of new diabetes drugs? Filip Krag Knop, MD Copenhagen, Denmark - - PowerPoint PPT Presentation
Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications Translating mechanisms to benefits: How can we explain the cardiovascular benefits of new diabetes drugs? Filip Krag Knop, MD Copenhagen, Denmark
Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications
Filip K. Knop, MD PhD
Professor, Consultant Endocrinologist, Head of Clinical Metabolic Physiology Steno Diabetes Center Copenhagen, Gentofte Hospital University of Copenhagen Copenhagen, Denmark
Thomsen R et al., Diabetes, Obesity and Metabolism 2015
2 4 6 8 10 12 14 16 18 20 6 7 8 9 10 11 12 Relative Risk Retinopathy Nephropathy Neuropathy Microalbuminuria A1C (%) 43 53 63 73 83 93 103
(blindness) (dialysis) (amputations) Nephropathy Neuropathy Retinopathy
*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
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
years
yrs
yrs No diabetes
Diabetes Diabetes + MI
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
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
issued guidance to industry for evaluating CV safety in diabetes drugs
new therapy will not result in an unacceptable increase in CV risk
95% CI of the risk ratio should be <1.8
CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration.
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
*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) 2019 2015 2020 2013 2014 2016 2017 2018 2021 Insulin
DEVOTE (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 (Canagliflozin, SGLT-2i) n=5826; duration ~3 yrs Q2 2017 – RESULTS CREDENCE (cardio-renal) (Canagliflozin, SGLT-2i) 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) n=4000; duration ~2 yrs 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) n=9574; duration ~4 yrs Q2 2018 - RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176*; duration ~1.5 yrs 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) n=6072; duration ~8 yrs 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
PPAR-αγ 2022
SCORED (Sotagliflozin, SGLT-1i & SGLT-2i) n=10,500*; duration ~4.5 yrs Completion Q1 2022
TZD
TOSCA IT (Pioglitazone, TZD) n=3028; duration ~10 yrs Q4 2017†– RESULTS
AGI
ACE (Acarbose, AGI) n=6522; duration ~8 yrs Q2 2017 – RESULTS AMPLITUDE-O (Efpeglenatide, GLP-1RA) n=4000*; duration ~3 yrs Completion Q2 2021 SOLOIST-WHF
(Sotagliflozin, SGLT-1i & SGLT-2i) n=4000*; duration ~2.7 yrs Completion Q1 2021
EXAMINE Alo vs. Pbo EMPA-REG Outcome Empa vs. Pbo ELIXA* Lixi vs. Pbo ORIGIN Glargine U100 vs. SOC SAVOR TIMI-53 Saxa vs. Pbo CANVAS Program Cana vs. Pbo FREEDOM-CVO ITCA 650 vs. Pbo DEVOTE Degludec vs. Glargine U100 TECOS* Sita vs. Pbo DECLARE-TIMI 58 Dapa vs. Pbo LEADER Lira vs. Pbo CARMELINA Lina vs. Pbo SUSTAIN-6 Sema vs. Pbo EXSCEL Exe OW vs. Pbo HARMONY Alb vs. Pbo REWIND Dul vs. Pbo
0,1 0,4 0,7 1,0 1,3 HR [95% CI]
Insulin
?
0,1 0,4 0,7 1,0 1,3 1,6 HR [95% CI]
GLP-1 RA ?
0,1 0,4 0,7 1,0 1,3 HR [95% CI]
DPP-4i
0,1 0,4 0,7 1,0 1,3 HR [95% CI]
SGLT2i
*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
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
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 Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys
Fat cells
Glucose uptake Lipolysis
Liver
Glycogen storage
Skeletal muscle
Glucose uptake
Blood vessel
Endothelium-dependent vasodilation
Pancreas
New β-cell formation β-cell apoptosis Insulin biosynthesis
DPP-4
GI tract
Motility
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
LS LS AP+NTS ARH LS SFO NTS LS ARH ME AP
Mouse
NTS AP
Monkey
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
Change in weight (%)
2 4 6 8 10 12 14 16 18 20 24 28 32 36 40 44 48 52
Semaglutide s.c. 0.05 mg Semaglutide s.c. 0.1 mg Semaglutide s.c. 0.2 mg Semaglutide s.c. 0.3 mg Semaglutide s.c. 0.4 mg Placebo pool
Week
Liraglutide 3.0 mg
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 Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys
Fat cells
Glucose uptake Lipolysis
Liver
Glycogen storage
Skeletal muscle
Glucose uptake
Blood vessel
Endothelium-dependent vasodilation
Pancreas
New β-cell formation β-cell apoptosis Insulin biosynthesis
DPP-4
GI tract
Motility
*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
% lesion area
15 10 5
Vehicle Lira Lira + Ex-9
Oil red O staining performed in the aorta
Lipid deposition
N=13‒16
Vehicle Lira Lira + Ex-9
M M I M I
Lesion development
Haemotoxylin and eosin staining in the aortic arch
*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)
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
10 15 20 TG (mmol/L)
*
5
Vehicle, chow Vehicle, western diet Semaglutide (1 nmol/kg) Semaglutide (3 nmol/kg) Semaglutide (15 nmol/kg)
10 20 30
Aortic plaque lesions
**
Plaque area (%)
** **
Vehicle, chow Vehicle, western diet
Semaglutide
