Ottimizzare la terapia del diabete mellito tipo 2

Ottimizzare la terapia del diabete

mellito tipo 2

Emanuele BosiProfessore Ordinario e Direttore Scuola di Specializzazione in Medicina Interna

Università Vita Salute San Raffaele e ospedale San Raffaele

Seminario ai Medici di Medicina Generale

14 Ottobre 2021 - ore 19.30

Incontri di formazione e confronto - Seminario ai Medici di Medicina Generale& Scuola di Specializzazione in Medicina Interna, Università vita Salute San Raffaele

Webinar, 14 Ottobre 2021 - ore 19.30

Due determinanti sono alla base della patogenesi del diabete

di tipo 2: insulino-resistenza e insulino-deficienza

Adapted from Inzucchi SE. JAMA 2002;287:360–72

INSULIN RESISTANCE

Increased

glucose

production

Decreased

glucose

uptake/

utilisation

Increased

lipolysis

Increased

free fatty acids

ISLET CELL

DYSFUNCTION

-cell dysfunction

α-cell dysfunction

Hyperglycaemia

Lipotoxicity Lipotoxicity

2

IFG=impaired fasting glucose; IGT=impaired glucose tolerance; NGT=normal glucose tolerance. Adapted from International Diabetes Center Adapted from Type 2 Diabetes BASICS. Minneapolis, Minn: International Diabetes Center; 2000

3

Complications

Blo

od

glu

co

se

Time

InsulinRisk of diabetes

Impaired islet cell function

Insulin resistance

Pro

po

rtio

na

l a

mou

nt o

f

insu

lin in r

ela

tio

n to

no

rma

l (%

)

Postprandial glucose

Fasting glucose

DiabetesPrediabetes

(IFG/IGT)NGT

Il diabete di tipo 2 è una malattia cronica e progressiva,

caratterizzata da insorgenza precoce delle complicanze

3

Il diabete di tipo 2 è associato a complicanze croniche a carico di

numerosi organi e tessuti

4

Microvascular Macrovascular

Brain(stroke, TIA)

Eye(retinopathy, cataracts,

glaucoma)

Kidney(nephropathy, ESRD)

Nerves(neuropathy,

peripheral and

autonomic)

Heart (angina, MI, CHF)

Extremities(peripheral vascular

disease, gangrene,

amputation)

CHF=congestive heart failure; ESRD=end-stage renal disease; MI=myocardial infarction; TIA=transient ischaemic attackAdapted from Cavender MA et al. Am J Cardiovasc Drugs 2010;10:209–16

Le malattie cardiovascolari sono la causa prima dell’eccesso di mortalità associato al diabete di tipo 2

The Emerging Risk Factors Collaboration. N Engl J Med 2011;364:829-841.

Il diabete come equivalente cardiovascolare

Haffner SM, et al. N Engl J Med. 1998;339:229-34.

DM=diabetes mellitus; MI=myocardial infarction

7-y

ear in

cid

en

ce

rate

of

MI (

%)

0

20

No DMNo MI

50

40

No DMMI

DMNo MI

DMMI

30

10

p<0.001

45.0

p<0.001

18.8 20.2

3.5

Non-diabetic(n=1373)

Diabetic(n=1059)

Incidenza dell’infarto acuto del miocardio in USA 1990-2010

Adapted from Gregg EW, et al. N Engl J Med 2014;370:1514–1523.

Il diabete come fattore di rischio della malattia cardiovascolare

• Le malattie cardiovascolari sono la causa principale di mortalità e di morbilità dei soggetti diabetici;

• Il controllo della glicemia risulta efficace nella prevenzione, alla condizione di essere perseguito precocemente e senza incorrere in ipoglicemia.

• Benché l’incidenza delle complicanze del diabete si sia ridotta nel corso degli ultimi 20 anni, un eccesso di mortalità (rischio residuo) per malattie cardiovascolari persiste;

• La riduzione del rischio cardiovascolare rimane pertanto come obiettivo primario del diabete di tipo 2.

