Cairo November 21 HOW TO GET ORIENTED Andrea Giaccari ... - Giaccari - Terapia Dt2 Cairo.… ·...

New Treatments in Diabetes

CairoNovember 21st

2014

Andrea Giaccari

EndocrineMetabolicDiseases

PoliclinicoGemelli

RomeItaly

HOW TO GET ORIENTEDIN DIABETES TREATMENT:THE ITALIAN GUIDELINES

Diapositiva preparata da Andrea Giaccari e ceduta alla Società Ita

liana di Diabetologia.

Per avere una versione originale si prega di scrivere a [email protected]

disclosure

During the last 2 years I received:

• consultancy fees from Astra Zeneca, Boehringer Ingelheim, Eli Lilly, sanofi and Takeda.

• Research grants from GSK, Laboratori Guidotti, MSD (Merck), Novartis.




gliptins

glinides

glitazons

amilin

GLP-1RA

colesevelam

acarbose

biguanidesbiguanides

sulphonilureas

α2 agonists

β blockers

Ca antagonists

α1 blockers

ACE-I

sartansrenin inhibit.

diuretics

vasodilatators

1950 1960 1970 1980 1990 2000 2010

USA

gliflozinsGR antagonistGK agonists

2

4

6

8

10

dopaminergic

classes of drugs for type 2 diabetes (USA)

n




reduced glucose uptake(insulin

resistance)

Ralph DeFronzo’s ominous octet

-cell

increased lipolysis

increased glucagon secretion

increased hepatic glucose

production

dysfunction of neurotransmitters

-cell

reduced incretineffect

reduced insulin

secretion

hyperglycemia

increased kidney glucose

reabsorption




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide

• Glibenclamide/glyburide

• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin

• Pioglitazone• Sitagliptin

• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin• Exenatide

• Exenatide LAR

• Liraglutide

• Lixisenatide

• 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

need to personalize!Diapositiva preparata da Andrea Giaccari e

ceduta alla Società Italiana di Diabetologia.


typical patient

Metformin

Gliptin

GLP-1 R.A.

Sulphonylurea or Repaglinide

Pioglitazone

Acarbose

Gliflozin

Insulin (basal)




the pyramid of evidences

expert opinion - consensus

case report

case - control

observational

1 RCT

RCTseries




the only evidence-based guideline




Recommendation 1:• add oral pharmacologic therapy

in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed





Recommendation 2:• prescribe monotherapy with

metformin for initial therapy to treat most patients with t2D





Recommendation 3:• add a second agent to

metformin to treat patients with persistent hyperglycemia





HOW TO PERSONALIZE TREATMENTOF TYPE 2 DIABETES

• glycemic phenotype and pathogenesis of hyperglycemia

• clinical phenotype

• weight

• age

• frailty

• comorbidities

• complications

• diabetes history

• diet

• fitness

• compliance

• work

• other

• insulin-resistance

– «primitive»

– obesity

– «hepatic»

– secretion

• first phase

• second phase

• global

– brain

– gut

– kidney

– incretindeficiency

whatever the patient, always start with

metformin!Diapositiva preparata da Andrea Giaccari e



1. At least 2g daily

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)

and then?

4 Rules for metformin Rx




T2D therapy: classes of drugs

• Detemir

• Glargine

• Degludec

• Lispro

• Aspart

• Glulisine

• NPH

• human

Insulins

• Gliclazide

• Glibenclamide/

glyburide

• Glimepiride

• Tolbutamide

• Chlorpropamide

• Glipizide

SUs

• Nateglinide

• Repaglinide

Glinides

• Metformin

Biguanides

• Pioglitazone

TZDs

• Sitagliptin

• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

Gliptins

• Exenatide

• Exenatide LAR

• Liraglutide

• Lixisenatide

GLP-1 RA

• Acarbose

• MiglitolαGlucosidae inhibitors

• Dapagliflozin

• Canagliflozin

• Empagliflozin

SGLT2 inhibitors




which combination?

•personal experience

•efficacy

•pathogenic therapy

•meta-analysis




which combination?

• 5 classes of drugs:

– sulphonylurea (and glinides)

–pioglitazone

– incretins (DPP-4 i & GLP1-RA)

–acarbose

– insulin




which combination?

• 5 classes of medicines:

• number of combinations:

5 *4 * 3 * 2 = 120

plus gliflozins 120 * 6 = 720

5!




which combination?


•efficacy




-2 -1 0 1

pioglitazone

rosiglitazone

metformin

sulphonylureas

repaglinide

nateglinide

acarbose

sitagliptin

vildagliptin

exenatide

5 (1705)

11 (2828)

7 (2194)

6 (1443)

18 (2494)

8 (596)

4 (1423)

4 (1423)

9 (1786)

5 (1229)

Bolen S. et al: Ann Intern Med 147:386, 2007

studies(patients)

%

Amori RE et al: JAMA 298:194, 2007

effect on HbA1c vs. placebometa-analysis of drug studies




which combination?


