terapia con ipoglicemizzanti orali e iniettivi
Centro per le Malattie
Endocrine e Metaboliche
Andrea Giaccari [email protected]
gliptins
glinides
glitazons
amilin
GLP-1RA
colesevelam
acarbose
biguanides biguanides
sulphonilureas
α2 agonists
β blockers
Ca antagonists
α1 blockers
ACE-I
sartans renin inhibit.
diuretics
vasodilatators
1950 1960 1970 1980 1990 2000 2010
USA
GK agonists GR antagonist FGF21 GPR40 … … …
2
4
6
8
10
gliflozins
classes of drugs for type 2 diabetes (USA)
n
diabetes therapy in elderly
main characteristic to be considered:
• risk for hypos
• Chronic Kidney Disease
• history of stroke/CHD
• history of Heart Failure
• glycemic phenotype
• endogenous insulin
• nutritional status
• ease of use
diabetes therapy in elderly
available medicines:
• metformin
• SU and glinides
• pioglitazone
• acarbose
• gliptins and GLP-1 RA
• gliflozins
• basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin
SU & glinides
pioglitazone
acarbose
gliptins
GLP-1 RAs
gliflozins
basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
0 3 6 9 12 15 0
20
40
60
events (%)
years
Conventional (411)
intensive (951)
metformin (342)
UKPDS: all diabetes-related events (only obese patients)
M vs. I p=0.0034
M vs. Conv. p=0.0023
ukpds
%
0 1 3 4 2 0
5
10
15
20
5
metformin add on to insulin: CVD Dt2 patients treated only with insulin
Kooy A et al. Arch Intern Med 6:616, 2009
40% events CV
metformin
placebo
years
1. At least 2g daily if IR, 1g if XR (less A.E.)
2. Run-in
3. For all patients with T2D
4. Attention to eGFR
a. Monitor if eGFR < 60 mL/min
b. Discontinue if eGFR < 30 mL/min
c. Discontinue (temp.) if procedures carry risk of acute renal failure (e.g. iodinated contrast media)
4 Rules for metformin Rx
metformin: pros & cons
pros safe cheap no hypos primary CV protection
cons not indicated with eGFR <30 ml/min GI side effects (lower with XR)
elderly bid or tid large
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast needed loss XR
SU & glinides
pioglitazone
acarbose
gliptins
GLP-1 RA
gliflozins
basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
SU and repa: pros & cons
pros rapid cheap
cons hypoglycemia! rapid beta-cell failure weight gain increased CV risk not indicated in CKD
elderly increased risk for myocardial infarction
hypoglycemia!
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast needed loss XR
SU & glinides YES gliclazide
only risk neutral various needed gain no
pioglitazone
acarbose
gliptins
GLP-1 RAs
gliflozins
basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
events
%
0
5
10
25
30
0 12 18 36 6
pioglitazone
placebo
months
PROACTIVE: primary outcome
24
20
15
HR 95% CI p value
pioglitazone vs placebo
0.904 0.802, 1.018 0.0951
Dormandy JA et al.: Lancet 366:1279, 2005
PROACTIVE: Heart failure risk
Erdmann E et al.: Diabetes Care 30:2773, 2007
events
%
0
2
4
6
0 12 18 30 36 6
pioglitazone
placebo
months
24
events
%
0
5
15
0 12 18 36 6
pioglitazone
months
PROACTIVE: MACE MI, stroke and CV mortality
24
10
pio vs. placebo HR 0.82
(0.70-0.97) p=0.02
Wilcox R. et al AHJ 155:712, 2008
placebo
months
IRIS primary endpoint (stroke or MI, fatal or non-fatal)
Insulin Resistance Intervention after Stroke
Kernan WN et al. NEJM 374:1321, 2016
years
5 0 1 2 3 4
0
3
6
9
12
15
18
pioglitazone
