Insulinoterapia

Tinte glicemice in DZ tip 1

Studii Clinice in DZ tip 1

Conf. Dr. Cristian Guja MD, PhD

National Institute of Diabetes, Nutrition and Metabolic Diseases

Prof. NC Paulescu, Bucharest, Romania
1915 - Dieta Allen
Starvation Diet

Dr. Frederick Madison Allen

Mortalitate la 1 an:
65% nainte de 1915
45% ntre 1915-1922
 naintea insulinoterapiei

Robin Goland, Columbia University New York, USA

(1869 - 1931)
August 1921 Descoperirea insulinei
 Concluzii

I. Dac la un animal cu diabet,

diabet indus prin ablaia pancreasului,
se injecteaz un extract pancreatic n vena jugular, vom observa:

a) Diminuarea i chiar supresia temporar a hiperglicemiei,

hiperglicemiei care
poate fi nlocuit de hipoglicemie i o diminuare sau chiar
supresie temporar a glicozuriei
b) Scderea considerabil a ureei sanguine i ureei urinare
c) Scderea considerabil a cetonemiei i a cetonuriei
1922 Toronto Tratment DZ1 la om
1922 Primele insuline
1922 Insulina Eli Lilly

George HA Clowes

George B Walden
 1923 Insulina in Europa - Denemarca

August Krogh
Nordisk Insulin
Laboratorium Hans Christian Hagedorn

Novo insulin

Pedersen Brothers
1923 Insulina in Europa - Germania

Farbwerke Hoechst,
1920s Frankfurt, Germany.
Primele seringi de insulina
Insulinoterapia in anii 1920-1950

R
Primele preparate de insulina cu durata
prelungita de actiune

1950

1953
 1955 Elucidarea structurii moleculare a insulinei

Frederick Sanger

Nobel Prize 1958

 Primele insuline umane

1978 Genentech and City of Hope National Medical

Center

1982 Insulina umana produsa prin inginerie genetica

1982 Insulina umana semisintetica

1983
 Insulinoterapia Conventionala

NPH R Premix
 Tratamentul DZ tip 1: 1950-1980

1-2 injecii insulin zilnic

Diet rigid

Teste pentru glicozurie / Glicemie sporadic

la laborator

Normalizarea glicemiei nesigur i cu

beneficiu incert

HbA1c de regul > 11%

Complicaiile renale i oculare

inevitabile
1978-1982 Primele glucometre
 Dispozitive injectare tip pen
1985 - NovoPen
Profilul insulinosecretiei fiziologice

