novel methods of treatment of diabetic patients. oral hypoglycemic agents, modern insulin...
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Novel methods of treatment of diabetic patients. Oral hypoglycemic agents, modern insulin preparations and its analogues.
assist. prof. Svystun I.I.
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Good Diabetes Management
Regular Blood Glucose Monitoring Healthy Nutrition
Regular Exercise
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Guidelines for glycaemic control in DM
IDF AACE (2011) ADA
HbA1c (%) <6.5 ≤6.5 <7.0
Fasting/preprandial glucose(mmol/L/ mg/dL)
<6.0 / <110 <6.0 / <110 3.9-7.2 / 70-130
2-h postprandial glucose(mmol/L/ mg/dL)
<7.8 / <140 <7.8 / <140 <10.0 / <180
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Indexes Level of compensation
good sufficient insufficient Fasting glycaemia (mmol/l)
4,4 - 6,0 6,0- 7,8 > 7,8
2 hours after meals
4,4 – 8,0 8,0-10,0 > 10,0
Hb A1c (%) < 6,5 6,5 – 8 > 8 Cholesterol (mmol/l)
< 5,0 5,0 – 6,5 > 6,5
Triglycerides (mmol/l)
< 1,7 1,7 – 2,2 > 2,2
HDL (mmol/l) > 1,1 0,9 – 1,1 < 0,9 Body mass index (kg/m2)
males < 25 females < 24
25- 27 24- 26
> 27 > 26
Blood pressure < 130/80 < 160/95 > 160/95
Criteria of DM compensation
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DCCT A1C levels and the risk of complications in type 1 diabetes
Patients with type 1 diabetes (n=1,441) Adapted from DCCT. Diabetes 1995;44:968-43.
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UKPDS: Tight glycamic control prevents complications
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(A) Association of severe hypoglycemia with mortality in intensive and standard treatment groups in ACCORD replotted from Bonds et al. (2010).
(B) Association of severe hypoglycemia with mortality in intensive and standard treatment groups in ADVANCE replotted from Holman et al. (2009).
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Treatment goal HbA1c
Dedov et al. Diabetes mellitus. 2011;4:6-17. © 2011,Diabetes Mellitus.
Age Young Middle Eldery and/or life expectancy <5 years
No complicationsNo risk of hypoglycemia
<6,5% < 7,0% <7,5%
Severe complications and /or risk of hypoglycemia
< 7,0% <7,5% < 8,0%
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An A1C ≤6.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy and retinopathy but this must be balanced against the risk of hypoglycemia
Less stringent A1C targets (7.1%–8.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following:a) Limited life expectancyb) High level of functional dependencyc) Extensive coronary artery disease at high risk of ischemic eventsd) Multiple comorbiditiese) History of recurrent severe hypoglycemiaf) Hypoglycemia unawarenessg) Longstanding diabetes for whom it is difficult to achieve an A1C ≤7.0% despite effective doses of multiple antihyperglycemic agents, including intensified basal-bolus insulin therapyADA: Executive Summary: Standards of Medical Care
in Diabetes—2012; Diabetes Care January 2012
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Methods of treatment DM Education Exercise program. Diet. Oral hypoglycemic agents or insulin
(indications for each vary with the type of DM and severity of the disease).
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Self - controlPhysician has to
educate: - techniques of insulin
administration and measurement of urine
and blood glucose level (if taking insulin)
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Exercise Exercise: Before diabetic patients engage in exercise program,
they should consult with their healthcare provider because they need to have a complete history and physical examination
Exercise (total of about 30 minutes a day, at least 5 days a week) lowers blood sugar levels by improving cell uptake of glucose.
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The main principles of diet
Balanced diet (diet should include physiologic meal components: carbohydrate comprises 50 – 60 % of total calories, fat – 24 – 25 % and protein – 16 – 15 %).
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The main principles of diet.
Normal-calorie diet in patients with type 1 DM (35-50 kcal/kg of ideal weight (weight = height – 100)) and
low-calorie diet in obese persons (mostly in patients with type 2 DM (20 – 25 kcal/kg of ideal weight)). We try to decrease weight in obese patients on 1-2 kg/month by such diet.