placebo
patients
with e
vents
(%
)
pio vs. placebo HR 0.76
(0.62-0.93) p=0.007
pioglitazone: pros & cons
pros secondary CV prevention no hypoglycemia cheap
cons slow action fluid retention and heart failure significant weight gain fractures
elderly weight gain (for underweight)
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk neutral various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose
gliptins
GLP-1 RAs
gliflozins
basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
acarbose: mechanism of action •acarbose is a powerful - glucosidase
inhibitor
•the inhibition is for substrate competition (diet carbohydrates)
•The inhibition is selective and reversible
Glu Fru
sucrose
enzyme/substrate complex
enzyme/inhibitor complex
Cy Az Glu
Glu
acarbose
acarbose: delayed CHO absorption
CHO absorption
w/o acarbose
Duodenum Jejunum Ileum
with acarbose
acarbose: pros & cons
pros not absorbed no hypoglycemia cheap
cons poor efficacy gastrointestinal side effects
elderly bid or tid GI side effects
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk neutral various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose NO not
absorb. maybe NO prandial neutral neutral no
gliptins
GLP-1 RAs
gliflozins
basal insulins
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
gliptin vs. glipizide add-on to metformin
%
6.0
7.5
8.0
7.0
6.5
weeks
glipizide + met
6 52 30 38 0 12 18 24 46
Nauck MA Diab Ob Metab 9:194, 2007
sitagliptin 100 mg + met
0
10
20
30
40
n episodes
hypos
titrated glipizide + met
gliptins: efficacy according to basal HbA1c the higher is HbA1c, the higher is efficacy
Reductions are placebo-subtracted Nauck MA Diab Ob Metab 9:194, 2007
-2.0
-1.5
-1.0
-0.5
0
<8 8-9 >9
Δ%
HbA1c
sitagliptin 100 mg + met
gliptins: time to insulin initiation
0%
10%
20%
30%
40%
0 1 2 3 4 5 6 7patients
requirin
g insulin initia
tion
years
N=7,728
sulphonylureas
sitagliptin
Blonde L for The Odyssee Observational Study Diabetes 63(S1): LB-35 - ADA 2014
N
N
N
N
N
N
N
O
O
NH2
Linagliptin
(Boehringer Ingelheim)
Vildagliptin
(Novartis)
N
O
N
N H
O H
Sitagliptin
(Merck)
F
F F O
F F
F
NH2
N
N N
N
Source: CF Deacon
Saxagliptin
(BMS/Astra Zeneca)
N
O
OH
NH2
N
N NH2
N
N
O
O
Alogliptin
(Takeda) H3C
DPP-4 Inhibitors are chemically different
SAVOR: Rates of Risk of Hospitalization for HF Over Time
0%
1%
2%
3%
4%
5%
0 180 360 540 720 900
Ho
sp
ita
liza
tio
n f
or
HF
Days
Saxagliptin Placebo
Scirica BM, et al. November 2013.
HR: hazard ratio
EXAMINE: events by history of HF
White WB et al. NEJM 369:1327; 2013
VIVIDD (LAF237A23118): Objectives
Primary Objective: • To evaluate the effect of vildagliptin on left ventricular function in
patients with T2DM and CHF (NYHA class I-III)
Secondary Objectives: • To evaluate the overall safety and tolerability of vilda versus
placebo in patients with special regard to signs and symptoms of heart failure
• To evaluate the glucose-lowering efficacy of vilda by assessing the HbA1c reduction with vildagliptin compared with placebo after 16 w of treatment
Exploratory Objectives: • To explore the effect of vilda compared with placebo on other ECG
parameters of ventricular structure and function • To explore the effect of vildagliptin compared with placebo on BNP
after 52 weeks of treatment.