The De Fronzo’s Ominous Octet

Difetti multipli contribuiscono all’iperglicemia nel

diabete di tipo 2

Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.

Hyperglycaemia

DecreasedInsulin

Secretion

IncreasedGlucagonSecretion

NeurotransmitterDysfunction

DecreasedIncretin Effect

IncreasedHGP Decreased

Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell

Trattamenti anti-diabete

1. Stili di vita (empiricamente dall’epoca pre-insulina)

2. Insulina (1922)

3. Sulfoniluree (1955)

4. Metformina (1957)

5. Acarbose (1995)

6. Glitazoni (1997)

7. GLP-1 agonisti (2005)

8. DPP-4 inibitori (2006)

9. SGLT-2 inibitori (2012)

Pharmacologic targets of current drugs used in

the treatment of T2DM

11

Glitazones

Decrease lipolysis in adipose

tissue, increase glucose uptake

in skeletal muscle and decrease

glucose production in liver

DPP-4 inhibitors

Prolong GLP-1 action leading

to improved pancreatic

islet glucose sensingGLP-1 receptor agonists

Improve pancreatic islet

glucose sensing, slow gastric

emptying, improve satiety

Glinides

Increase insulin secretion

from pancreatic -cells

a-glucosidase inhibitors

Delay intestinal

carbohydrate absorption

Sulphonylureas

Increase insulin secretion

from pancreatic -cells

Adapted from Cheng AY, Fantus IG. CMAJ 2005;172:213–26. Adapted from Ahrén B, Foley JE. Int J Clin Pract 2008;62:8–14. Adapted from Kim Y, Babu AR.

Diabetes Metab Syndr Obes. 2012;5:313–27

SGLT-2 inhibitors

Lower the renal glucose threshold to

increase urinary glucose excretion

Pathogenetic site of action of oral anti-diabetic agents

Hyperglycaemia

DecreasedInsulin

Secretion





Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell

Metformin

Adapted from De Fronzo RA. Diabetes. 2009;58:773-95

Targeting insulin resistance


Hyperglycaemia

DecreasedInsulin

Secretion





Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell

Sulphonylureas

Glinides


Targeting islet dysfunction

Hyperglycaemia

DecreasedInsulin

Secretion





Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell



Pioglitazone

Targeting insulin resistance

Hyperglycaemia

DecreasedInsulin

Secretion





Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell

GLP-1 &

DPP4-inhibitors



Targeting islet dysfunction

Hyperglycaemia

DecreasedInsulin

Secretion





Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-a cell

SGLT2-inhibitors



Insulin independent action

The usual paradigm:

Before UKPDS (1998): Sulfonylureas, ± Metformin → Insulin(Basal, Mix, Basal-bolus)

After UKPDS (1998): Metformin first, when possible, thenSulfonylureas and/or Insulin (Basal, Mix, Basal-bolus)

Management of hyperglycemia in type 2 diabetes: before 2006 no clear pathway of therapy to follow

2006

The first proposal

of an algorithm

Algorithm for the metabolic management of type 2 diabetes.

David M. Nathan et al. Diabetes Care 2006;29:1963-1972

2008

Update warning on

thiazolidinediones

Algorithm for the metabolic management of type 2 diabetes.


2009

Introduction of GLP-1

receptor agonists

Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at

every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months.


2012

Concept of patient-centered approach

Introduction of DPP-4 inhibitors

Antihyperglycemic therapy in type 2 diabetes: general recommendations.

Inzucchi SE et al. Diabetes Care 2012;35:1364-1379

Sequential Insulin Strategies in T2DM Inzucchi SE et al. Diabetes Care 2012;35:1364-1379

Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandial glucose < 180 mg/dL

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

HDL: > 40 mg/dL (1.04 mmol/l)

> 50 mg/dL (1.30 mmol/l)

TG: < 150 mg/dL (1.69 mmol/l)

ADA. Diabetes Care. 2012;35:S11-63HDL = high-density lipoprotein; LDL = low-density

lipoprotein; PG = plasma glucose; TG = triglycerides.

