Translating mechanisms to benefits: How can we explain the … · 2019-04-23 · Number and rate*...

Translating mechanisms to benefits: How

can we explain the cardiovascular benefits

of new diabetes drugs?

Filip Krag Knop, MDCopenhagen, Denmark

Session: Game changing clinical trials in T2DM & CVD: Novel insights &

implications

Cardio Diabetes Master ClassFebruary 22-23, 2019 - Barcelona, Spain

Translating mechanisms to benefits:

How can we explain the cardiovascular benefits of new diabetes drugs?

Filip K. Knop, MD PhD

Professor, Consultant Endocrinologist, Head of Clinical Metabolic Physiology

Steno Diabetes Center Copenhagen, Gentofte Hospital

University of Copenhagen

Copenhagen, Denmark

• Filip K. Knop has served on scientific advisory panels and/or been part of

speaker’s bureaus for, served as a consultant to and/or received research

support from:

Disclosures

• Amgen

• AstraZeneca

• Boehringer Ingelheim

• Carmot Therapeutics

• Eli Lilly

• Gubra

• MedImmune

• MSD/Merck

• Munidpharma

• Norgine

• Novo Nordisk

• Sanofi

• Zealand Pharma

Pre-treatment HbA1c decreased substantially over time (2000-2012)

- more patients attain HbA1c goal

Thomsen R et al., Diabetes, Obesity and Metabolism 2015

Glycaemic control reduces the risk of microvascular complications

0

2

4

6

8

10

12

14

16

18

20

6 7 8 9 10 11 12

Rela

tive

Ris

k

RetinopathyNephropathy

NeuropathyMicroalbuminuria

A1C (%)43 53 63 73 83 93 103

(blindness)

(dialysis)

(amputations)

Nephropathy

Neuropathy Retinopathy

Number and rate* of adults who began treatment for end-stage

renal disease attributed to diabetes, 2000–2014

*Rate per 100,000 persons with diabetes and age-standardized to the 2000 U.S.

standard population, excluding Alaska, Vermont, and Wyoming because of the

small annual number (<50) of new ESRD-D cases during the study period.Burrows et al. Morbidity and Mortality Weekly Report 2017

Life expectancy is reduced by 12 years in

diabetes patients with previous CVD*

In this case, CVD is represented by MI or stroke

*Male, 60 years of age with history of MI or stroke

CVD, cardiovascular disease; MI, myocardial infarction

Emerging Risk Factors Collaboration et al. JAMA 2015;314:52–60

60 End of lifeyears

–6 yrs

–12yrs

No diabetes

Diabetes

Diabetes + MI

CVD is the leading cause of death in people with T2D

1. Seshasai et al. N Engl J Med 2011;364:829-41; 2. Centers for Disease Control and Prevention National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 3. International Diabetes

Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.orgPresented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.

http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

http://www.diabetesatlas.org/

Summary of glycaemic intervention studies

Study Micro CVD Mortality

DCCT

UKPDS

ACCORD

ADVANCE

VADT

ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease Preterax and Diamicron MR; CVD, cardiovascular disease;

DCCT, Diabetes Control and Complications Trial; UKPDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial

• In December 2008, the US FDA

issued guidance to industry for

evaluating CV safety in diabetes drugs

• Industry should demonstrate that

new therapy will not result in an

unacceptable increase in CV risk

• The upper bound of the two-sided

95% CI of the risk ratio should be <1.8

FDA guidance for industry

CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration.

FDA. Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008. Available at:

www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

Contemporary CVOTs in diabetes

*Estimated enrolment; †Stopped early after a median follow-up of 57.4 months following futility analysis. Trials with filled boxes are completed. Trials with a white background are ongoing. ClinicalTrials.gov

(August 2018)