CHF, congestive heart failure; NYHA, New York Heart Association; T2DM, type 2 diabetes mellitus
TECOS: First hospitalization for HF
TECOS, McGuire DK et al.: JAMA Cardiol 1:126, 2016
years
4 1 0 2 3
patients
with e
vents
(%
) 5
4
3
2
1
0
placebo
sitagliptin
gliptins: pros & cons
pros absence of hypoglycemia stimulate insulin / inhibit glucagon rare side effects no effects on CV risk factors no gastrointestinal side effects no titration (except CKD)
cons cost
elderly heart failure (only for some of them)
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk NO various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose NO not
absorb. maybe NO prandial neutral neutral no
gliptins NO YES NO different
medicines both needed neutral yes
GLP-1 RAs
gliflozins
basal insulins
different medicines
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide BID
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
short and long-acting GLP-1R agonists
Short-acting GLP-1 RA
Long-acting GLP-1 RA
FPG reduction + +++
PPG reduction +++ ++
HbA1c reduction ++ +++
Body weight reduction ++ ++
Gastric empting rate +++ +
fasting glucagon secr. +/Neutral ++
GI effects ++ +
Compliance + ++
short and long-acting GLP-1 R As 24h plasma glucose profile
plasma glucose mg/dl
hours
Kapitza C et al. Diabetes Obes Metab 15: 642–649, 2013
250
200
150
100 0 1.5 3.5 4.5 6.5 8.5 10.5 12.5 14.5 24
lixisenatide (basal)
liraglutide (basal)
lixisenatide (day 28)
liraglutide (day 28)
LEADER: primary composite CV outcome
MACE 3: CV death, non-fatal MI or stroke
years
5 0 1 2 3 4
0
3
6
9
12
15
18
liraglutide
placebo
Marso SP et al.: NEJM 375:311, 2016
HR: 0.87 95% CI: 0.78.097 p<0.001 for non-inferiority p=0.01 for superiority
patients
with e
vents
(%
)
EXSCEL: primary composite CV outcome
MACE 3: CV death, non-fatal MI or stroke
years
5 0 1 2 3 4
HR (95% CI) 0.91 (0.83, 1.00)
P value (non-inferiority) <.001
P value (superiority) 0.061
0
3
6
9
12
15
18
exenatide
placebo
Holman RR et al.: NEJM in press, 2017
patients
with e
vents
(%
)
EXSCEL: All cause mortality
Holman RR et al.: NEJM in press, 2017
years
5 0 1 2 3 4
0
3
6
9
12
15
18
exenatide
placebo
HR (95% CI) 0.86 (0.77, 0.97)
P value 0.016
patients
with e
vents
(%
)
GLP1 R A: pros & cons
pros absence of hypoglycemia reduced CV risk factors easy titration
cons gastrointestinal side effects (some less) injections cost
elderly not indicated in CKD weight loss
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk NO various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose NO not
absorb. maybe NO prandial neutral neutral no
gliptins NO YES NO different
medicines both needed neutral yes
GLP-1 RAs NO NO NO various needed loss
gliflozins
basal insulins
different medicines
different medicines
different medicines
• Detemir
• Glargine
• Glargine U300
• Degludec
• NPH
• Gliclazide
• Glibenclamide/glyburide
• Glimepiride
• Gliquidone
• Glipizide
• Nateglinide
• Repaglinide
• Metformin
• Pioglitazone • Sitagliptin
• Saxagliptin
• Vildagliptin
• Linagliptin
• Alogliptin
• Exenatide BID
• Exenatide LAR
• Liraglutide
• Lixisenatide
• Dulaglutide
• Acarbose
• Miglitol • Dapagliflozin
• Canagliflozin
• Empagliflozin
INSULIN SULPHONYLUREAS
GLINIDES
BIGUANIDES
TZDs
GLIPTINS
GLP-1 RA
ALPHA GLUCOSIDASES INHIBITORS
SGLT2 INHIBITORS
classes of medicines for type 2 diabetes
add on to
mono therapy
efficacy of gliflozins in various settings compared vs. placebo at 24 weeks
-0,23 -0,3
-0,04 -0,13
-0,42
-0,3
-0,89 -0,84
-0,45
-0,82
-0,97 -0,9
-1,2
-1
-0,8
-0,6
-0,4
-0,2
0
1Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2Bailey CJ, et al. Lancet 2010;375:2223-33. 3Jabbour et al., Diabetes Care, pub online 15Jan2014 ; 4Strojek K, et al. Diabetes Obes Metab 2011;13:928-38. 5Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P. 6Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract 0078-OR.