2015

Introduction of SGLT-2 inhibitors

Initial drug therapy:Advancing to dual combination Advancing to triple combination

Transitions to and titrations of insulin

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk

neutral/loss

GI / lactic acidosis

low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-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 +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione

intermediate low risk

neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

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):

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:

Metformin +

Combination injectable therapy‡

GLP-1-RA Mealtime Insulin

Insulin (basal)

+

Figure 2. Anti-hyperglycemic therapy in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



or

or

or

Insulin (basal)

+

Figure 2A. Anti-hyperglycemic therapy in T2DM: Avoidance of hypoglycemia Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+

or

or

or


Figure 2B. Anti-hyperglycemic therapy in T2DM: Avoidance of weight gain



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+

Figure 2C. Anti-hyperglycemic therapy in T2DM: Minimization of costs Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442



neutral/loss


low


Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk

gain

edema, HF, fxs

low

Thiazolidine- dione


neutral

rare

high

DPP-4 inhibitor

highest high risk

gain

hypoglycemia

variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea

+

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione

+ SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk

loss

GI

high


Sulfonylurea

high moderate risk

gain

hypoglycemia

low

SGLT2 inhibitor


loss

GU, dehydration

high

SU

TZD

Insulin§


+

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk

Weight

Side effects

Costs

Dual therapy†

Efficacy* Hypo risk

Weight

Side effects

Costs

Triple therapy

or

or

DPP-4 Inhibitor

+ SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i



Metformin +



Insulin (basal)

+


2018in type 2 diabetes, established CVD is a compelling indication

for treatment with a GLP-1 receptor agonist or SGLT2

inhibitor;

in patients with HF, SGLT2 inhibitors are recommended

The 2008 FDA Revolution

38

FDA requirements for CV outcome for new

antidiabetic agents

39

2013 2014 2015 2016 2017 2018 2019 2020

SGLT2i

GLP-1

DPP-4

Source: ClinicalTrials.gov. ‘Completion date’ is the estimated completion date for the primary outcomes measure. *Also known as C-SCADE-8.

TECOS(Sitagliptin, DPP-4i)

n=14,671; follow-up ~3 yrsQ1 2015 - RESULTS

CARMELINA(Linagliptin, DPP-4i)

n= 8,300; duration ~4 yrs completion Q1 2018

CAROLINA(Linagliptin, DPP-4i vs SU)n= 6,000; duration ~8 yrs

completion Q3 2018

SAVOR TIMI-53(Saxagliptin, DPP-4i)

n=16,492; follow-up ~2 yrs Q2 2013 - RESULTS

EXAMINE(Alogliptin, DPP-4i)

n=5,380; follow-up ~1.5 yrsQ3 2013 - RESULTS

ALECARDIO(Aleglitazar, PPAR-αγ)

n=7,226; follow-up 2.0 yrsTermin. Q3 2013 RESULTS

LEADER(Liraglutide, GLP-1)

n=9,340; duration 3.5-5 yrscompletion Q4 2015

ELIXA(Lixisenatide, GLP-1)

n=6,068; follow-up ~2 yrsQ1 2015 –RESULTS

EMPA-REG OUTCOME*(Empagliflozin, SGLT2i)

n=7,097; duration up to 5yrs Q2 2015 –RESULTS

SUSTAIN 6(Semaglutide, GLP-1)

n=3,297; duration ~2.8 yrscompletion Q1 2016

EXSCEL(Exenatide QW, QW GLP-1)

n=14,000; duration ~7.5 yrscompletion Q4 2017

OMNEON(Omarigliptin, QW DPP-4i)n=4,000; duration ~3 yrs

completion Q4 2017

CANVAS(Canagliflozin, SGLT2i)

n=4,407; duration 4+yrscompletion Q2 2017

CANVAS-R(Canagliflozin, SGLT2i)

n=5,865; duration ~3 yrscompletion Q1 2017

DEVOTE(Insulin degludec, basal insulin)