Mic dejun Prnz Cin

Timp (ore)
Analogi de insulina cu actiune rapida

1996 - Lispro 2000 - Aspart

Analogi prandiali

2004 - Glulisine
Analogi de insulina cu actiune prelungita
Analogi bazali

2001 2005
Profil actiune insuline utilizate
curent in practica
 Insulin Productor Debut Vrf aciune Durat
(ore) (ore) (ore)
Analogi rapizi insulin
Lispro (Humalog) Eli Lilly 10-15 min 1-2 3-5
Aspart (Novorapid) Novo Nordisk 10-15 min 1-2 3-5
Glulisin (Apidra) Sanofi 10-15 min 1-2 3-5
Analogi leni insulin
Glargine U100 (Lantus) Sanofi 2-4 - pn la 24 h
Glargine U300 (Toujeo) Sanofi 2-4 - > 24 h
Detemir (Levemir) Novo Nordisk 1-2 12h ? 20-24
Degludec (Tresiba) Novo Nordisk 0.5-1.5 - > 24
Insulin uman rapid (regular)
Actrapid HM (uman) Novo Nordisk 0.5 2-3 5-8
Humulin R (uman) Eli Lilly 0.5 2-3 5-8
Insuman Rapid (uman) Sanofi 0.5 2-3 5-8
Insulin NPH
Insuman Bazal (uman) Sanofi 1.5-4 4-10 12-20
Humulin N (uman) Eli Lilly 1.5-4 4-10 12-20
Insulin premixat
Humulin M 1-5 Eli Lilly 0.5 4-10 12-20
Mixtard 10-50 Novo Nordisk 0.5 4-10 12-20
Insuman Comb 25, 50 Sanofi 0.5 4-10 12-20
Insulin premixat analog
Humalog Mix 25, 50 Eli Lilly 10-15 min 4-10 12-20
NovoMix 30 Novo Nordisk 1-8 12-18
Locuri de injectare a insulinei
Lipodistrofia insulinica
Insulinoterapia in DZ1
Insulinoterapie tip Basal-bolus
Insulinoterapie functionala / fiziologica
 Principii
Estimarea necesarului de insulin bazal, Ajustarea
dozei n funcie de glicemia a jeun
Estimarea necesarului de insulina prandial per 10 g
HC (sau HC pentru 1 U of insulina)
Estimarea cantitii de HC, individualizarea dozei n
funcie de cantitatea alimentelor
Estimarea dozei de insulin pentru corecia
hiperglicemiei (Insulin correction Factor)
Estimarea cantitii HC pentru corecia hipoglicemiei
 Iniierea insulinoterapiei
Necesar insulin (Total Daily Dose TDD)
0.5 U/kg/zi (CC abseni)
0.7 U/kg/zi (CC prezeni)
Insulin Bazal: 50% TDD (Total Daily Dose)
Insulin prandial: 50% TDD
- (Distribuit n mod egal ntre cele 3 mese)
- Insulin-to-Carbohydrate Ratio 500/TDD = g CH pt 1 U IR
Corecia hiperglicemiei
1800/TDD (Analog Rapid) sau 1500/TDD (Ins Uman)
Corecia hipoglicemiei:
15 g HC, verific glicemia dup 15 min

ADA & International Diabetes Center (IDC) www.internationaldiabetescenter.com

 Tinte glicemice la pacientii DZ1

HbA1c (%) Glicemie a jeun Glicemie pp

ADA (adulti) < 7%* (53 mmol/mol) 80-130 mg/dl < 180 mg/dl
AACE (adulti) < 6.5% (47.5 mmol/mol) < 110 mg/dl < 140 mg/dl
ADA (copii) < 7.5%* (58 mmol/mol) 90-130 mg/dl 90-150 mg/dl
ISPAD (copii) < 7.5% (58 mmol/mol) 90-145 mg/dl 90-180 mg/dl
Insulinoterapie in DZ2
 Healthy eating, weight control, increased physical activity & diabetes education
Mono-
therapy Metformin
Efcacy* high
Hypo risk low risk
Weight neutral/loss
Side effects GI / lactic acidosis
Costs low
Metformin If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
intolerance or any specific preference - choice dependent on a variety of patient- & disease-specific factors):

contraindicati Metformin Metformin Metformin Metformin Metformin Metformin

+ + + + + +
on
Dual Sulfonylurea Thiazolidine- DPP-4 SGLT2 GLP-1 receptor Insulin (basal)
therapy dione inhibitor inhibitor agonist
Efcacy* high high intermediate intermediate high highest
moderate risk low risk low risk low risk low risk high risk
HbA Hypo risk
Weight gain gain neutral loss loss gain
1c Side effects hypoglycemia edema, HF, fxs rare GU, dehydration GI hypoglycemia
9% Costs low low high high high variable

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin Metformin Metformin Metformin Metformin Metformin
+ + + + + +
Triple Sulfonylurea Thiazolidine-
dione
DPP-4
Inhibitor
SGLT-2
Inhibitor
GLP-1 receptor
agonist
Insulin (basal)
therapy + + + + + +
TZD SU SU SU SU TZD

or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i

or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin or SGLT2-i

or GLP-1-RA or GLP-1-RA or Insulin or Insulin or GLP-1-RA

Uncontrolled
hyperglycemia or Insulin or Insulin
(catabolic
features, If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
BG 300-350 Metformin
mg/dl, HbA1c +
Combination
10-12%)
injectable Basal Insulin + Mealtime Insulin or GLP-1-RA
therapy DiabetesCare2015;38:140149;Diabetologia 2015;58:429-442
 ADA/EASD Initierea insulinoterapiei