20192015 20202013 2014 2016 2017 2018 2021

InsulinDEVOTE

(Insulin degludec, insulin)

n=7637; duration ~2 yrs

Q2 2017 – RESULTS

SGLT-2i

EMPA-REG OUTCOME

(Empagliflozin, SGLT-2i)

n=7000; duration up to 5 yrs

Q3 2015 – RESULTS

CANVAS

(Canagliflozin, SGLT-2i)

n=4418; duration 4+ yrs

Q2 2017 – RESULTS

DECLARE-TIMI 58

(Dapagliflozin, SGLT-2i)

n=17,276; duration ~6 yrs

Q3 2018 – RESULTS

CANVAS-R



Q2 2017 – RESULTS

CREDENCE (cardio-renal)


n=4401; duration 4.5 yrs

Q3 2018 – TERMINATED (+ve

efficacy)

VERTIS CV

(Ertugliflozin, SGLT-2i)

n=8000*; duration ~6.3 yrs

Completion Q3 2019

GLP-1RA

ELIXA

(Lixisenatide, GLP-1RA)

n=6068; follow-up ~2 yrs

Q1 2015 – RESULTS

FREEDOM

(ITCA 650, GLP-1RA in DUROS)


Q2 2016 – TOPLINE RESULTS

REWIND

(Dulaglutide, QW GLP-1RA)

n=10,010; duration ~6.5 yrs

Q3 2018 – TOPLINE RESULTS

SUSTAIN 6

(Semaglutide, QW GLP-1RA)

n=3297; duration ~2.8 yrs

Q3 2016 – RESULTS

LEADER

(Liraglutide, GLP-1RA)

n=9340; duration 3.5–5 yrs

Q2 2016 – RESULTS

EXSCEL

(Exenatide ER, QW GLP-1RA)

n=14,752; follow-up ~3 yrs

Q3 2017 – RESULTS

HARMONY OUTCOMES

(Albiglutide, QW GLP-1RA)


Q2 2018 - RESULTS

PIONEER 6

(Oral semaglutide, GLP-1RA)


Q4 2018 - TOPLINE RESULTS

DPP-4i

TECOS

(Sitagliptin, DPP-4i)

n=14,671; duration ~3 yrs

Q1 2015 – RESULTS

SAVOR-TIMI 53

(Saxagliptin, DPP-4i)

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

Q2 2013 – RESULTS

EXAMINE

(Alogliptin, DPP-4i)

n=5380; follow-up ~1.5 yrs

Q3 2013 – RESULTS

CAROLINA

(Linagliptin, DPP-4i vs SU)


Q3 2018 - RESULTS

CARMELINA

(Linagliptin, DPP-4i)

n=7003; duration 4.5 yrs

Q1 2018 - RESULTS

ALECARDIO

(Aleglitazar, PPAR-αγ ) n=7226;

follow-up 2 yrs

Termin. Q3 2013 – RESULTS

PPAR-αγ

2022

SCORED

(Sotagliflozin, SGLT-1i & SGLT-2i)

n=10,500*; duration ~4.5 yrs

Completion Q1 2022

TZD

TOSCA IT

(Pioglitazone, TZD)


Q4 2017†– RESULTS

AGI

ACE

(Acarbose, AGI)


Q2 2017 – RESULTS

AMPLITUDE-O

(Efpeglenatide, GLP-1RA)

n=4000*; duration ~3 yrs

Completion Q2 2021

SOLOIST-WHF (Sotagliflozin, SGLT-1i & SGLT-2i)


Completion Q1 2021

EXAMINEAlo vs. Pbo

EMPA-REG OutcomeEmpa vs. Pbo

ELIXA*Lixi vs. Pbo

ORIGINGlargine U100 vs. SOC

SAVOR TIMI-53Saxa vs. Pbo

CANVAS ProgramCana vs. Pbo

FREEDOM-CVOITCA 650 vs. Pbo

DEVOTEDegludec vs.Glargine U100

TECOS*Sita vs. Pbo

DECLARE-TIMI 58Dapa vs. Pbo

LEADERLira vs. Pbo

CARMELINALina vs. Pbo

SUSTAIN-6Sema vs. Pbo

EXSCELExe OW vs. Pbo

HARMONYAlb vs. Pbo

REWINDDul vs. Pbo

0,1 0,4 0,7 1,0 1,3HR [95% CI]

Insulin

?

0,1 0,4 0,7 1,0 1,3 1,6HR [95% CI]

GLP-1 RA

?