•efficacy





reduced glucose uptake(insulin

resistance)

Ralph DeFronzo’s ominous octet

-cell

increased lipolysis

increased glucagon secretion

increased hepatic glucose

production

dysfunction of neurotransmitters

-cell

reduced incretineffect

reduced insulin

secretion

hyperglycemia

increased kidney glucose

reabsorption




exenatide: add on metformineffect on HbA1c

6,5

7

7,5

8

8,5

9

9,5

basal 30 weeks

6,5

7

7,5

8

8,5

9

9,5

basal 30 weeks

%

DeFronzo RA, et al. Diabetes Care 27:1092, 2005




Evidence for personalized therapy

This drug should be prescribed for obese diabetic

patients

Does this mean that it might not be used in lean

patients?

You had better not say that!




but then, which combination?


•efficacy


•meta-analysis




rosiglitazone:the final meta-analysis for MI

0.2 0.5 1 2 5 risk

RECORD

ADOPT

DREAM

3 arms

2 arms

all

Nissen SE & Walski K: Arch Intern Med 170:1191, 2010

Steve Nissen

P<0.05




Higher doses of SUs do not reduce

HbA1c more than lower doses

1. Hirst JA, et al. Diabetologia 2013;56:973-984. 2. Goldberg RB, et al. Diabetes

Care 1996;19:849-856. 3. Rosenstock J, et al. Diabetes Care 1996;19:1194-1199.

4. Simonson DC, et al. Diabetes Care 1997;20:597-606. 5. Stenman S, et al. Ann

Intern Med 1993;118:169-172

Meta-analysis of head-to-head studies (N=911)1

Pooled mean difference in HbA1c (high vs low dose): 0.05, 95% CI -0.17, 0.26

GlimepirideGoldberg et al2

Goldberg et al2

Rosenstock et al3 bid

Rosenstock et al3 qd

Subtotal (I2=0.0%, p=0.582)

GlipizideSimonson et al4

Simonson et al4

Simonson et al4

Stenman et al5

Stenman et al5

Subtotal (I2=22.9%, p=0.269)

Overall (I2=13.9%, p=0.319)

115

115

166

171

134

83

55

36

36

1

1

8

8

5

10

40

10

10

8

4

16

16

20

15

60

20

40

0.50 (-0.07, 1.07)

0.20 (-0.37, 0.77)

0.10 (-0.35, 0.55)

0.00 (-0.44, 0.44)

0.16 (-0.08, 0.41)

12.00

12.00

17.74

18.15

59.89

0.00 (-0.50, 0.50)

-0.71 (-1.34, -0.08)

-0.17 (-0.95, 0.61)

0.30 (-0.72, 1.32)

0.40 (-0.62, 1.42)

-0.13 (-0.50, 0.25)

0.05 (-0.17, 0.26)

14.96

9.97

6.87

4.15

4.15

40.11

100.00

-1.5 0 1.5

Favours higher doseFavours lower dose

Authors

Lower

dose

(mg)

Higher

dose

(mg)n

HbA1c

difference

(95% CI) % weight

meta-analysisare NOT

evidences




but then, which combination?


•efficacy


•meta-analysis

evidence-basedpros and cons

of each treatment




T2D therapy: classes of drugs

• Detemir

• Glargine

• Degludec

• Lispro

• Aspart

• Glulisine

• NPH

• human

Insulins

• Gliclazide

• Glibenclamide/

glyburide

• Glimepiride

• Tolbutamide

• Chlorpropamide

• Glipizide

SUs

• Nateglinide

• Repaglinide

Glinides

• Metformin

Biguanides

• Pioglitazone

TZDs

• Sitagliptin

• Saxagliptin

• Vildagliptin

• Linagliptin

• Alogliptin

Gliptins

• Exenatide

• Exenatide LAR

• Liraglutide

• Lixisenatide

GLP-1 RA

• Acarbose

• MiglitolαGlucosidae inhibitors

• Dapagliflozin

• Canagliflozin

• Empagliflozin

SGLT2 inhibitors




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





gliptin vs. glipizideadd-on to metformin

%

6.0

7.5

8.0

7.0

6.5

weeks

glipizide + met

6 5230 380 12 18 24 46

Göke B Int J Clin Pract. 64:1619; 2010

saxa + met

0

10

20

30

40

n episodes

hypos

glipizide + met




events

%

0

63

6

9

12

0 300 450 750 900150

saxagliptin

placebo

days

SAVOR-TIMI: MACE cumulative incidence

600

Hazard ratio, 1.00 (95% CI, 0.89–1.12)P<0.001 for non inferiority

Scirica BM et al: NEJM 369:1317, 2013




events

%

0

6

12

18

24

0 10 15 25 305

alogliptin

placebo

months

EXAMINE: MACE cumulative incidence

20

White WB et al. NEJM 369:1327; 2013




gliptins: pros & cons

prosabsence of hypoglycemiano weight increase (decrease)rare side effectsno effects on CV risk factorsno gastrointestinal side effectsno titration

conscost

doubtsheart failure?