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Oral hypoglycemic agents. Inadequate control of hyperglycemia by the diet and
exercises interventions suggests the need for a good glucose-lowering agent.
Oral hypoglycemic agents are useful only in the chronic management of patients with type 2 DM.
The most commonly used are: 1. sulfonilureas, 2. biguanides, 3. alpha-glucosidase inhibitors, 4. non-sulfonylureas insulin stimulators (glinides), 5. thiazolidinediones (glitazones), 6. dipeptidyl peptidase IV (DPP-IV) inhibitors,7. glucagon-like peptide-1 (GLP-1) receptor agonist,8. analogue of amylin (pramlintide)
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2 nd generation drugs (mg) Dose Additional effects Glibenclamide (Maninil, Euglucan, Daonil, Glinil, Gilamat, Gliben, Glucoven)
1; 1,75; 3,5; 5
1-2 12-24
Gliquidone (Glurenorm, Beglicor)
30 30-120
8-12 Without hepato- and nephrotoxic effects, metabo-lism through the intestinum
Gliclazide (Diamicron, Diabeton, Predian, Glizid) Diabeton MR
80 30
80-320 30-120
8-12 24
Normalizes micro- circulation, blood aggregation
Glipizide (Minidiab, Glucontrol, Antidiab)
5 20 8-12
3 rd generation drugs (mg)
Glimepiride (Amaryl) 1-6 6 24
Commonly used sulfonylureas
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Action of sulfonilureas1. Influence on the pancreatic gland: increasing of the β-cells sensitivity to the glucose
and as a result higher secretion of insulin; stimulation of the exocytosis of insulin by
insulocytes;2. Nonpancreatic influence: increasing number of the receptors to insulin; normalization of receptors’ sensitivity to insulin; increasing of glucose transportation inside muscle
cells; stimulation of glycogen synthesis; decreasing of glycogenolysis and
glyconeogenesis; decreasing of glucagon secretion and others.
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Side effects of sulfonilureas hypoglycemia (hypoglycemic effect of
sulfonilureas will be the most obvious in 7 – 12 days from the beginning of the treatment);
allergy; influence on gastrointestinal tract (nausea and
others); leucopenia (decreasing of the quantity of white
blood cells); primary or secondary resistance; weight gain .
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Contrandications to sulfanilureas usage type 1 DM; blood diseases; acute infections, acute coronary heart and
cerebral diseases; trauma; pregnant diabetics or lactation; III – IV stages of angiopathy (but Glurenorm
can be used in patients chronic renal failure, because of gastrointestinal tract excretion);
coma and precoma.
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Commonly used biguanides
Name of drug Dose in 1 tabl.
Daily dose
Duration of
action (hours)
Metformin (Dianormet, Siofor, Metfogamma, Glucophage Forte)
0,25; 0,5; 0,85; 1,0
0,5-2,5
8-10 12-14
Buformin (Adebit) Buformin Retard was withdrawn from the market in some countries due to an elevated risk of causing lactic acidosis
0,05 0,17
0,1-0,2 0,17-0,34
8-10 12-14
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Action of biguanides
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Contraindications to biguanides usage
type 1 DM; heart and lung disease with their insufficiency
(chronic heart and lung failure); status with hypoxemia; acute and chronic liver and kidney diseases with
decreased function; pregnant diabetics, lactation; old age; alcoholism; coma and precoma.
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Alpha-glucosidase inhibitors
Name of drug Dose in 1 tabl.
Daily dose
Duration of action(hour
s) Acarbosa (Glucobay, Glucor, Prandase, Precose)
0,05; 0,1 0,15-0,6 2,7-9,6
Miglitol 0,025; 0,05; 0,1
0,05-0,3 2-4
Guar Gum (Guarem)
5,0 (gra-nules)
15-30 -
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Action of alpha-glucosidase inhibitors
inhibition of gastrointestinal tract absorption (block of α-glucozidase);
lowering of postprandial glucose level (postprandial “spikes” in blood glucose are increasingly implicated as a major cause of cardiovascular complications);
partly reducing fasting glucose levels by indirectly stimulating insulin secretion in patients who retain β-cell function (and acarbose has a protective effect on β-cells).
www.rushakoff.com
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Contrandications to alpha-glucosidase inhibitors
type 1 DM; Chronic gastrointestinal disorders:
pancreatitis, colitis, hepatitis.