0,1 0,4 0,7 1,0 1,3HR [95% CI]

DPP-4i

0,1 0,4 0,7 1,0 1,3HR [95% CI]

SGLT2i

Recent CVOTs with antidiabetic agentsPrimary composite endpoint: MACE

*MACE+

White et al. N Engl J Med 2013; 369:1327–35;

Scirica et al. N Engl J Med 2013;369:1317–26;

Green et al.

N Engl J Med 2015;373:232–42; McGuire et al.

Presented at EASD 2018, Berlin

(https://www.easd.org/myeasd/home.html#!res

ources/cardiovascular-outcomes-748e1b14-

d08e-441d-b7d2-40b36cccea67)

Zinman et al. N Engl J Med 2015; 373:2117-

28; Neal et al. N Engl J Med 2017;377:644–

57; Wiviott et al. N Engl J Med 2018;

doi:10.1056/NEJMoa1812389

*MACE+

Pffefer et al. N Engl J Med 2015;373:2247–57; Intarcia press

release 06 May 2016; Marso et al. N Engl J Med 2016;375:311–22;

Marso et al. N Engl J Med 2016;375:1834–44; Holman et al. N

Engl J Med 2017;377:1228–39; Hernandez et al. Lancet

2018;doi:10.1016/S0140-6736(18)32261-X; Eli Lilly press release,

November 2018 (https://investor.lilly.com/news-releases/news-

release-details/trulicityr-dulaglutide-demonstrates-superiority-

reduction)

Gerstein et al. N Engl J Med 2012;367:

319–28; Marso et al. N Engl J Med 2017;377:723–

32

https://www.easd.org/myeasd/home.html#!resources/cardiovascular-outcomes-748e1b14-d08e-441d-b7d2-40b36cccea67

https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-demonstrates-superiority-reduction

GLP-1: beyond glucose metabolism

DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1

Adapted from Meier et al. Nat Rev Endocrinol 2012;8:728–42

Brain

Neuroprotection

Neurogenesis

Memory

Heart

Myocardial contractility

Heart rate

Myocardial glucose uptake

Ischaemia-induced

myocardial damage

Kidney

Natriuresis

GLP-1

His Ala Thr Thr SerPheGlu Gly AspVal

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly ArgLys

Fat cells

Glucose uptake

Lipolysis

Liver

Glycogen storage

Skeletal muscle

Glucose uptakeBlood vessel

Endothelium-dependent

vasodilation

Pancreas

New β-cell formation

β-cell apoptosis

Insulin biosynthesis

DPP-4

GI tractMotility

In the rodent and monkey brain, GLP-1R is abundantly

expressed in many regions

ARH, arcuate nucleus; AP, area postrema; GLP-1R, glucagon-like peptide-1 receptor; LS, septal nucleus; ME, median eminence; NTS, nucleus tractus solitarus

Heppner et al. Endocrinology 2015;156:255–67

LSLS

AP+NTS

ARH

LS

SFO

NTS

LS

ARH

ME

AP

Mouse

NTS

AP

Monkey

Change in body weight (%)Baseline to week 52: J2R-MI data (phase 2)

J2R-MI, jump-to-reference – multiple imputation; s.c., subcutaneous

All randomised, effectiveness estimand. Graph is estimated mean data ± min/max

O’Neil et al. Presented at: ENDO 2018: The Endocrine Society Annual Meeting; Chicago, IL; March 17-20, 2018. Abstract OR12-5

Cha

nge

in w

eig

ht

(%)

-15

-10

-5

0

0 2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52

Semaglutide s.c. 0.05 mg





Placebo pool

Week

Liraglutide 3.0 mg


DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1.