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





short and long-acting GLP-1R agonists

Short-actingGLP-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 As24h plasma glucose profile

plasmaglucosemg/dl

hours

Kapitza C et al. Diabetes Obes Metab 15: 642–649, 2013

250

200

150

1000 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)




DURATION-6: change in HbA1ca head to head comparison between Exe QW vs. Lira QD

Δ%

-2.0

1.0

0

-1.5

-0.5

0 8 18 2214 26

weeksBuse J, et al. Lancet 381:117, 2013

exenatide QW (n=461)liraglutide QD (n=450)

- 1.28 %

- 1.48 %

*

* * * *




Exenatide QW (N = 461)

Liraglutide QD(N = 450)

Nausea 9.3 << 20.7

Diarrhea 6.1 << 13.1

Vomiting 3.7 << 10.7

Dyspepsia 2.4 < 6.0

Headache 5.9 < 8.4

Nasopharyngitis 6.7 = 7.1

Injection site bump 10.4 >>> 1.1

DURATION-6: incidence of adverse events a head to head comparison between Exe QW vs. Lira QD

Treatment-emergent Adverse Events with Incidence ≥5%

In Either Treatment Group

Buse J, et al. Lancet 381:117, 2013




GLP1 R A: pros & cons

prosabsence of hypoglycemiasignificant weight lossreduced CV risk factorseasy titration

consgastrointestinal side effects (some less)injectionscost

doubtsnot indicated in CKD




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





SU and repa: pros & cons

prosrapidcheap

conshypoglycemia!rapid beta-cell failureweight gainincreased CV risknot indicated in CKD

doubtsmyocardial infarction




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





PROACTIVE: fatal/non fatal MI (silent MI excluded)

0.02

0.04

0.06

0.08

0.10

0 6 12 18 24 30 36

Kaplan-Meier event rate

Time from randomization (months)

N at risk: 2445 2387 2337 2293 2245 2199 399(139)

pioglitazone (65 / 1230)

placebo (88 / 1215)

0.0

HR 95% CI p value

pioglitazone vs placebo

0.72 0.52, 0.99

0.045

- 28%




PROACTIVE: Heart failure risk

Erdmann E et al.: Diabetes Care 30:2773, 2007

events

%

0

2

4

6

0 12 18 30 366

pioglitazoneplacebo

months

24Diapositiva preparata da Andrea Giaccari e



pioglitazone: pros & cons

prossecondary CV preventionno hypoglycemiacheap

consslow actionheart failure and fluid retentionsignificant weight gainfractures

doubtsbeta-cell preservation?




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





acarbose: pros & cons

prosnot absorbedno hypoglycemiacheap

conspoor efficacygastrointestinal side effects

doubtsreduced CV risk?




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





basal insulin: pros & cons

prosmost effective

conshypoglycemia! (some less)weight gaininjectionpoor effect on post-prandial glucose

doubtsno




• Detemir

• Glargine

• Degludec

• NPH

• Gliclazide


• Glimepiride

• Gliquidone

• Glipizide

• Nateglinide

• Repaglinide

• Metformin


• Saxagliptin

• Vildagliptin

• Linagliptin


• Exenatide LAR

• Liraglutide

• Lixisenatide

• Acarbose


• Canagliflozin

• Empagliflozin


GLINIDES

BIGUANIDES

TZDs

GLIPTINS

GLP-1 RA


SGLT2 INHIBITORS





seg. 1 of proximal tubule

SGLT-2reabsorbs 95 % of glucose

seg. 3 of proximal tubule

SGLT-1reabsorbs 5 % of glucose or40% of remaining glucose

renal glucose reabsorption




renal glucose fluxflux (

mg/m

l)

0

100

200

300

150

50

250

0 100 200 25050 150 300

filtered reabsorbed

glycosuria

blood glucose (mg/dl)

-40%

Ferrannini E Diabetes 60:695, 2011




flux in glycosuria

300

200

100

0

50 g/day0,5 mg·kg-1·min-1

150 g/day1,5 mg·kg-1·min-1Diapositiva preparata da Andrea Giaccari e



flux in glycosuria

300

200

100

0

the amount of glucose lost in the urine depends exclusively from:

1. glycemia

2. renal function (eGFR)




-1,2

-1

-0,8

-0,6

-0,4

-0,2

0placebo 2,5 mg 5 mg 10 mg

Ferrannini E Diabetes Care 33:2217, 2010

HbA1c (

%)

