disease
 Advanced heart failure, stroke, myocardial infarction
 Radiographic contrast studies
 Acidosis
THE DOSAGE OF METFORMIN
SULPHONYLUREAS-MECHANISM OF ACTION:
 The major action of sulfonylureas is to increase insulin release from the pancreas
and reduction of serum glucagon concentrations
 Sulphonylureas (e.g. glibenclamide, gliclazide) are used for type 2 diabetics who have
not responded adequately to diet alone or diet and metformin
 They improve symptoms of polyuria and polydipsia, but (in contrast to metformin)
stimulate appetite
SULPHONYLUREAS-ADVERSE EFFECTS:
 Sulphonylureas can cause hypoglycaemia
 Allergic reactions to sulphonylureas include rashes, drug fever, gastrointestinal
upsets, transient jaundice (usually cholestatic) and haematopoietic changes,
including thrombocytopenia, neutropenia and pancytopenia
 Serious effects other than hypoglycaemia are uncommon
 Contraindications: Renal/liver disease
THE DOSAGE OF SULPHONYLUREAS
THIAZOLIDINEDIONES (GLITAZONES):
 Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type 2 diabetes
mellitus patients who are inadequately controlled on diet alone or diet and other oral
hypoglycaemic drugs
 Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a
nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes
 They lower blood sugar but cause weight gain and fluid retention
 They are contraindicated in heart failure
ALPHA-GLUCOSIDASE INHIBITORS-ACARBOSE:
 Acarbose is used in type 2 diabetes mellitus in patients who are inadequately
controlled on diet alone or diet and other oral hypoglycaemic agents
 It can be used in combination with insulin or metformin and sulphonylureas
 Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and
reduce postmeal glucose excursions by delaying the digestion and absorption of
starch and disaccharides
ACARBOSE- ADVERSE EFFECTS:
 Fermentation of unabsorbed carbohydrate in the intestine leads to:
 Abdominal or stomach pain
 Bloated feeling or passing of gas
 Diarrhea
 Contraindications to Acarbose are: Renal and liver impairment, bowel or intestinal
disorder, a stomach disorder
THE DOSAGE OF ACARBOSE
GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS:
 Mechanism of action:
 potentiation of glucosemediated insulin secretion,
 suppression of postprandial glucagon
 slowed gastric emptying, and a central loss of appetite (weight loss)
 Exenatide (Byetta )and Liraglutide (Victoza)
GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS, ADVERSE EFFECTS:
 nausea, vomiting, diarrhea
 allergic reaction
CONTRAINDICATIONS: Renal disease
DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS:
 Sitagliptin, saxagliptin, and linagliptin are inhibitors of DPP-4, the enzyme that
degrades incretin hormones
 These drugs increase circulating levels of native GLP-1 and glucose-dependent
insulinotropic polypeptide (GIP), which ultimately decrease postprandial glucose
excursions by increasing glucose-mediated insulin secretion and decreasing glucagon
levels
 Dosage should be reduced in patients with renal impairment and may need to be
adjusted to prevent hypoglycemia if there is concurrent insulin secretagogue or
insulin therapy
ADVERSE EFFECTS:
 nausea and vomiting
 skin reaction ( e.g hives)
 epigastric pain
Reduced dose with renal disease
SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS:
 Mechanism of action: ↑ Urinary glucose excretion
 Clinical use:
 Monotherapy when diet and exercise alone do not provide adequate glycaemic
control in patients for whom use of metformin is considered inappropriate due to
intolerance;
 Add-on combination therapy in combination with other glucose-lowering medicinal
products including insulin, when these, together with diet and exercise, do not
provide adequate glycaemic control
ADVERSE EFFECTS:
 urinary and vaginal infections, dehydration, an exacerbate tendency to
hyperkalemia
 Contraindications: moderate renal insufficiency
Dapagliflozin , Canagliflozin
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INSULIN-CHARACTERISTICS OF AVAILABLE INSULIN PREPARATIONS:
RAPID-ACTING INSULIN:
Human analog:
insulin lispro- Humalog
insulin aspart- NovoRapid
insulin glulisine- Apidra
The rapid-acting insulin permit more physiologic prandial insulin replacement
because their rapid onset and an early peak action mimic normal endogenous
prandial insulin secretion more closely than regular insulin does, and they have the
additional benefit of allowing insulin to be taken immediately before the meal
Their duration of action is rarely more than 4–5 hours, which decreases the risk of
