Management? Sanjay Rajagopalan, MD FACC FAHA Herman Hellerstein - - PowerPoint PPT Presentation
Are New Incretin Agent Outcome trials Changing the Fundamentals of Diabetes Management? Sanjay Rajagopalan, MD FACC FAHA Herman Hellerstein Professor of CV Research Chief, Cardiovascular Medicine, University Hospitals Director, Cardiovascular
3 Adapted from JAMA 2007; 298; 765-75 Am J Cardiol. 2016 Aug 1;118(3):345-52
N=9,492 patients with ACS in Europe N=62,036 patients with ACS, 11 TIMI trials
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LOOK-AHEAD. N Engl J Med. 2013 Jul 11;369(2):145-54.
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1 2 3 4 5 6 7 10 8 9 1 2 3 4 5 6 7 10 8 9
E st i m at e d M e a n (k g)
Year
100 98 96 94 92 90 Intervention Control
Main effect, -4 (95% CI, -5 to -3) P < 0.001
7.4 7.2 7.0 6.8 0.0 6.6 Intervention Control
Main effect, -0.22 (95% CI, -0.28 to -0.16) P < 0.001
E st i m at e d M e a n (k g)
Year
The primary outcome was composite of death from CV causes, nonfatal MI, nonfatal CVA, or hospitalization for angina.
Control Intervention 20 16 12 8 4 2 4 6 10 8
%
P at ie nt s w it h E v e nt s Years
Intervention 2570 2447 2326 2192 2049 505 Control 2575 2425 2296 2156 2019 688
GLP-1R
PHYSIOLOGIC SUBSTRATES GLP-1 SDF-1 SUBTANCE P GIP GLP-2 PYY PHARMACOLOGIC SUBSTRATES BNP EOTAXIN NPY EPO GLUCAGON GM-CSF GRP IP-10 MIG RANTES
Zhong J and Rajagopalan S, et al. Circ Res 2015;116(8):1491-504.
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Glu Gly Phe Thr Thr Ser Asp Val Ser Ser Ala His Tyr Leu Glu Gly Gln Ala Ala Arg Phe Ile Trp Ala Leu Val Lys Gly Glu Lys
Amide
GLP-1 (7-36)Amide
Proteolytic attack (DPP-4)
7 30 25 20 15 10 35 36
Glu Gly Phe Thr Thr Ser Asp Leu Ser Lys Gly His Gln Met Glu Glu Glu Ala Val Gly Pro Phe Ile Trp Glu Leu Lys Asn Gly Leu Arg Pro Ser Ser Ser Gly Ala Pro Pro
Amide
Exenatide (exendin-4), Amylin/Eli Lilly & Co./Bristol-Myers Squibb)
Glu Gly Phe Thr Thr Ser Asp Val Ser Ser Ala His Tyr Leu Glu Gly Gln Ala Ala Arg Gly Phe Ile Trp Ala Leu Val Arg Gly Glu Lys Glu
Albumin
Liraglutide (Novo Nordisk)
C-16 Free fatty acid (noncovalent binding to albumin)
Glu Gly Phe Thr Thr Ser Asp Val Ser Ser AIB His Tyr Leu Glu Gly Gln Ala Ala Arg Phe Ile Trp Ala Leu Val Lys AIB Glu Lys
Amide
Taspoglutide* (Roche)
7 30 25 20 15 10 35 36
Glu Gly Phe Thr Thr Ser Asp Leu Ser Lys Gly His Gln Met Glu Glu Glu Ala Val Gly Pro Phe Ile Trp Glu Leu Lys Asn Gly Leu Arg Ser Ser Gly
Lixisenatide* (Sanofi)
Lys Lys Lys Lys Ala Pro Pro Lys Lys Ser Glu Gly Phe Thr Thr Ser Asp Val Ser Ser AIB His Tyr Leu Glu Gly Gln Ala Ala Arg Gly Phe Ile Trp Ala Leu Val Arg Gly Glu Lys
Semaglutide* (Novo Nordisk)
C-18 Free fatty acid (noncovalent binding to albumin)
*Not FDA approved.