HbA1c 7-10% HbA1c >10%

-0.23%

-0.58%

-0.77%

-0.89%

dose response: SGLT-2 monotherapy (drug-naïve patients)




dose response: SGLT-2 monotherapy (drug-naïve patients)

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0placebo 2,5 mg 5 mg 10 mg 5 mg 10 mg

Ferrannini E Diabetes Care 33:2217, 2010

HbA1c (

%)

HbA1c 7-10% HbA1c >10%

-0.23% -0.58% -0.77% -0.89%

-2.88%-2.66%Diapositiva preparata da Andrea Giaccari e



*

gliflozin vs. glipizide in add on to met.(met ≥ 1.500 mg, dapa ≤10 mg, glipizide ≤ 20 mg)

HbA1c (

%)

-1.0

-0.8

-0.4

0

-0.6

0.2

0 52 78 9142 65 104weeks

glipizide – 0.14%

dapagliglozin -0.32%

Nauck et al. DOM 16:1111, 2014

2618




gliflozin as add on to insulinHbA1c: dapagliflozin vs. placebo

HbA1c (

%)

-1.2

-0.8

-0.4

0

-0.6

-1.0

0.2

0 16 32 408 24 48

weeksWilding JPH, et al. Ann Intern Med 156:405; 2012

placebo -0.39%

dapagliflozin 10 mg -0.96%




gliflozin as add on to insulinUnits of insulin: dapa vs. placebo

Units

-5

+5

+15

0

+10

0 16 32 408 24 48

weeks

placebo + 10.5 UI

dapagliflozin 10 mg -0.7 UI

Wilding JPH, et al. Ann Intern Med 156:405; 2012




gliflozin: effect on weight

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0met dapa

-5

-4

-3

-2

-1

0

1

2dapa glipizide

weight mass

kg

fatlean

kg

Nauck et al. DOM 16:1111, 2014 Bolinder et al JCEM 97:1020, 2012

-3.7 kg

+1.4 kg-0.74

-0.60

-2.22

-1.10




gliflozin vs. glipizide as add on to met(met ≥ 1.500 mg, dapa ≤ 10 mg, glipizide ≤ 20 mg)

HbA1c (

%)

3

0 2 3 4years

glipizide

dapagliglozin


1

2

1

0

-1

-2

-3

-4

-5

0.73 kg

−3.65 kg

difference −4.38 kg




gliflozin: effect on BP and Uric Ac.

-3,5

-3

-2,5

-2

-1,5

-1

-0,5

0

0,5

1

1,5

2dapa glipizide

blood pressure uric acid

mg/d

l

mm

Hg

-1,2

-1

-0,8

-0,6

-0,4

-0,2

0

0,2dapa placebo


-2.7

+1,2




familiar renal glycosuriagenetic forms – clinic aspects

presentation• glycosuria: 1-170 g die

• completely asymptomatic

blood• normal blood glucose

• no hypoglycemia or hypovolemia

kidney / bladder• no tubular dysfunction

• normal histology and function

complications

• No increased incidence of

– chronic kidney disease

– diabetes

– urinary tract infection

Santer R, et al. Clin J Am Soc Nephrol 5:133, 2010




gliflozins: pros & cons

proseffective on all patientsno hypoglycemiaremoves glucose toxicitysignificant and persistent weight lossreduces blood pressure

consnot effective with low eGFRGU infections

doubtsincreased food intake?




typical patient

Metformin

Gliptin

GLP-1 R.A.

Sulphonylurea or Repaglinide

Pioglitazone

Acarbose

Gliflozin

Insulin (basal)




1A 1B Rare 1A 1B 2B2 1A elevated

1A 1Anot

indicated in CKD

3B 1A 2B 1C elevated

1D 1Dnot

indicated in CKD

3C 1B 1B 1A low

1A 1D Fractures 1A 1A 1E 1A medium

1A 1C Rare 2B 2B 3C 1C low

1A 1AG.U.

infections3C 2B 2B 1A ???

1D 1D Rare 1B 1A 1B 1A

start with lifestyle improvement (unless severe hyperglycemia is present)

add (with appropriate run in) metformin, up to a dose of at least 2 g/day

1 to 5: grade of evidenceA to E: strength of recommendation

add on to metformin

gliptin

GLP-1 R. A.

SU or repaglinide

pioglitazone

acarbose

gliflozin

basal insulin

Hypos weightother

effectsCVD

CV risk factors

Heart failure

G.I. effects

Cost




Take home messages

• There is no “one-size-fits-all” solution: treatment needs to be individualized

• There is no strict evidence suggesting appropriateness of certain drugs for certain patients

however

• There are well demonstrated pros and cons for each drug

• Our duty is to ponder each of them, and match our patients with the best therapy for each of them




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