Brain

Neuroprotection

Neurogenesis

Memory

Heart


Heart rate


Ischaemia-induced myocardial

damage

Kidney

Natriuresis

GLP-1


Ser


Phe

Glu


Fat cells

Glucose uptake

Lipolysis

Liver

Glycogen storage

Skeletal muscle



vasodilation

Pancreas


β-cell apoptosis


DPP-4

GI tractMotility

Liraglutide inhibits progression of early, low-burden

atherosclerotic lesion development in apolipoprotein E-/- mice

*p<0.05 vs vehicle by one-way ANOVA; data are mean ± SEM; performed in ApoE–/– mice with early, low-burden atherosclerotic lesions

ApoE–/–, apolipoprotein E knockout; ANOVA, analysis of variance; Ex-9, exendin-9; IMR, intima:media ratio; Lira, liraglutide; SEM, standard error of the mean

Gaspari et al. Diab Vasc Dis Res 2013;10:353‒60

IMR

0.4

0.3

0.2

0.1

0.0

Vehicle Lira Lira + Ex-9

*

IMR analysis performed in the aortic arch

Intima:media ratio (IMR)

N=6‒10

% lesio

n a

rea

15

10

5

0Vehicle Lira Lira + Ex-9

Oil red O staining performed in the aorta

Lipid deposition

N=13‒16

Vehicle Lira Lira + Ex-9

MM

I

M

I

Lesion development

Haemotoxylin and eosin staining in the aortic arch

Semaglutide significantly attenuates aortic plaque lesions in

LDLr-/- mice in a dose-independent manner

*p<0.05; **p<0.001, vs vehicle. LDLr, low-density lipoprotein receptor; TG, triglyceride

Rakipovski et al. Abstract 244-OR presented at the American Diabetes Association 77th Scientific Sessions; Jun 9–13, 2017; San Diego, USA

Body weight (g)

0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119

15

20

25

30

35

40

Time (experiment day)

Western diet

(high fat, sugar + 0.2% cholesterol)

Plasma triglyceride

0

10

15

20

TG

(m

mol/L)

*

5

Vehicle, chow

Vehicle, western diet

Semaglutide (1 nmol/kg)



0

10

20

30

Aortic plaque lesions

**

Pla

que a

rea (

%)

** **

Vehicle, chowVehicle,

western diet

Semaglutide

1 nmol/kg 3 nmol/kg 15 nmol/kg

Semaglutide affects several genes related to the process of

atherosclerosis in LDLr-/- mice

Rakipovski et al. JACC Basic to Translational Science 2018, DOI: 10.1016/j.jacbts.2018.09.004

A B C A 1 P T G IS C C L 2 IL 1 R N IL 6 S E L E V C A M 1 O P N M M P 3 M M P 1 3

- 2

0

2

4

6

8

Re

lati

ve

E

xp

res

sio

n

(Lo

g2

)

L D L -R- /-

W D

L D L -R- /-

4 µ g /k g S e m a g lu t id e , W D

L D L -R- /-

1 2 µ /k g S e m a g lu t id e , W D

L D L -R- /-

6 0 µ g /k g S e m a g lu t id e , W D

C h o le s te ro l

M e ta b o lis m

L e u k o c y te

re c ru itm e n t

L e u k o c y te a d h e s io n

& e x tra v a s a tio n

E x tra c e llu la r m a tr ix

p ro te in tu rn o v e r

ABCA1: ATP-binding cassette transporter

PTGIS: Prostaglandin I2 synthase

CCL2: Chemokine ligand 2

IL1RN: Interleukin-1 receptor antagonist

IL6: Interleukin-6

SELE: Selectin E

VCAM1: Vascular cell adhesion molecule 1

MMP3: Matrix metalloproteinase-3

MMP13: Matrix metalloproteinase-13

OPN: Osteopontin

• 87 genes related to inflammation were significantly regulated

23 April 2019 21

• Analysis of macrophages for MΦ1 (pro-atherogenic) and MΦ2 (pro-resolving) macrophage markers,

showed that liraglutide modulates macrophage cell fate towards MΦ2 pro-resolving macrophages

• This coincided with decreased atherosclerotic

lesion formation

Liraglutide reduces atherosclerotic lesion formation via

modulation of macrophage cell fate in ApoE-/- mice

Bruen et al. Cardiovasc Diabetol 2017;16:143

MΦ

MΦ1

MΦ2

Macrophage

Pro-atherogenic

Pro-resolving

Atherosclerotic

lesion

Semaglutide reduces CRPEstimated mean by week and ratio to baseline at week 56 (SUSTAIN 3)

