terapia con ipoglicemizzanti orali e iniettivi

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


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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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


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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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!


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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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)


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



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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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


risk of hypo

use in CKD

CVD prev

Heart Failure

pheno-type

endog. insulin

nutr. status

ease of use





acarbose NO not

absorb. maybe NO prandial neutral neutral no

gliptins

GLP-1 RAs

gliflozins

basal insulins

• Detemir

• Glargine

• Glargine U300

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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)


risk of hypo

use in CKD

CVD prev

Heart Failure

pheno-type

endog. insulin

nutr. status

ease of use



only risk NO various needed gain no


acarbose NO not


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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide BID

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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


risk of hypo

use in CKD

CVD prev

Heart Failure

pheno-type

endog. insulin

nutr. status

ease of use





acarbose NO not




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


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

• Exenatide BID

• Exenatide LAR

• Liraglutide

• Lixisenatide

• Dulaglutide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS


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


risk of hypo

use in CKD

CVD prev

Heart Failure

pheno-type

endog. insulin

nutr. status

ease of use





acarbose NO not





gliflozins NO NO YES prevent both neutral loss yes

basal insulins

different medicines

different medicines

different medicines


risk of hypo

use in CKD

CVD prev

Heart Failure

pheno-type

endog. insulin

nutr. status

ease of use





acarbose NO not





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


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.

Date post:	12-Apr-2022
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