n=7,637; duration up to 5yrscompletion H2 2016

FREEDOM-CVO(ITCA 650, GLP-1 in DUROS)

n=4,000; duration ~2 yrscompletion Q3 2018

CREDENCE (cardio-renal)(Canagliflozin, SGLT2i)

n= 3,700; duration ~5.5 yrs completion Q1 2019

REWIND(Dulaglutide, QW GLP-1)

n=9,622; duration ~6.5yrscompletion Q2 2019

DECLARE-TIMI-58(Dapagliflozin, SGLT2i)

n=17,150; duration~6 yrscompletion Q2 2019

NCT01986881(Ertugliflozin, SGLT2i)

n=3,900; duration~6.3 yrscompletion Q2 2021

HARMONY OUTCOMES(Albiglutide, GLP-1)

n=9,400; duration ~4yrs completion by Q2 2019

Completed with results Ongoing

Ongoing and recently completed cardiovascular outcomes trials within diabetes

Cardiovascular outcomes trials in diabetes:

Primary endpoint (CV death, nonfatal MI, nonfatal stroke) results

SAVOR-TIMI 53: Saxagliptin

HR=hazard ratio; KM=Kaplan-Meier

Days8071

7983

7836

7761

7313

7267

4920

4855

847

851

Saxagliptin

Placebo

8280

8212

Pati

en

ts W

ith

En

dp

oin

ts (

%) 14

12

10

8

6

4

2

0

0 180 360 540 720 900

HR 1.00; 95% CI, 0.89–1.12P<0.001 for noninferiorityP=0.99 for superiority Saxagliptin: 2-yr KM rate: 7.3%

Rate: 3.7/100 person-years

Placebo: 2-yr KM rate: 7.2%Rate: 3.7/100 person-years

Scirica BM, et al. N Engl J Med 2013;369:1317–1326

RCT Evidence

Events, No. (%)

Alogliptin: 305 (11.3)

Placebo: 316 (11.8)

Cum

ula

tive

Incid

ence o

f th

e

Prim

ary

Endpoin

t (%

) Hazard ratio, 0.96 (one-sided repeated CI bound, 1.16)

Median exposure: 18 months

24

18

12

6

03024181260

Months

Alogliptin

Placebo

821

805

1394

1375

1899

1891

2316

2299

2701

2679

Alogliptin (n):

Placebo (n):

296

286

White WB et al. N Engl J Med. 2013;369:1327–1335

EXAMINE: AlogliptinRCT Evidence

44Green JB, et al. N Engl J Med. 2015;373:232-242

TECOS: SitagliptinRCT Evidence

ELIXA: Lixisenatide

45

Pfeffer MA et al. N Engl J Med 2015;373:2247-2257

RCT Evidence

EMPA-REG: Empagliflozin

46Zinman B, et al. N Engl J Med. 2015;373:2117-28

RCT Evidence

Marso SP et al. N Engl J Med. 2016;375:311-22

LEADER: LiraglutideRCT Evidence

Marso SP et al. N Engl J Med. 2016; 375: 1834-1844

SUSTAIN 6: SemaglutideRCT Evidence

EXSCEL: Once weekly Exenatide

Holmann RR et al. N Engl J Med. 2017; 377: 1228-1239

RCT Evidence

Neal B et al. N Engl J Med. 2017 Aug 17;377(7):644-657

CANVAS: CanagliflozinRCT Evidence

HARMONY: Albiglutide

Hernandez AF et al. Lancet. 2018 Oct 27;392(10157):1519-1529

RCT Evidence

DECLARE: Dapagliflozin

Wiviott SD et al. N Engl J Med. 2019 Jan 24;380(4):347-357.