AIB: Alpha Amino Isobutyric acid
Pancreas GI tract
Insulin biosynthesis Glucagon Release Beta-cell proliferation Beta-cell apoptosis INCRETINS
Brain
Weight Loss Appetite Insulin secretion Glucagon secretion Gastric emptying
Stomach
Cardioprotection Cardiac output
Liver
Insulin sensitivity Glucose production VLDL Production
Muscle
Apo 48 production CM Production
Heart
Inflammation Vasodilation Endothelial function
Vasculature 8
Katout and Rajagopalan S. Am J Hypertens 2014;27:130-139
90 60 30 8 12 16 20 24 Time (h) GLP-1 (pmol/L) GLP-1 receptor agonist 90 60 30 8 12 16 20 24 Time (h) GLP-1 (pmol/L) DPP4 inhibitor
Adapted from Nauck MA, et al. Am J Med. 2011;124(1 suppl):s3-s18.
No blood pressure lowering or weight loss effects?
Waldrop G, Rajagopalan S et al. J Am Coll Cardiol. 2016 Mar 29;67(12):1488-96
MA, et al. N Engl J Med. 2015 Dec 3;373(23):2247-57; 5.Marso S et al. N Engl J Med. 2016 Sep 15; 6. Marso P et al. N Engl J Med. 2016 Jul 28;375(4):311-22;. Zinman B, et al. N Engl J Med. 2015 Nov 26;373(22):2117-28
EXAMINE1 SAVOR-TIMI2 TECOS3 ELIXA4 SUSTAIN-65 LEADER6
Alogliptin Saxagliptin Sitagliptin Lixisenatide Semaglutide Liraglutide Time to first MACE event:
stroke Time to first eMACE event:
ischaemic stroke Time to first eMACE event:
stroke
angina Time to first MACE event:
stroke
angina Time to first MACE event:
ischaemic stroke Time to first MACE event:
stroke
EMPA-REG7
Empagliflozin Time to first MACE event:
DPP-4 Inhibitors GLP-1 Agonists SGLT-2 Inhibitors 2013 2016
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EXAMINE1 Alogliptin (n=2,701) SAVOR-TIMI2 Saxagliptin (n=8,280) TECOS3,4 Sitagliptin (n=7,332) ELIXA5 Randomized population (N=6,068) Mean age (years) 61.0 65.1 65.4 60.3 Median/mean duration
7.1 10.3 11.6 9.3 Median/mean weight (kg) 80.2 87.7 NA NA Median or mean BMI (kg/m2) 28.7 31.1 30.2 30.2 Average/mean HbA1c 8.0 8.0 7.2 7.7 CV history/risk factors Prior MI (%) Prior stroke (%) Heart failure (%) Hypertension (%) PAD (%) Dyslipidemia (%) Coronary revascularization (%) 88.4 7.2 28.0 82.5 9.7 27.1 62.5 38 NA 12.8 81.2 11.9* 71.2 43.1 42.7 17.7 17.8 NA 16.6 77† 38.9 22 5.2 12.4 75.5 6.0 NA 16.5
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International, multicenter, randomized, double-blind phase 3 study of alogliptin versus placebo in post-ACS patients with T2D receiving standard antihyperglycemic and CV drug therapy
White WB, et al. N Engl J Med 2013;369:1327–35.
Alogliptin* OD + standard of care† (n=2,701) Placebo OD + standard of care† (n=2,679)
Days –14 to –1 Day 1 Month 1 Month 12 End of study 2-week follow-up Baseline/ randomisation Screening visit Visits at months 3, 6, and 9 Visits every 4 months Median duration of exposure to alogliptin: 18 months
Treatment period (4.5 years)
Inclusion criteria
diagnosed with ACS 15 90 days before randomization
*At randomization, patients were assigned to receive 25, 12.5, or 6.25mg OD based on renal function.
After randomization, dose adjustments were allowed on the basis of changes in renal function.
†Investigators were permitted to adjust any antidiabetic therapy in alogliptin and placebo arms if
required (with the exception of the addition of a DPP-4 inhibitor or GLP-1 analogue).
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* 99% one-sided confidence interval, p<0.001 for non-inferiority; p=0.32 for superiority White WB, et al. N Engl J Med 2013;369(14):1327-1335.
Cumulative Incidence of Events (%) 25 20 15 10 5 6 12 18 24 30
History of Heart Failure Prior to Randomization Hazard ratio, 0.90 (95% Cl, 0.70 – 1.17) Events, No. (%) Placebo: 120 (15.7%)
No History of Heart Failure Prior to Randomization Hazard ratio, 1.14 (95% Cl, 0.85, 1.54) Events, No. (%) Placebo: 81 (4.2%)
Months Alogliptin Placebo
Zannad F, et al. Lancet. 2015;385:2067-76.