Side effects of alpha-glucosidase inhibitors
- flatulence, abdominal bloating, diarrhea.
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Non-sulfanylureas insulin stimulators
Name of drug Dose in 1 tabl.
Daily dose
Duration of action (hours)
Repaglinid (Novonorm, Roglid) (meglitinide analogs)
0,001; 0,002; 0,003; 0,004
0,001-0,016
3 - 4
Nateglinid (Starlix) (D-Phenilalanine-derivative)
0,06; 0,12; 0,18
0,18-0,54
1,5 - 3
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Action of non-sulfanylureas insulin stimulator.
Stimulation of insulin production at meal times;
very rapid absorbtion from the intestine and metabolism in the liver;
(plasma half-life is less than 1 hour).
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Indications to non-sulfanylureas insulin stimulator.
- can be used in elderly with type 2 DM (due to short half-life) and in renal impairment (because it is metabolized in liver).
Contraindications to non-sulfanylureas insulin stimulator.
- as for the sulfanilureas
Side effects of non-sulfanylureas insulin stimulator.
- hypoglycemia, transient elevation of liver enzymes, rash and visual disturbances.
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Commonly used thiazolidinediones
Name of drug Dose in 1 tabl.
Daily dose
Duration of action (hours)
Rosiglitazone (Avandia, Roglit, Rosinorm)
0,002; 0,004; 0,008
0,004-0,008
Pioglitazone (Actos, Pionorm)
0,015; 0,03; 0,045
0,015-0,03
Up to 24 hours
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Action of thiazolidinediones
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Contraindications to thiazolidinediones usage
Diabetic coma, precoma, ketoacidosis; Acute and chronic diseases of the liver; Heart failure; Pregnancy, lactation; Children, teenagers; Allergic reactions to the drug.
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GLP-1 Analogues Exenatide
Synthetic form of Exendin-4, derived from the
salivary secretions of the Gila monster lizard (Heloderma suspectum)
Liraglutide Novel long-acting analog obtained by acylation of
GLP-1 with fatty acid chain
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0 3 6 9 12
0
100000
200000
300000
400000
Time After Meal (h)
Pla
sma
Exe
nd
in-4
Co
nce
ntr
atio
n (
pg
/mL
)
Exendin-4 in the Gila Monster
♦Exendin-4 was originallyisolated from thesalivary secretions ofthe Gila monster
♦Exendin-4 wassubsequently found tocirculate as a meal-related peptide in this animal
Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome 2002, 235-262
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GLP-1 Modes of Action in Man GLP-1 Modes of Action in Man
GLP-1 is secretedfrom the L-cells
in the jejunumand ileum • Stimulate insulin secretion only when
blood glucose concentration is elevated
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effectsdemonstrated in animals…
• Increases beta-cell cell mass and maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…Upon ingestion of food…
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171
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Structure of native GLP-1 and two GLP-1 analogues
97% homology to native GLP-1
53% homology to native GLP-1
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Exenatide (Byetta)
♦ Pen prefill- one month’s supply♦ Given bid, 30-60 minutes prior to meal (250 cal)♦ Nausea experienced by almost all initially, typically
remits within days♦ Start at 5 mcg BID, then increase to 10 mcg BID after 1
month♦ Current indication: failing SFU, metformin, or both♦ Not FDA approved with insulin or monotherapy♦ Pancreatitis warning♦ Continue exenatide only if a person has a reduction in
HbA1c>1% and >3% of initial body weight in 6 months
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LIRAGLUTIDE 97% homologous with native human GLP-1 Half life of 11-15 hours Permitting once daily injection 1.2 and 1.8 mg/day Added to metformin, it reduces HbA1c by 1.5%