1 nmol/kg 3 nmol/kg 15 nmol/kg
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 4 6 8
R e la tiv e E x p re s s io n (L o g 2 ) 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 r e c r u itm e n t L e u k o c y te a d h e s io n & e x tr a v a s a tio n E x tra c e llu la r m a trix p r o te in tu r n 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
23 April 2019 21
showed that liraglutide modulates macrophage cell fate towards MΦ2 pro-resolving macrophages
lesion formation
Bruen et al. Cardiovasc Diabetol 2017;16:143
MΦ MΦ1 MΦ2
Macrophage Pro-atherogenic Pro-resolving Atherosclerotic lesion
Estimated 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 mg 0.80† (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 56 Semaglutide 1.0 mg Exenatide ER
CRP (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. 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 Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg Lys
Fat cells
Glucose uptake Lipolysis
Liver
Glycogen storage
Skeletal muscle
Glucose uptake
Blood vessel
Endothelium-dependent vasodilation
Pancreas
New β-cell formation β-cell apoptosis Insulin biosynthesis
DPP-4
GI tract
Motility
Proposed modes of action:
DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system
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 Empagliflozin Dapagliflozin DPP-4 inhibitor Metformin Sulphonylurea –3 –2 –1 1 kg
Body weight
2
0.0
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 Change in body composition (kg)*
DAPA, dapagliflozin; MET, metformin; PBO, placebo. Bollinder et al Diabetes, Obesity and Metabolism 2014;16;159–169
DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system
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
Baseline Acute dosing Chronic dosing
Patient with type 2 diabetes (n=66) No diabetes (n=25)
Meal ingestion Meal ingestion -hydeoxybutyrate (µmol/L) 300 240 180 120 60 –60 –120 –180 300 600 900 300 240 180 120 60 –60 –120 –180 300 600 900 -hydroxbutyrate (µmol/L) Baseline Acute dosing Chronic dosing
Mudaliar et al. Diabetes Care 2016
metabolic advantage exists in using ketone bodies as a fuel
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
↓ Incidence/progression
↑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
DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system
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.
2 –2 –4 –6 mmHg
Systolic blood pressure
Canagliflozin Empagliflozin Dapagliflozin DPP-4 inhibitor Metformin Sulphonylurea
In general, no effect on heart rate
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
1 2 3 4 5
Placebo EMPA 10 mg EMPA 25 mg
Haematocrit, % Changes in haematocrit with empagliflozin n = 3695 n = 3806 n = 4782
30 20 –10 –20 –30 10 –40 Placebo Dapagliflozin Hydrochlorothiazide Red cell mass change from baseline (%) P: –1.2 (–3.2 to +1.3) D: +6.6 (+1.0 to +9.3) H: –6.5 (–16.1 to +3.8)
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% 0.624 HbA1c 16.1% 0.665 FPG Vascular tone –7.5% 0.593 Systolic BP –0.3% 0.614 Diastolic BP 2.0% 0.621 Heart rate Lipids 6.9% 0.636 HDL-C –6.5% 0.596 LDL-C –3.4% 0.605 Triglycerides Renal factors 11.1% 0.649 Log UACR 5.3% 0.631 eGFR Adiposity –12.4% 0.579 Weight –12.8% 0.578 BMI –5.8% 0.598 Waist circumference Other 24.6% 0.693 Uric acid Volume 51.8% 0.791 Haematocrit 0.615
DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system
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
DeFronzo et al. Nat Rev Nephrol 2017;13:11–26. Ang, angiotensin; CV, cardiovascular; SNS, sympathetic nervous system
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 hypoglycaemia 0.69 (0.51 ; 0.93) 0.016 114 2.4 153 3.3 Favours liraglutide Favours placebo
1 0 .5 1 .5
Hazard ratio (95% CI)
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
Pieber et al. Diabetologia 2018;61:58–65
Hazard ratio [95% CI]
Higher risk of all-cause death any time following severe hypoglycaemia
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
Baseline End of clamp Recovery Day 1 Day 7
Fibrin clot dynamics Platelet assays Coagulation, inflammatory markers Catecholamines Cortisol Insulin Fibrin clot dynamics Platelet assays Coagulation, inflammatory markers Catecholamines Cortisol Insulin Fibrin clot dynamics Platelet assays Coagulation, inflammatory markers Catecholamines Cortisol Insulin
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
Δ Lysis time (s) †† †† †† * * 0.05 0.00
Δ Clot absorbance (AU) †† * * 0.10 0.05 0.00
Δ Clot absorbance (AU) * 0.10 100
Δ Lysis time (s)
HYPO EU HYPO EU HYPO EU
possibly via modulation of macrophage function
nerve activity) may reduce vascular wall stress and myocardial stretch
by markers of plasma volume changes (haematocrit)
the more energy-efficient ketones, improving myocardial efficiency
GLP-1RA, glucagon-like peptide-1 receptor agonist.