CRP ETR* 95% CI p value

Semaglutide 1.0 mg:

Exenatide ER 2.0 mg0.80† (0.71 ; 0.90) P=0.0001

Overall mean at baseline: 2.8 mg/L

1.8 mg/L

2.2 mg/L

1,5

2,0

2,5

3,0

0 56

Semaglutide 1.0 mg Exenatide ER

CR

P (

mg

/L)

Time since randomisation

(week)

*p<0.0001. Data are estimated means (± standard errors) from a mixed model for repeated measurements analysis using ‘on-treatment without rescue medication’ data from patients in

the full analysis set. Dashed line indicates the overall mean value at baseline.

CI, confidence interval; CRP, C-reactive protein; exenatide ER, exenatide extended release; ETR, estimated treatment ratio.

Novo Nordisk data on file


DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GLP-1, glucagon-like peptide-1.


Brain

Neuroprotection

Neurogenesis

Memory

Heart


Heart rate


Ischaemia-induced myocardial

damage

Kidney

Natriuresis

GLP-1


Ser


Phe

Glu


Fat cells

Glucose uptake

Lipolysis

Liver

Glycogen storage

Skeletal muscle



vasodilation

Pancreas


β-cell apoptosis


DPP-4

GI tractMotility

SGLT-2 inhibition

Proposed modes of action:

• Fluid reduction

• Haemodynamic effects

• Heart metabolism

• Renal effects

Potential mechanisms for the beneficial effect of SGLT2

inhibitors on cardiovascular outcomes

DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system

Effects of SGLT2is on body weight vs placebo in patients with T2D

Data are reported as mean difference [95% confidence interval] vs placebo (dashed line) from a network meta-analysis.

SGLT2i, sodium–glucose co-transporter 2 inhibitor.

Zaccardi F et al. Diabetes Obes Metab 2016;18:783–94.

Canagliflozin

EmpagliflozinDapagliflozin

DPP-4 inhibitorMetforminSulphonylurea

–3

–2

–1

0

1

kg

Body weight2

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

-4.0

-4.5

-5.0

-0.65

-0.40

-2.16

-1.00

-1.46

-0.90

-2.80

-1.30

24 weeks

PLA

+ MET (n=86)

DAPA 10 mg

+ MET (n=83)

PLA

+ MET (n=71)

DAPA 10 mg

+ MET (n=66)

102 weeks

Total lean tissue mass

Total fat tissue mass

Cha

ng

e in

bo

dy c

om

po

sitio

n (

kg

)*

DAPA, dapagliflozin; MET, metformin; PBO, placebo.

Bollinder et al Diabetes, Obesity and Metabolism 2014;16;159–169




Empagliflozin increases circulating β-hydroxybutyrate and

stimulates ketogenesis

Ferrannini et al. Diabetes 2016;65:1190-1195

SGLT2-mediated glycosuria results in a shift in fuel utilisation towards fatty substrates. The associated hormonal

changes (lower insulin-to-glucagon ratio) favours ketogenesis

BaselineAcute dosingChronic dosing

Patient with type 2 diabetes (n=66) No diabetes (n=25)

Meal ingestion Meal ingestion

-h

yd

eo

xyb

uty

rate

(µm

ol/

L)

0

300240180120600–60–120–180

300

600

900

0

300240180120600–60–120–180

300

600

900

-h

yd

rox

bu

tyra

te(µ

mo

l/L

)

BaselineAcute dosingChronic dosing

Possible changes in myocardial fuel metabolism before and after

SGLT2 inhibitor therapy

Mudaliar et al. Diabetes Care 2016

• In the failing diabetic heart, a

metabolic advantage exists in

using ketone bodies as a fuel

• The failing myocardium is able

to effectively use ketone bodies

as an alternative fuel

Type 2 diabetes heart

↑ Fat oxidation

↓ Glucose oxidation

↓ P/O ratio

↓ Cardiac work efficiency

↓ Fat oxidation

↑ Glucose oxidation

↑↑ BHOB Ox

↑ P/O ratio

↑ Cardiac work efficiency

↓Myocardial contractility

↑ Incidence/progression

of heart failure

↓ Incidence/progression

of heart failure

↑Myocardial

contractility

P/O, number of molecules of ATP produced per atom of oxygen reduced by the mitochondrial electron transport chain;