(p<0.01) Main side effects are nausea and vomiting
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Inhibition of DPP-4 Increases Active GLP-1
GLP-1 (9-36)inactive
IntestinalGLP-1
release
Mixed meal
GLP-1 (7-36)active
DPP-4
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
DPP-4inhibitor
GLP-1 (7-36)active
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Summary of DPP-4 Inhibition
• Increases fasting and postprandial GLP-1 levels• Reduces fasting and postprandial glycemia• Improves ß-cell function
– Increases insulin secretion, reduces proinsulin/insulin ratio– Increases beta-cell mass
• Inhibits glucagon secretion– Reduces hepatic glucose production
• Increases insulin sensitivity• Reduces postprandial lipemia• No effect on gastric emptying or body weight• Reduces HbA1c by ~1%• Is safe and tolerable in short term• In renal impairment, dose decreased by 50%
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SITAGLIPTIN
Licensed for use in T2DM at a dose of 100 mg once a day Can be added to metformin, a glitazone, a sulfonylurea
or a sulfonylurea+metformin, when current regime does not achieve glycemic control
HbA1c reduction of 0.5-1% Weight neutral and low risk of hypoglycemia Post prandial glucose also reduced (p<0.05) compared
to placebo Slightly higher rates of constipation, nasopharyngitis and
dizziness
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VILDAGLIPTIN
Licensed at a dose of 50 mg once or twice daily In T2DM as dual oral therapy Reduces HbA1c by 0.6-1.1% Reduces postprandial glucose Weight neutral and low risk of hypoglycemia Main side effects are headache,
nosopharyngitis, dizziness
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DPP-4 inhibitors
Continue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 months
DPP-4 inhibitor is preferable to a Glitazone if further weight gain would cause significant problems
TZDs are contraindicated
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Therapy Expected A1c (%) decrease with monotherapy
Lifestyle modifications 1.0-2.0
Metformin 1.5-2.0
Sulfonylurea 1.5-2.0
GLP-1 agonist 0.5-0.9
TZD 0.5-1.5
a-glucosidase inhibitor 0.3-1.0
Glinide 0.8-1.0
DPP-IV inhibitor 0.7-1.0
Pramlintide 0.4-0.5
Insulin unlimited
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ADA Algorithm for Management of DiabetesDiabetes Care. 2009, 32:193-203
At diagnosis:Lifestyle
+Metformin
Lifestyle+Metformin+
Pioglitazone(No hypoglycemia, edema,
CHF, bone loss)
Lifestyle+Metformin+
Sulfonylurea
Lifestyle+Metformin+
Intensive insulin
Lifestyle+Metformin+
Basal Insulin
Lifestyle+Metformin+
GLP1 (No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin+
Pioglitazone+
Sulfonylurea
Lifestyle+Metformin+
Basal Insulin
Tier 2: less well-validatedtherapies
Tier 1: Well-validated core therapies
Step 1Step 1 Step 2Step 2 Step 3Step 3
Amylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected
patients
*Useful when hypoglycemia is to be
avoided
2009
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Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach: Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes
(EASD).
Inzucchi SE, Bergenstal RM, Buse JB, et al. Diabetes Care. 2012 Apr 19.
2012
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From the history of insulin
Banting1891 - 1941
Best1899 - 1978
Macleod1876 - 1935
Collip1893 - 1965
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Indications for insulin therapy
1. All patients with type 1 DM.2. Some patients with type 2 DM: uncontrolled diabetes by diet or oral
hypoglycemic agents; ketoacidosis, coma; acute and chronic liver and kidneys disease with
decreased function; pregnancy and lactation; II – IV stages of angiopathy; infection diseases; acute heart and cerebral diseases; surgery.