RCT Evidence

CARMELINA: Linagliptin

Rosenstock J et al. JAMA. 2019 Jan 1;321(1):69-79

RCT Evidence

REWIND: Dulaglutide

Gerstein HC et al. Lancet. 2019 Jul 13;394(10193):121-130

RCT Evidence

Grandi studi di esito cardiovascolare (CVOT): caratteristiche al basale

Trial EMPA-REG CANVAS DECLARE ELIXA EXSCEL LEADER SUSTAIN HARMONY REWIND SAVOR EXAMINE TECOS CARMELINA

Baseline Empagliflozin Canagliflozin Dapagliflozin

Lixisenatide

Exenatide

Liraglutide Semaglutide

Albiglutide Dulaglutide Saxagliptin Alogliptin Sitagliptin Linaglitptin

n 7020 10142 17160 6068 14752 9340 3297 9463 9901 16492 5400 14671 6991

Age (yr) 63 63.3 64 60 62 64.3 64.6 64.1 66.2 65 61 66 66

Diabetes (yr) 57%>10y 13.5 11 9.3 12 12.8 13.9 14.1 9.5 10 7.2 9.4 15

BMI (kg/m2) 30.6 32 32 30.1 31.8 32.5 32.8 32.3 32.3 31 29 29 31.4

Insulin (%) 48 50 41 39 46 44 58 59 24 41 30 23 58

HbA1c (%) 8.1 8.2 8.3 7.7 8.0 8.7 8.7 8.7 7.2 8.0 8.0 7.3 7.9

Prior CV disease (%)

99 65 40.5 100 73.1 ≈81 ≈83 100 31.5% 78 100 100 57

Types of prior CV disease

MI, CHD, CVD, PVD

MI, CHD, CVD, PVD

MI, CHD, CVD, PVD

ACS <180 days

MI, CHD, CVD, PVD

≥50y+CV disease*/CKD/≥60y+≥1 CV RF

≥40y + MI, CHD, CVD, PVD

MI, CHD, CVD, PVD

≥40y+CVD or

≥55y+≥1 CV RF

ACS<90 days

CHD, CVD, PVD

MI, CHD

Hypertension (%)

94 89.9 - 76.4 85 92 92.8 86 93 81 83 86 91

Follow-up (yr)