HbA1c (
%)
met gliptin SU pio insulin
CANVAS & EMPAREG MACE 3: CV death, non-fatal MI or stroke
EMPAREG, Zinman B et al.: NEJM 373:2117, 2015 CANVAS, Neal B et al.: NEJM Jun 12, 2017
years
5 6 1 0 2 3 4
patients
with e
vents
(%
)
20
16
12
8
4
0
EMPAREG: 99 % with previous CV event
CANVAS: 65 % with previous CV event
placebo
canagliflozin
empaglifllozin
database N events HR (95%CI)
US 143,264 250 0.38 (0.29, 0.50)
Norway 25,050 364 0.55 (0.44, 0.68)
Denmark 18,468 323 0.46 (0.37, 0.57)
Sweden 18,378 317 0.47 (0.37, 0.60)
UK 10,462 80 0.73 (0.47, 1,15)
Total 215,622 1334 0.49 (0.41, 0.57)
CVD-REAL: all cause death primary analysis (N=215,622)
0.25 0.5 2
favor SGLT-2i favor other medicines
Hazard Ratio 1
Kosiborod M. et al.: Circulation 18:249, 2017
gliflozins induce stable weight loss (met ≥ 1.500 mg, dapa ≤ 10 mg, glipizide ≤ 20 mg)
Weig
ht
(%
)
3
0 2 3 4 years
glipizide
dapagligflozin
Nauck et al. DOM 16:1111, 2014
1
2
1
0
-1
-2
-3
-4
-5
0.73 kg
−3.65 kg
difference −4.38 kg
gliflozins: pros & cons
pros effective on all patients no hypoglycemia removes glucose toxicity reduces blood pressure
cons not effective with low eGFR GU infections (genital)
elderly weight loss hypotension
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk NO various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose NO not
absorb. maybe NO prandial neutral neutral no
gliptins NO YES NO different
medicines both needed neutral yes
GLP-1 RAs NO NO NO various needed loss
gliflozins NO NO YES prevent both neutral loss yes
basal insulins
different medicines
different medicines
different medicines
diabetes drugs in elderly
risk of hypo
use in CKD
CVD prev
Heart Failure
pheno-type
endog. insulin
nutr. status
ease of use
metformin NO no<30 YES NO fast neutral loss XR
SU & glinides YES gliclazide
only risk NO various needed gain no
pioglitazone NO no<15 YES YES fast neutral gain yes
acarbose NO not
absorb. maybe NO prandial neutral neutral no
gliptins NO YES NO different
medicines both needed neutral yes
GLP-1 RAs NO NO NO various needed loss
gliflozins NO NO YES prevent both neutral loss yes
basal insulins YES YES NO NO fast! fast gain no
different medicines
different medicines
different medicines
diabetes therapy in elderly
main characteristic to be considered:
• risk for hypos
• Chronic Kidney Disease
• history of stroke/CHD
• history of Heart Failure
• glycemic phenotype
• endogenous insulin
• nutritional status
• ease of use
Take home messages
• Non esiste un farmaco per tutti: la scelta deve essere personalizzata
• Non c’è stretta evidenza che alcuni farmaci siano migliori per alcuni pazienti
tuttavia
• Esistono ben dimostrati pro e contro per ognuno dei farmaci
• il nostro compito è conoscere i farmaci, i pazienti, e cercare di ottenere il migliore rapporto rischio beneficio possibile.