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InsulinType+(Trade Name) Onset of Action Peak Duration Nursing Intervention
Rapid-acting (Clear)
Insulin Lispro (Humalog) Insulin Aspart (Novorapid)
Apidra (insulin glulisine)
10-15min 60-90min 4-5hrs Take within 15 min before meals or within 20 min after meals
Short Acting/Regular Insulin (clear)
Humulin R
30-60 2-4hrs 5-8hrs Take 30 min before meals
Intermediate-acting (cloudy)
(NPH/Lente)
1-4hrs 4-12hrs 18-24hrs
Ultra Lente and Glargine
(clear)
4-8hrs 18hrs 24-38hrs Note: Glargine can not be mixed with any other insulin
Premixed: 10/90, 20/80, 30/70, 40/60, 50/50(cloudy)
ideal time to give patients with their premixed is
30 min before their meal, with their meal and after their meal
Drawing up Insulin: Clear then cloudy to avoid contaminating the clear insulin
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Insulin preparations of ultrashort action(human analog, recombinant)
Insulin action
beginning maximum duration
NovoRapid (Insulin aspart) Novo-Nordisk
2-10 min 40 - 50 min 3 - 5 h
Humalog (insulin lispro)Lilly
Apidra (insulin glulisine)
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Insulin preparations of short actionInsulin action
beginning maximum duration
Humodar R 100 Indar - human insulin (semi-synthetic)
30 min 1 - 3 h 5 - 8 hHumodar R 100 R Indar - human insulin (recombinant)
Farmasulin H (regular insulin human injection, [rDNA origin])
Farmak
Actrapid (НМ)
Novo-Nordisk
Humulin R (regular insulin human injection, [rDNA origin]),
Lilly
Insuman rapid (regular insulin human injection, [rDNA origin])
Sanofi-aventis
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Insulin preparations of intermediate action
Insulin actionbeginning maximum duration
Humodar B 100 R Indar
1 – 1,5 h 6 - 8 h 12 – 18 h
Farmasulin Н NР Farmak
Protaphan (МС, НМ)
Novo-Nordisk
Insuman basal Aventis
Humulin NPH Lilly
Monotard НМ Novo-Nordisk
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Insulin preparations of long action
Insulin actionbeginning maximum duration
Farmasulin Н L Farmak
3 – 4 h 10 -12 h 24 – 30 h
Ultralente Humulin Lilly
Ultratard НМ
Glargine (Lantus)Aventis
-(human analog, recombinant)
24 hDetemir (Levemir) Novo Nordisk
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Insuman comb 25/75
Aventis 30 min 1,5-2 h 12-18 h
Humodar C15 Indar 30-45 min
1,5-3 h 12-18 h
Humodar C25 Indar 30-45 min
1,5-3 h 12-18 h
Humodar C50 Indar 30 min 1-3 h 6-10 h NovoMix® 30 Novo-
Nordisc 30 min 2-8 h 24 h
Insulin preparationscombined
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Storing and Handling Insulin
Opened bottles stored at room temperature (15 to 30°C).
If stored in a refrigerator, unopened bottles are good until the expiration date printed on the bottle.
Opened bottles that are stored in a refrigerator should be used within one month of being opened.
Protect your insulin (bottles, pens, and cartridges) from extremes of hot and cold.
Never store your insulin in the freezer - once insulin is frozen, it loses its potency.
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Initiation and modification of insulin therapy
It is started as soon as possible in an attempt to “rest” the damaged islet cells and help to “induce” a remission (“honeymoon” phase).
1 Unite
It is activity of 0,04082 mg of crystalic insulin (standart)
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Initiation and modification of insulin therapy
We can use traditional or multiple component insulin program. The last is better.
Advantages include the following: hypoglycemic reactions may be decreased or
prevented because smaller doses of insulin are needed;
more physiologic match of insulin to meals is achieved.
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Initiation and modification of insulin therapy to achieve diabetic control.Step 1: Estimate Total Daily Insulin (TDI) The daily insulin requirement in patients:- on the first year of the disease is 0,3 – 0,5
unite of insulin per kilogram of body weight (0,5 – if the patient with ketosis or DKA);
- on the next years is 0,6 – 0,8 – 1,0 unite/ kg of body weight.
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Secretion of insulin in health people
Con
cen
trat
ion
of
insu
lin
3 Breakfast 2, Meal secretion 3 Lunch Dinner 1,5 1 0,5 7.00 12.00 19.00 24.00 7.00 0
Basal secretion
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Initiation and modification of insulin therapy
2/3 of the total daily dose we give before breakfast, 1/3 in the evening and then make correction due to the glucose blood level. Insulin doses should be given 30 minutes before meals to allow for adequate absorption of regular insulin.
