12(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).
14≤7%≥7%<8,5>6,0An 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 hypoglycemiaLess 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
15Methods of treatment DM EducationExercise program.Diet.Oral hypoglycemic agents or insulin (indications for each vary with the type of DM and severity of the disease).
16Self - controlPhysician has to educate: - techniques of insulin administration and measurement of urine and blood glucose level (if taking insulin)
17ExerciseExercise: Before diabetic patients engage in exercise program, they should consult with their healthcare provider because they need to have a complete history and physical examinationExercise (total of about 30 minutes a day, at least 5 days a week) lowers blood sugar levels by improving cell uptake of glucose.
18The 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 %).
19The main principles of diet. Normal-calorie diet in patients with type 1 DM (35-50 kcal/kg of ideal weight (weight = height – 100)) andlow-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.
20Oral 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:sulfonilureas,biguanides,alpha-glucosidase inhibitors,non-sulfonylureas insulin stimulators (glinides),thiazolidinediones (glitazones),dipeptidyl peptidase IV (DPP-IV) inhibitors,glucagon-like peptide-1 (GLP-1) receptor agonist,analogue of amylin (pramlintide)
22Action of sulfonilureas 1. 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.
24Side 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 .
25Contrandications 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.
28Contraindications 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.
30Action 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).
31Contrandications to alpha-glucosidase inhibitors type 1 DM;Chronic gastrointestinal disorders: pancreatitis, colitis, hepatitis.Side effects of alpha-glucosidase inhibitors- flatulence, abdominal bloating, diarrhea.
33Action 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).
34Indications 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 sulfanilureasSide effects of non-sulfanylureas insulin stimulator.- hypoglycemia, transient elevation of liver enzymes, rash and visual disturbances.
37Contraindications 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.
38GLP-1 Analogues Exenatide Liraglutide Synthetic form of Exendin-4, derived from the salivary secretions of the Gila monster lizard (Heloderma suspectum)LiraglutideNovel long-acting analog obtained by acylation of GLP-1 with fatty acid chain
39Exendin-4 in the Gila Monster Plasma Exendin-4 Concentration (pg/mL) Exendin-4 was originally isolated from the salivary secretions of the Gila monsterExendin-4 was subsequently found to circulate as a meal-related peptide in this animal400000300000Plasma Exendin-4 Concentration (pg/mL)200000Exendin-4 is present in high concentration in the saliva of the Gila monster. It is secreted 4x greater in response to an oral glucose stimulus compared to an intravenous stimulus similar to the incretin effect seen in human subjects.10000036912Time After Meal (h)Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome 2002,
40GLP-1 Modes of Action in Man Upon ingestion of food…Slows gastric emptyingReduces food intakeGLP-1 is secretedfrom the L-cellsin the jejunumand ileumSuppresses glucagon secretionStimulate insulin secretion only when blood glucose concentration is elevatedLong term effects demonstrated in animals…Increases beta-cell cell mass and maintains beta-cell efficiencyDrucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:
41Structure of native GLP-1 and two GLP-1 analogues 97% homology to native GLP-153% homology to native GLP-141
42Exenatide (Byetta) Pen prefill- one month’s supply Given bid, minutes prior to meal (250 cal)Nausea experienced by almost all initially, typically remits within daysStart at 5 mcg BID, then increase to 10 mcg BID after 1 monthCurrent indication: failing SFU, metformin, or bothNot FDA approved with insulin or monotherapyPancreatitis warningContinue exenatide only if a person has a reduction in HbA1c>1% and >3% of initial body weight in 6 months
43LIRAGLUTIDE 97% homologous with native human GLP-1 Half life of hoursPermitting once daily injection1.2 and 1.8 mg/dayAdded to metformin, it reduces HbA1c by 1.5% (p<0.01)Main side effects are nausea and vomiting
44Inhibition of DPP-4 Increases Active GLP-1 Mixed mealIntestinalGLP-1releaseGLP-1 (7-36)activeGLP-1 (7-36)activeDPP-4DPP-4 inhibitorGLP-1 (9-36)inactiveAdapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.