BHOB, β-hydroxybutyrate; SGLT2, sodium-glucose co-transporter 2

SGLT2

treatment




Effects of SGLT2is on systolic blood pressure vs placebo

in patients with T2D

Data are reported as mean difference [95% confidence interval] vs placebo (dashed line) from a network meta-analysis. Cana, canagliflozin; CV, cardiovascular; Dapa, dapagliflozin; DPP-4, dipeptidyl peptidase-4; Empa, empagliflozin; SGLT2i,

sodium–glucose co-transporter 2 inhibitor.

Zaccardi F et al. Diabetes Obes Metab 2016;18:783–94.

0

2

–2

–4

–6

mm

Hg

Systolic blood pressure

Canagliflozin

EmpagliflozinDapagliflozin

DPP-4 inhibitorMetforminSulphonylureaIn general, no

effect on heart rate

SGLT2 inhibition is associated with increased haematocrit

1. Kohler S, Clin Ther 2016;38:1299–1313

Pooled data from 17 randomised trials in patients

with type 2 diabetes1

Increased red blood cell mass (~6%) was observed with

dapagliflozin, which may indicate stimulation of

erythropoiesis2

CV, cardiovascular; EMPA, empagliflozin;

SGLT2, sodium–glucose co-transporter 2

-2

-1

0

1

2

3

4

5

Placebo EMPA 10 mg EMPA 25 mg

Hae

ma

toc

rit,

%

Changes in haematocrit with empagliflozin

n = 3695

n = 3806 n = 4782

30

20

–10

–20

–30

0

10

–40

Placebo Dapagliflozin Hydrochlorothiazide

Red

ce

ll m

as

s c

ha

ng

e f

rom

ba

se

lin

e (

%)

P: –1.2 (–3.2 to +1.3)

D: +6.6 (+1.0 to +9.3)

H: –6.5 (–16.1 to +3.8)

and red blood cell mass

2. Lambers Heerspink HJ, et al. Diabetes Obes Metab 2013;15:853–862

Univariate analysis of potential mediators of improved

cardiovascular mortality following SGLT2 inhibition

Inzucchi et al. Diabetes Care 2018

Hazard ratio (95% CI) % contribution to

CV benefit

HR

Empa vs placebo

Unadjusted

0.25 0.50 1.00 2.00 4.00

Mechanism Covariate

Glycaemia 3.0%0.624HbA1c

16.1%0.665FPG

Vascular tone –7.5%0.593Systolic BP

–0.3%0.614Diastolic BP

2.0%0.621Heart rate

Lipids 6.9%0.636HDL-C

–6.5%0.596LDL-C

–3.4%0.605Triglycerides

Renal factors 11.1%0.649Log UACR

5.3%0.631eGFR

Adiposity –12.4%0.579Weight

–12.8%0.578BMI

–5.8%0.598Waist circumference

Other 24.6%0.693Uric acid

Volume 51.8%0.791Haematocrit

0.615




Empagliflozin does not increase muscle sympathetic

nerve activity (MSNA) despite its diuretic effect

Jordan et al. J Am Soc Hypertension 2017;11: 604-612

Sympathetic nerve activity

The authors speculate: “Our findings suggest that an increase in MSNA through increased diuresis may be

compensated for a hitherto unknown inhibitory effect of empagliflozin on the sympathetic nervous system”

Urine volume




GLP-1RAs and SGLT-2is work in glucose-dependent fashions…

…and are therefore not associated with high risk of hyperglycaemia

Hypoglycaemia reported in

LEADER Rate ratio

(95% CI) P value

Liraglutide Placebo

N % N %

Confirmed hypoglycaemia 0.80

(0.74 ; 0.88) <0.001 2039 43.7 2130 45.6

Severe hypoglycaemia0.69

(0.51 ; 0.93)0.016 114 2.4 153 3.3

Favours liraglutide Favours placebo

10 .5 1 .5

Hazard ratio (95% CI)

Important for their beneficial CVD effects?