3.1 3.6 4.2 2.1 3.2 3.8 2.1 1.6 5.4 2.1 1.5 2.8 2.2

SGLT-2 inhibitors GLP-1 receptor agonists DPP-4 inhibitors

Trial EMPA-REG CANVAS DECLARE ELIXA EXSCEL LEADER SUSTAIN HARMONY REWIND SAVOR EXAMINE TECOS CARMELINA

Empagliflozin

Canagliflozin

Dapagliflozin

Lixisenatide

Exenatide

Liraglutide

Semaglutide

Albiglutide Dulaglutide

Saxagliptin

Alogliptin Sitagliptin

Linagliptin

3pt MACE 0.86*0.74, 0.99

0.86*0.75, 0.97

0.930.84, 1.03

1.020.89, 1.17

0.910.83, 1.00

0.87*0.78, 0.97

0.74*0.58, 0.95

0.78*0.68, 0.90

0.88*0.79, 0.99

1.00.89, 1.08

0.96Upper≤1.1

6

0.980.89, 1.08

1.020.89, 1.17

CV death 0.62*0.49, 0.77

0.87*0.72, 1.06

0.980.82, 1.17

0.980.78, 1.22

0.880.76, 1.02

0.78*0.66, 0.93

0.980.65, 1.48

0.930.73, 1.19

0.910.78, 1.06

1.030.87, 1.22

0.790.60, 1.04

1.030.89, 1.19

0.960.81, 1.14

Non-fatal MI

0.870.70, 1.09

0.850.69, 1.05

0.890.77, 1.01

1.030.87, 1.22

0.970.85, 1.10

0.880.75, 1.03

0.740.51, 1.08

0.75*0.61, 0.90

0.960.79, 1.16

0.950.80, 1.12

1.080.88, 1.33

0.950.81, 1.11

1.150.91,1.45

Non-fatalstroke

1.240.92, 1.67

0.900.71, 1.15

1.010.84, 1.21

1.120.79, 1.58

0.850.7, 1.03

0.890.72, 1.11

0.61*0.38, 0.99

0.860.66, 1.14

0.760.61, 0.95

1.110.88, 1.39

0.910.55, 1.50

0.970.79-1.19

0.880.63, 1.23

Hospitalized HF

0.65*0.50, 0.85

0.670.52, 0.87

0.73*0.61, 0.88

0.960.75, 1.23

0.940.78, 1.13

0.870.73, 1.05

1.110.77, 1.61

0.850.70, 1.04

0.930.77, 1.12

1.27*1.07, 1.51

1.190.90, 1.58

1.000.83, 1.20

0.900.74, 1.08

All cause death

0.68*0.57, 0.82

0.870.74, 1.01

0.930.82, 1.04

0.940.78, 1.13

0.86*0.87,0.97

0.85*0.74, 0.97

1.050.74, 1.50

0.950.79, 1.16

0.900.80, 1.01

1.110.96, 1.27

0.880.71, 1.09

1.010.90, 1.14

0.980.84, 1.13

SGLT-2 inhibitors GLP-1 receptor agonists DPP-4 inhibitors

Grandi studi di esito cardiovascolare (CVOT): risultati eventi CV

Terapia anti-diabete e rischio cardiovascolare: alcuni farmaci funzionano meglio di altri

• Nei grandi studi di esito cardiovascolare (CVOT) le evidenze indicano i seguenti effetti:

• PPRγ agonisti: Pioglitazone protettivo (PRO-Active)

• DPP4 inibitori: Saxagliptin, Alogliptin, Sitagliptin neutrali (SAVOR-TIMI, EXAMINE, TECOS)

• GLP-1R agonisti: Lixisenatide, Exenatide QW neutrali (ELIXA, EXSCEL)

• GLP-1R agonists: Liraglutide, Semaglutide, Albiglutide protettivi (LEADER, SUSTAIN 6, HARMONY)

• SGLT-2 inibitori : Empagliflozin, Canagliflozin, protettivi (EMPA-REG, CANVAS)

• SGLT-2 inibitori: Dapagliflozin, parzialmente protettivo (DECLARE)

• Insulina: Degludec neutrale vs Glargine U100 (DEVOTE)

Glucose-lowering medication in type 2 diabetes: overall approach.

Davies MJ et al. Diabetes Care 2018;41:2669-2701

Choosing glucose-lowering medication in those with established ASCVD, HF, and CKD. CV, cardiovascular; DPP-4i, dipeptidyl

peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.

Davies MJ et al. Diabetes Care 2018;41:2669-2701

2019GLP-1 receptor agonists can also

be considered in patients with T2D without established CVD, but with indicators of high risk;

Further recommendation for SGLT-2 inhibitors in HF and CKD

Consider initial combination therapy in new-onset T2D

Choosing glucose-lowering medication in those with indicators of high-risk or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF).

Buse JB. et al. Diabetes Care 2020;43:487-493

Come ottimizzare la terapia dl diabete di tipo 2: conclusioni

• L’armamentario terapeutico dei farmaci contro il diabete di tipo 2 si è molto arricchito nel corso degli ultimi 20 anni;

• Il controllo della glicemia rimane l’obiettivo centrale per ridurre il rischio cardiovascolare associato, prima causa di morte nel diabete di tipo 2;

• La normoglicemia deve essere perseguita sin dalle prime fasi di malattia, evitando l’ipoglicemia che rappresenta a propria volta un rischio per morbilità e mortalità;

• Alcuni farmaci (GLP-1 agonisti e SGLT-2 inibitori) hanno dimostrato, in aggiunta alla azione anti-iperglicemizzante, un effetto di protezione cardiovascolare significativo;

• La valutazione del rischio cardiovascolare è oggi incorporata nei criteri alla base delle scelte della terapia anti-diabete

Ottimizzare la terapia del diabete

mellito tipo 2

Grazie

Incontri di formazione e confronto - Seminario ai Medici di Medicina Generale& Scuola di Specializzazione in Medicina Interna, Università vita Salute San Raffaele

Webinar, 14 Ottobre 2021 - ore 19.30

Ottimizzare la terapia del diabete mellito tipo 2

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