45Summary of DPP-4 Inhibition Increases fasting and postprandial GLP-1 levelsReduces fasting and postprandial glycemiaImproves ß-cell functionIncreases insulin secretion, reduces proinsulin/insulin ratioIncreases beta-cell massInhibits glucagon secretionReduces hepatic glucose productionIncreases insulin sensitivityReduces postprandial lipemiaNo effect on gastric emptying or body weightReduces HbA1c by ~1%Is safe and tolerable in short termIn renal impairment, dose decreased by 50%
46SITAGLIPTIN 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 controlHbA1c reduction of 0.5-1%Weight neutral and low risk of hypoglycemiaPost prandial glucose also reduced (p<0.05) compared to placeboSlightly higher rates of constipation, nasopharyngitis and dizziness
47VILDAGLIPTIN Licensed at a dose of 50 mg once or twice daily In T2DM as dual oral therapyReduces HbA1c by %Reduces postprandial glucoseWeight neutral and low risk of hypoglycemiaMain side effects are headache, nosopharyngitis, dizziness
48DPP-4 inhibitorsContinue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 monthsDPP-4 inhibitor is preferable to a Glitazone if further weight gain would cause significant problemsTZDs are contraindicated
49TherapyExpected A1c (%) decrease with monotherapyLifestyle modificationsMetforminSulfonylureaGLP-1 agonistTZDa-glucosidase inhibitorGlinideDPP-IV inhibitorPramlintideInsulinunlimited
50ADA Algorithm for Management of Diabetes Diabetes Care 2009Tier 1: Well-validated core therapiesAt diagnosis:Lifestyle+MetforminLifestyle+Metformin+Basal InsulinLifestyle+Metformin+Intensive insulinLifestyle+Metformin+SulfonylureaStep 1Step 2Step 3Tier 2: less well-validatedtherapiesLifestyle+Metformin+PioglitazoneSulfonylureaLifestyle+Metformin+Pioglitazone(No hypoglycemia, edema,CHF, bone loss)*Useful when hypoglycemia is to be avoidedLifestyle+Metformin+GLP1(No hypoglycemia, wt loss,Nausea/vomiting)Lifestyle+Metformin+Basal InsulinAmylin agonists, GlinidesDPP-4 inhibitors may be appropriate in selected patients
52Management 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).2012Inzucchi SE, Bergenstal RM, Buse JB, et al. Diabetes Care Apr 19.
53From the history of insulin BestBantingMacleodCollip
54Indications 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.
55Insulin Type+(Trade Name) Onset of Action Peak Duration Nursing InterventionRapid-acting (Clear)Insulin Lispro (Humalog) Insulin Aspart (Novorapid)Apidra (insulin glulisine)10-15min60-90min4-5hrsTake within 15 min before meals or within 20 min after mealsShort Acting/Regular Insulin (clear)Humulin R30-602-4hrs5-8hrsTake 30 min before mealsIntermediate-acting (cloudy)(NPH/Lente)1-4hrs4-12hrs18-24hrsUltra Lente and Glargine(clear)4-8hrs18hrs24-38hrsNote: Glargine can not be mixed with any other insulinPremixed: 10/90, 20/80, 30/70, 40/60, 50/50 (cloudy)ideal time to give patients with their premixed is30 min before their meal, with their meal and after their mealDrawing up Insulin: Clear then cloudy to avoid contaminating the clear insulin
57Insulin preparations of short action beginningmaximumdurationHumodar R 100 Indar - human insulin (semi-synthetic)30 min1 - 3 h5 - 8 hHumodar R 100 R Indar - human insulin (recombinant)Farmasulin H (regular insulin human injection, [rDNA origin])FarmakActrapid (НМ)Novo-NordiskHumulin R (regular insulin human injection, [rDNA origin]),LillyInsuman rapid (regular insulin human injection, [rDNA origin])Sanofi-aventis
58Insulin preparations of intermediate action beginningmaximumdurationHumodar B 100 R Indar1 – 1,5 h6 - 8 h12 – 18 hFarmasulin Н NР FarmakProtaphan (МС, НМ)Novo-NordiskInsuman basal AventisHumulin NPH LillyMonotard НМ Novo-Nordisk
59Insulin preparations of long action beginningmaximumdurationFarmasulin Н L Farmak3 – 4 hh24 – 30 hUltralente Humulin LillyUltratard НМGlargine (Lantus)Aventis-(human analog, recombinant)24 hDetemir (Levemir)Novo Nordisk
62Storing 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.
63Initiation 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 UniteIt is activity of 0,04082 mg of crystalic insulin (standart)
64Initiation 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.
65Initiation 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.
67Initiation 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.
71NPH-Based Multiple-Dose Insulin Therapy (MDI) 2 injections:• Premix 70/30 before AM and evening mealORNPH + R/aspart/lispro/glulisine (ratio 2:1) before AM and evening meal; mix insulins in same syringe.Starting Dose: units/kg/day divided as follows: 2/3 morning, 1/3 evening; before meals
77Site Selection for the Injections 4 major areas:Arms-posterior surfaceAbdomen-avoid 1 inch area around navelThighs-anterior surfaceHipsNote:Systematic rotation of injection sites within an anatomic area to prevent lipodystrophy.Administering each injection 0.5-1inch away from the previous injection.
78Some 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 fromthe abdomen;exercise accelerates insulin absorption (before planned exercise program patient has to decrease insulin dose or take more caloric diet).
80Side 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.
81Side 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.
82Side effects (complications) of insulin therapy 2. 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.
83Side effects (complications) of insulin therapy 3. 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.
84Side 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.
85Side effects (complications) of insulin therapy 5. 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.
86Side 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.