It using three or four shots of short-acting insulin (1/3 of total daily dose) plus intermediate-acting (2/3 of total daily dose) insulin daily twice a day.
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2/3 TDI
1/3 TDI
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Treatment of type 2 DM
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NPH-Based Multiple-Dose Insulin Therapy (MDI)
2 injections: • Premix 70/30 before AM and evening meal OR NPH + R/aspart/lispro/glulisine (ratio 2:1)
before AM and evening meal; mix insulins in same syringe.
Starting Dose: 0.3-0.5 units/kg/day divided as follows: 2/3 morning, 1/3 evening; before meals
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Methods of delivery insulin
Intravenous (IV) Syringes (SC) Pens Jet injectors Insulin pumps
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Site Selection for the Injections
4 major areas: Arms-posterior surface Abdomen-avoid 1 inch
area around navel Thighs-anterior surface HipsNote: Systematic rotation of injection sites
within an anatomic area to prevent lipodystrophy.
Administering each injection 0.5-1inch away from the previous injection.
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Some peculiarities of insulin therapy:
insulin acts faster when is administrated i/v;
subcutaneous and intramuscular absorption of insulin is decreased in the dehydrated or hypotensive patients;
the most rapid absorption from the abdomen;
exercise accelerates insulin absorption (before planned exercise program patient has to decrease insulin dose or take more caloric diet).
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Side effects (complications) of insulin therapy.1. Hypoglycemia. - This complication represents insulin excess and it
can occur at any time (frequently at night (common symptom: early-morning headache)).
- Precipitating factors: irregular ingesting of food; extreme activity; alcohol ingestion; drug interaction; liver or renal disease; hypopituitarism; adrenal insufficiency.
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Side effects (complications) of insulin therapy.
1. Hypoglycemia
It is a syndrome characterized by symptoms of sympathetic nervous system stimulation or central nervous system dysfunction that are provoked by an abnormally low plasma glucose level.
Hypoglycemia represents insulin excess and it can occur at any time.
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Side effects (complications) of insulin therapy2. Somogyi effect (Somogyi phenomenon,
rebound effect). It is caused by overinsulinization: hyperglycemia
proceeded by insulin – induced hypoglycemia. Hypoglycemia causes an increase in the secretion of the counterregulatory hormones (glucagon, epinephrine, cortisol, growth hormone), which inhibit insulin secretion and increase glucose output by the liver (as a result of the stimulation of glucogenolysis and glucogenesis).
Treatment: gradual reduction of insulin dose.
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Side effects (complications) of insulin therapy3. Dawn phenomenon. Many patients with type 1 DM demonstrate an
early morning (4 – 8 a.m.) rise in glucose levels, because of activation of counterregulatory hormones. It may be confused with the Somogyi phenomenon. Sampling of glucose levels throughout the night might help differentiate the two conditions.
Treatment: some have recommended an earlier injection in the morning (5 – 6 a.m.), and most suggest a late evening (before bedtime) injection of intermediate-acting insulin.
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Side effects (complications) of insulin therapy
4. Allergic reactions.
These include burning and itching at the site of insulin injection; skin rash; vasculaties; purpura and anaphylactic reaction.
Treatment:
- antihistamines;
- changing of standard insulin to pure pork insulin or to human insulin;
- in extreme cases – glucocorticoids.
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Side effects (complications) of insulin therapy5. Insulin resistance. - Clinical status characterized by insulin
resistance: obesity; therapy with oral contraceptives; glucocorticoid therapy; acromegaly; Cushing’s syndrome; acanthosis nigricans; chronic liver or renal disease. - Non-true insulin resistance may be caused by
long-time injections of insulin into the one site.
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Side effects (complications) of insulin therapy
6. Lipodystrophy.
- It is atrophy or hypertrophy of the adipose tissue, which occur at the site of insulin injection.
- Treatment: changing the site of injection; the usage of human insulin.
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Thank you for
attention!