Window (days)

Hazard ratio

[95% CI]

With prior severe hypoglycaemia

in window

Without prior severe

hypoglycaemia in window

n R n R

Any time 2.51 [1.79; 3.50] 38 7.32 385 2.64

365 days 2.78 [1.92; 4.04] 30 7.78 393 2.67

180 days 3.13 [1.99; 4.90] 20 8.56 403 2.71

90 days 3.28 [1.85; 5.83] 12 8.95 411 2.74

60 days 2.74 [1.30; 5.79] 7 7.40 416 2.77

30 days 3.66 [1.51; 8.84] 5 9.84 418 2.77

15 days 4.20 [1.35; 13.09] 3 11.23 420 2.78

0,25 0,5 1 2 4 8 16

Increased risk of all-cause death following a severe

hypoglycaemic eventDEVOTE pooled data

Pieber et al. Diabetologia 2018;61:58–65

Hazard ratio [95% CI]

Higher risk of all-cause death any time

following severe hypoglycaemia

What are the possible mechanisms for this temporal relationship?

EU, euglycaemic; HYPO, hypoglycaemic

Chow et al. Diabetes Care 2018;doi:10.2337/dc18-0050

Hyperinsulinaemic clamp visit

6 mmol/L

(60 min)

6 mmol/L

(60 min)

2.5 mmol/L

(60 min)

2.5 mmol/L

(60 min)

Post clamp day 1 Post clamp day 7

AM PM

EU arm

HYPO arm

Sampling

time points

Ba

se

line

En

d o

f cla

mp

Reco

ve

ry

Day 1

Day 7

Fibrin clot dynamics

Platelet assays

Coagulation, inflammatory markers

Catecholamines

Cortisol

Insulin


Platelet assays


Catecholamines

Cortisol

Insulin


Platelet assays


Catecholamines

Cortisol

Insulin

What are the possible mechanisms for this temporal relationship?

Data are mean (SE). ††p <0.01 euglycaemia vs. hypoglycaemia at equivalent time points; *p <0.05, **p <0.01 vs. baseline

Chow et al. Diabetes Care 2018;doi:10.2337/dc18-0050

Type 2 diabetes Controls

HYPO

EU

Glycaemic arm

p=0.001

Time

x glycaemic arm

p=0.19

Glycaemic arm

p=0.002

Time

x glycaemic arm

p=0.02

Glycaemic arm

p=0.99

Time

x glycaemic arm

p=0.36

Glycaemic arm

p=0.02

Time

x glycaemic arm

p=0.80

100

0

-100

-200

-300

ΔL

ysis

tim

e (

s)

††

††††

* *

0.05

0.00

-0.05

-0.10ΔC

lot a

bso

rban

ce (

AU

)

††

*

*

0.10

0.05

0.00

-0.05

-0.10ΔC

lot a

bso

rban

ce (

AU

)

*

0.10

100

0

-100

-200

-300

ΔL

ysis

tim

e (

s)

HYPO

EU

HYPO

EU

HYPO

EU

• GLP-1RAs reduce body weight and systolic blood pressure (and blood lipids)

• GLP-1RAs cause a small increase in heart rate

• In mouse models of atherosclerosis, GLP-1 protected against atherosclerotic plaque development,

possibly via modulation of macrophage function

• SGLT-2is reduce systolic blood pressure and body weight

• Reduced plasma volume from osmotic diuresis and natriuresis (without compensatory sympathetic

nerve activity) may reduce vascular wall stress and myocardial stretch

• Mediation analyses of EMPA-REG OUTCOME highlighted potential mediation of heart failure benefit

by markers of plasma volume changes (haematocrit)

• SGLT-2is are hypothesised to cause a shift in heart fuel supply in T2D from fatty acids and glucose to

the more energy-efficient ketones, improving myocardial efficiency

Summary

GLP-1RA, glucagon-like peptide-1 receptor agonist.

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