Basal Insulin
(usually with metformin +/-
other non-insulin agent)

Start: 10U/day or 0.1-0.2 U/kg/day

Adjust: 10-15% or 2-4 U once-twice weekly to
reach FBG target.
For hypo: Determine & address cause;
dose by 4 units or 10-20%.

Diabetes Care 2015;38:140-149;

Diabetologia 2015;58:429-442
 reach FBG target.
For hypo: Determine & address cause;

ADA/EASD Intensificarea insulinoterapiei dose by 4 units or 10-20%.

If not
controlled after
FBG target is reached
(or if dose > 0.5 U/kg/day),
treat PPG excursions with
meal-time insulin.
(Consider initial
Add 1 rapid insulin* injections GLP-1-RA Change to
before largest meal trial.) premixed insulin* twice daily

Start: 4U, 0.1 U/kg, or 10% basal dose. If Start: Divide current basal dose into 2/3 AM,
A1c<8%, consider basal by same amount. 1/3 PM or 1/2 AM, 1/2 PM.
Adjust: dose by 1-2 U or 10-15% once- Adjust: dose by 1-2 U or 10-15% once-
twice weekly until SMBG target reached. twice weekly until SMBG target reached.
For hypo: Determine and address cause; For hypo: Determine and address cause;
corresponding dose by 2-4 U or 10-20%. corresponding dose by 2-4 U or 10-20%.

If not If not
controlled, Add 2 rapid insulin* injections controlled,
consider basal- consider basal-
bolus.
before meals ('basal-bolus) bolus.
Start: 4U, 0.1 U/kg, or 10% basal dose/meal. If
A1c<8%, consider basal by same amount.
Adjust: dose by 1-2 U or 10-15% once-twice
weekly to achieve SMBG target.
For hypo: Determine and address cause;
Diabetes Care 2015;38:140-149; corresponding dose by 2-4 U or 10-20%.
Diabetologia 2015;58:429-442
 Bariere iniiere insulin

Nu accept
Am HbA1c 9,6% Vreau s mai
DOCTOR
i glicemia 250 mg% ncerc cu pastile!

O s mi spun Nu vreau s m
de insulin nep. i dac m
din nou? ngra

Nu mai am Am euat. Nu sunt

nici o ans! bun de nimic.
S-a terminat
Insulin is a remedy primarily for the wise and
not for the foolish, whether they be patients or
doctors

Elliot P Joslin 1923

Evidence Based Medicine (EBM)

Medicina bazat pe dovezi

 naintea EBM

J.J. Jackson 1836

Dac putem considera
ceva ca fiind indubitabil
n tratamentul bolilor,
aceasta este c
sngerarea este
folositoare n bolile
inflamatorii i mai ales
n cele ale viscerelor
toracice
 naintea EBM Sngerearea

A hotrt s foloseasc noua

metod numeric (statistica)
ca s vad cte viei putea
salva n urma aplicrii
sngerrii la pacienii cu
pneumonie bacterian
Pierre Alex. Louis
1787 - 1872
 naintea EBM Sngerearea

Spre consternarea sa, Dr. Pierre Louis a constatat

c sngerarea ducea de fapt la creterea mortalitii
 Anii 60-70 Complicatiile cronice nu sunt
determinate de hiperglicemia cronica