late postmeal hypoglycemia
SHORT-ACTING INSULIN:
Its effect appears within 30 minutes, peaks between 2 and 3 hours after
subcutaneous injection, and generally lasts 5–8 hours
Human insulin, short-acting: Actrapid, Gensulin R, Humulin R, Insuman Rapid ,
Polhumin R
Regular insulin should be injected 30–45 or more minutes before the meal
INTERMEDIATE-ACTING NPH (ISOPHANE INSULIN)
NPH insulin is an intermediate-acting insulin whose absorption and onset of action
are delayed by combining appropriate amounts of insulin and protamine so that
neither is present in an uncomplexed form (“isophane”)
After subcutaneous injection, proteolytic tissue enzymes degrade the protamine to
permit absorption of insulin
NPH insulin has an onset of approximately 2–5 hours and duration of 4–12 hours
It is usually mixed with regular, lispro, aspart, or glulisine insulin and given two times
daily
LONG-ACTING INSULIN, INSULIN GLARGINE:
Insulin glargine is a soluble, “peakless” long-acting insulin analog
Insulin glargine has a slow onset of action (1–1.5 hours) and achieves a maximum
effect after 4–6 hours
This maximum activity is maintained for 11–24 hours or longer
Glargine is usually given once daily, although some very insulin-sensitive or insulinresistant individuals benefit from split (twice a day) dosing
LONG-ACTING INSULIN, INSULIN DETEMIR:
Insulin detemir has a dose-dependent onset of action of 1–2 hours and duration of
action of more than 12 hours
It is given once or twice a day to obtain a smooth background insulin level
MIXTURES OF INSULIN
TYPE 2 DIABETES MELLITUS-TREATMENT:
 Pharmacological treatment- STEP 1:
 lifestyle modification + Metformin
-metformin intolerance or contraindication ( Sulphonylureas or Glucagon-like
polypeptide-1 (GLP-1) receptor agonists or Dipeptidyl peptidase-4 (DPP-4) inhibitors
or Sodium-glucose cotransporter 2 inhibitors)
 Pharmacological treatment- STEP 2 (dual therapy) :
 lifestyle modification + Metformin +
-Sulphonylureas or
-Glucagon-like polypeptide-1 (GLP-1) receptor agonists or
-Dipeptidyl peptidase-4 (DPP-4) inhibitors or
-Sodium-glucose cotransporter 2 inhibitors ( SGLT-2) or
- Thiazolidinediones (glitazones- PPAR-γ )
 Pharmacological treatment- STEP 2 (triple therapy)
 lifestyle modification + Metformin + two different drugs with different mechanisms
of action
It is also possible to add Basal Insulin to Metformin (a direct transition from STEP 1 to
STEP 3)
 Pharmacological treatment- STEP 3:
 lifestyle modification+ Metformin+ Insulin (Basal insulin): NPH 1x/daily or Longacting analog
 Pharmacological treatment- STEP 4:
 lifestyle modification+ Metformin+ Insulin in two doses ( Basal insulin or Mixtures of
insulin)
 lifestyle modification + Metformin+ intensive insulin therapy
There is a possibility of adding to insulin other antidiabetic drugs (besides metformin)
THE CRITERIA FOR STARTING INSULIN TREATMENT IN TYPE 2 DIABETES:
 newly diagnosed diabetes:
-glucose ≥ 300 mg / dl (16.7 mmol / l) with clinical symptoms of hyperglycemia;
 the ineffectiveness of oral diabetic medications (HbA1c> 7%, despite the
intensification of behavioral therapy)
INDICATIONS TO INSULIN TREATMENT (INDEPENDENT OF THE CONCENTRATION OF
GLUCOSE):
 pregnancy
 the patient's request
 latent autoimmune diabetes in adults
 diabetes associated with cystic fibrosis
INDICATIONS FOR TEMPORARY INSULIN THERAPY:
 surgery , stroke , acute coronary syndrome , percutaneous transluminal coronary
angioplasty , decompensation of diabetes (e.g caused by infection, injury, steroid
therapy) , other acute illness requiring hospitalization in Intensive Care Unit
THE METABOLIC SYNDROME:
 CRITERIA FOR THE METABOLIC SYNDROME:
 Three or more of the following:
 Central obesity: waist circumference>=95 cm(men), >= 80cm ( female)
 Hypertriglyceridemia: triglyceride level >=150 mg/dL or specific medication
 Low HDL cholesterol: <40 mg/dL for men and <50 mg/dL for women, respectively, or
specific medication
 Hypertension: blood pressure ≥130 mmHg systolic or
≥85 mmHg diastolic or specific medication
 Fasting plasma glucose level ≥100 mg/dL or specific medication or previously
diagnosed type 2 diabetes
THE METABOLIC SYNDROME- TREATMENT:
All components of metabolic syndrome should be treated: obesity (weight reduction
is the primary approach to the disorder, recommendations for weight loss include a
combination of caloric restriction, increased physical activity, and behavior
modification) insulin resistance ( metformin) dyslipidaemia (statins, fibrate),
hypertension.