1. Novel methods of treatment of diabetic patients
Novel methods of treatment of diabetic patients. Oral hypoglycemic agents, modern insulin preparations and its analogues.
assist. prof. Svystun I.I.

2. Good Diabetes Management
Regular Blood Glucose Monitoring
Healthy Nutrition 
Regular Exercise

4. 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 /
2-h postprandial glucose
<7.8 / <140
<10.0 / <180

5. Criteria of DM compensation

8. 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:

10. UKPDS: Tight glycamic control prevents complications

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).

13. Dedov et al. Diabetes mellitus. 2011;4:6-17. © 2011,Diabetes Mellitus.
Treatment goal HbA1c
Age
Young
Middle
Eldery and/or life expectancy <5 years
No complications
No risk of hypoglycemia
<6,5%
< 7,0%
<7,5%
Severe complications and /or risk of hypoglycemia
< 8,0%
Dedov et al. Diabetes mellitus. 2011;4:6-17. © 2011,Diabetes Mellitus.

14. ≤7%
≥7%
<
8,5
>
6,0
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 expectancy
b) High level of functional dependency
c) Extensive coronary artery disease at high risk of ischemic events
d) Multiple comorbidities
e) History of recurrent severe hypoglycemia
f) Hypoglycemia unawareness
g) 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 therapy
ADA: Executive Summary: Standards of Medical Care in Diabetes—2012; Diabetes Care January 2012

15. 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).

16. Self - control
Physician has to educate: - techniques of insulin administration and measurement of urine and blood glucose level (if taking insulin)

17. 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.

18. 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 %).

19. 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.

20. 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:
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)

21. Commonly used sulfonylureas

22. Action 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.

24. 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 .

25. 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.

26. Commonly used biguanides

27. Action of biguanides

28. 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.

29. Alpha-glucosidase inhibitors

30. 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).

31. Contrandications to alpha-glucosidase inhibitors
type 1 DM;
Chronic gastrointestinal disorders: pancreatitis, colitis, hepatitis.
Side effects of alpha-glucosidase inhibitors
- flatulence, abdominal bloating, diarrhea.

32. Non-sulfanylureas insulin stimulators

33. 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).

34. 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.

35. Commonly used thiazolidinediones

36. Action of thiazolidinediones

37. 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.

38. GLP-1 Analogues Exenatide Liraglutide
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

39. Exendin-4 in the Gila Monster Plasma Exendin-4 Concentration (pg/mL)
Exendin-4 was originally isolated from the salivary secretions of the Gila monster
Exendin-4 was subsequently found to circulate as a meal-related peptide in this animal
400000
300000
Plasma Exendin-4 Concentration (pg/mL)
200000
Exendin-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.
100000 3 6 9 12
Time After Meal (h)
Data from Young AA. Insulin Resistance and Insulin Resistance Syndrome 2002,

40. GLP-1 Modes of Action in Man
Upon ingestion of food…
Slows gastric emptying
Reduces food intake
GLP-1 is secreted
from the L-cells
in the jejunum
and ileum
Suppresses glucagon secretion
Stimulate insulin secretion only when blood glucose concentration is elevated
Long term effects demonstrated in animals…
Increases beta-cell cell mass and maintains beta-cell efficiency
Drucker DJ. Curr Pharm Des 2001; 7: Drucker DJ. Mol Endocrinol 2003; 17:

41. Structure of native GLP-1 and two GLP-1 analogues
97% homology to native GLP-1
53% homology to native GLP-1 41

42. Exenatide (Byetta) Pen prefill- one month’s supply
Given bid, 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

43. LIRAGLUTIDE 97% homologous with native human GLP-1
Half life of 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

44. Inhibition of DPP-4 Increases Active GLP-1
Mixed meal
Intestinal
GLP-1
release
GLP-1 (7-36)
active
GLP-1 (7-36)
active
DPP-4
DPP-4 inhibitor
GLP-1 (9-36)
inactive
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

45. 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%

46. 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

47. VILDAGLIPTIN Licensed at a dose of 50 mg once or twice daily
In T2DM as dual oral therapy
Reduces HbA1c by %
Reduces postprandial glucose
Weight neutral and low risk of hypoglycemia
Main side effects are headache, nosopharyngitis, dizziness

48. 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

49. Therapy
Expected A1c (%) decrease with monotherapy
Lifestyle modifications
Metformin
Sulfonylurea
GLP-1 agonist
TZD
a-glucosidase inhibitor
Glinide
DPP-IV inhibitor
Pramlintide
Insulin
unlimited

50. ADA Algorithm for Management of Diabetes Diabetes Care
2009
Tier 1: Well-validated core therapies
At diagnosis:
Lifestyle +
Metformin
Lifestyle+Metformin +
Basal Insulin
Lifestyle+Metformin +
Intensive insulin
Lifestyle+Metformin +
Sulfonylurea
Step 1
Step 2
Step 3
Tier 2: less well-validated
therapies
Lifestyle+Metformin +
Pioglitazone
Sulfonylurea
Lifestyle+Metformin +
Pioglitazone
(No hypoglycemia, edema,
CHF, bone loss)
*Useful when hypoglycemia is to be avoided
Lifestyle+Metformin +
GLP1
(No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin +
Basal Insulin
Amylin agonists, Glinides
DPP-4 inhibitors may be appropriate in selected patients

52. 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).
2012
Inzucchi SE, Bergenstal RM, Buse JB, et al. Diabetes Care Apr 19.

53. From the history of insulin
Best
Banting
Macleod
Collip

54. 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.

55. Insulin Type+(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

56. Insulin preparations of ultrashort action (human analog, recombinant)
beginning
maximum
duration
NovoRapid (Insulin aspart)
Novo-Nordisk
2-10 min
min
3 - 5 h
Humalog (insulin lispro)
Lilly
Apidra (insulin glulisine)

57. Insulin preparations of short action
beginning
maximum
duration
Humodar R 100 Indar - human insulin (semi-synthetic)
30 min
1 - 3 h
5 - 8 h
Humodar 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

58. Insulin preparations of intermediate action
beginning
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

59. Insulin preparations of long action
beginning
maximum
duration
Farmasulin Н L Farmak
3 – 4 h h
24 – 30 h
Ultralente Humulin Lilly
Ultratard НМ
Glargine (Lantus)Aventis -
(human analog, recombinant)
24 h
Detemir (Levemir)
Novo Nordisk

60. Insulin preparations combined

62. 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.

63. 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)

64. 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.

65. 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.

67. 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.

68. 2/3 TDI
1/3 TDI

70. Treatment of type 2 DM

71. 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: units/kg/day divided as follows: 2/3 morning, 1/3 evening; before meals

75. Methods of delivery insulin
Intravenous (IV)
Syringes (SC)
Pens
Jet injectors
Insulin pumps

77. Site Selection for the Injections
4 major areas:
Arms-posterior surface
Abdomen-avoid 1 inch area around navel
Thighs-anterior surface
Hips
Note:
Systematic rotation of injection sites within an anatomic area to prevent lipodystrophy.
Administering each injection 0.5-1inch away from the previous injection.

78. 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).

80. 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.

81. 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.

82. Side 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.

83. Side 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.

84. 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.

85. Side 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.

86. 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.

87. Thank you for attention!