2,1 2,1 1,8 2,3 7,5 6,4 17,5 19,4 1,1 1,1 1,4 1,4 3,7 3,7 7,6 10,9 1,1 1,1 0,5 0,9 3,8 2,7 9,9 8,5 5 10 15 20 25 Alogliptin (N=656) Placebo (N=652) Alogliptin (N=661) Placebo (N=650) Alogliptin (N=628) Placebo (N=676) Alogliptin (N=684) Placebo (N=623) Q1: HR=1.03 95% CI (0.48, 2.19) Q2: HR=0.80 95% CI (0.38, 1.70) Q3: HR=1.16 95% CI (0.76, 1.75) Q4: HR=0.90 95% CI (0.70, 1.16)
Heart Failure Outcomes (%)
Composite Endpoint CV Death Hosptitalization for Heart Failure
HRs refer to the composite end point.
Quartiles of NT-proBNP (pg/mL)
Zannad F, et al. Lancet. 2015;385:2067-76.
Filion KB et al. N Engl J Med 2016;374:1145-1154
Canadian Network for Observational Drug Effect Studies (CNODES) + Clinical Practice Research Datalink (CPRD + Marketscan Database (US) N= 1,499,650, 79,800 with a history of heart failure
Lixisenatide: 406/3034 = 13.4% Placebo: 399/3034 = 13.2% HR = 1.02 (0.89, 1.17)
Pfeffer MA, et al. N Engl J Med. 2015 Dec 3;373(23):2247-57
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15 10 20 5 6 12 18 24 30 36 42 48 54
Placebo Liraglutide Patients with an event (%) Months since randomisation
Hazard ratio, 0.87 (95% CI, 0.78–0.97) P<0.001 for noninferiority P=0.01 for superiority
First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-to-event analysis in patients with type 2 diabetes and high CV risk.
Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial
Adapted from: Marso SP et al., NEJM 2016
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15 10 20 5 6 12 18 24 30 36 42 48 54
Placebo Liraglutide Patients with an event (%) Months since randomisation Hazard ratio, 0.78 (95% CI, 0.66–0.93) P=0.007
Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial
Adapted from: Marso SP et al., NEJM 2016
Hazard ratio (95% CI) Primary composite endpoint* 0.87 (0.78-0.97) Expanded composite endpoint† 0.88 (0.81-0.96) Death from any cause 0.85 (0.74-0.97) CV death 0.78 (0.66-0.93) Fatal or nonfatal MI 0.88 (0.75-1.03) Stroke 0.89 (0.71-1.11)
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*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016 Jun 13. [Epub ahead of print]
Favors liraglutide
Hazard ratio (95% CI) P value Primary composite endpoint* 0.74 (0.58-0.95) 0.02 Expanded composite endpoint† 0.74 (0.62-0.89) 0.002 Death from any cause 1.05 (0.74-1.50) 0.79 CV death 0.98 (0.65-1.48) 0.92 Non-fatal MI 0.74 (0.51-1.08) 0.11 Stroke 0.61 (0.38-0.99) 0.04 Revascularization 0.61 (0.50-0.86) 0.65
*CV death, nonfatal MI (including silent MI), or nonfatal stroke; †CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016 Sep 15
Favors Semaglutide
HF Hospitalizations was comparable between Semaglutide and Placebo (HR 1.11. CI 0.77-1.61)
Blood pressure=-2.59 mm Hg lower in 1.0 mg dose
Sept 2016
Reduction 26% Slow onset Stroke driven ARR=2.3 ARR=1.9 ARR=1.6 NNT=63 NNT=53 NNT=44
GLP-1 agonists have larger effects on glycemia control and anciliary CV surrogates such as blood pressure and weight loss and may drive CV benefit through these mechanisms Although efficacy has alluded DPP-4i trials, overall safety in a range of patient populations including CKD may allow their utilization with other agents Together both GLP-1 agonists and DPP-4 inhibitors have a definitive role in the management of patients at high risk for CVD GLP-1 trials demonstrate an important effect on MACE with one trial (LEADER) showing a mortality benefit DPP-4i trials demonstrate safety of these agents. EXAMINE the only trial in high risk ACS patients demonstrating overall safety