J Clin Invest 1968 47:1973-1999

 Controlul glicemic si riscul de
complicaii cronice ale DZ

EP Joslin 1917
The Treatment of Diabetes Mellitus

Jean Pirart
Diab Metab 1977
Diabetes Care 1978
 Studiul DCCT - Scop

Sa determine daca:
Ameliorarea controlului metabolic in DZ1 prin
insulinoterapie intensificat (Bazal Bolus) cu
scderea HbA1c sub 7% duce la scderea
frecvenei complicaiilor cronice comparativ cu
insulinoterapia conventional
 DCCT Impact pe HbA1c si glicemie
300 - 11 -
Conventional

Glycosylated hemoglobin (%)

Conventional
Capillary glucose (mg/dl)

10 -
250 -

9-

200 -
8-

7-
150 -
6-
Intensive
Intensive
100 - 5-
Breakfast Lunch Dinner Bedtime 0 1 2 3 4 5 6 7 8 9 1
Time Year of study 0

NewEngl J Med 1993, 329, 977

 DCCT: Impact pe retinopatie
60 -

50 -
% pacieni

40 -
Conventional
30 -
76%
20 -
p<0.001
10 -
Intensiv
0-
0 1 2 3 4 5 6 7 8 9
Year of study

DCCT Study Group NEJM 1993, 329:977-986

 DCCT: Impact pe nefropatie

Intensiv

30 Conventional

Patients (%)
20
34%

10

0
0 2 4 6 8 10
Year

*Urinary albumin excretion 40 mg per 24 hours

DCCT Study Group NEJM 1993, 329:977-986

DCCT: Preul pentru controlul metabolic
Relaia dintre HbA1c i hipoglicemiile severe

DCCT Study Group NEJM 1993, 329:977-986

 Epidemiology of Diabetes
Interventions and Complications
Study - EDIC
 Evoluia HbA1c n EDIC

Intensiv
Conventional Pacientii tratai
11
convenional au trecut
10 la tratament intensificat
HbA1c (%)

0
1 2 3 4 5 6 7 8 9 DCCT 1 2 3 4 5 6 7
end
DCCT EDIC
Ani

Adapted from: N Engl J Med 1993;329:97786, EDIC: JAMA 2002;287:25639

 EDIC

10 ani de urmrire dup terminarea DCCT

Scdere semnificativ a:
Retinopatiei diabetice
Neuropatiei diabetice
Bolii renale diabetice
Evenimentelor cardiovasculare majore

1. White et al 2008 Dec;126(12):1707-15. 2. Genuth Endocrine Practice 2006 Jan-Feb;12 Suppl 1:34-41.
 DCCT / EDIC Memorie
Metabolic

1. White et al 2008 Dec;126(12):1707-15. 2. Genuth Endocrine Practice 2006 Jan-Feb;12 Suppl 1:34-41.
 De reinut ! (1)

Insulinoterapia n DZ1:

Indicaie major insulin n regim bazal bolus

Analogi insulin cu aciune rapid (Novorapid,

Apidra, Humalog) la mese.
mese

Analogi de insulin cu aciune lent (Lantus,

Levemir, Toujeo) o dat pe zi.
 De reinut ! (2)

Insulinoterapia n DZ2:

Poate fi iniiat nc din treapta a 2-a de tratament

dup eecul monoterapiei cu metformin

Analogi de insulin cu aciune lent (Lantus,

Levemir, Toujeo) o dat pe zi.

Titrarea dozei de insulin bazal n funcie de

glicemia a jeun

. Insulinoterapia de tip bazal bolus ar trebui s fie o

excepie n DZ2 !
 De reinut ! (3)

Controlul metabolic intensiv se asocieaz cu:

Scderea riscului de complicaii cronice

microvasculare att n DZ tip 1 ct i n DZ tip 2

Scderea riscului de complicaii macrovasculare la

pacienii cu DZ tip 1.
1

Scderea riscului de complicaii macrovasculare la

pacienii cu DZ tip 2, mai ales tineri, cu DZ de scurt
durat. Efectul benefic se manifest dup cel puin 7-10
ani.