Clinical Relevance of Blood Pressure Lowering Effect of Modern Antidiabetic Drugs

Transcription

1 Clinical Relevance of Blood Pressure Lowering Effect of Modern Antidiabetic Drugs Professor Guntram Schernthaner Medical University of Vienna, Austria

2 Agenda Glucose lowering drugs temporal development The ominous Octet in the Pathogenesis and Treatment of Type 2 Diabetes Blood Pressure lowering effects of SGLT-2 inhibitors Blood Pressure lowering effects of GLP-1 receptor agonists Blood Pressure lowering effects of Glitazones Cardiovascular Outcome trials (CVOTs) with glucose lowering drugs Effect of glucose lowering drugs on Blood pressure and CV outcomes Summary

3 Treatment Options for T2DM Understanding the History ( ) Schernthaner G & Schernthaner GH. INTERNIST 2012; 53: SGLT2-Inhibitors Exenatide LAR Linagliptin Saxagliptin Sitagliptin / Vildagliptin Exenatide / Liraglutide Pramlintide Insulin detemir Insulin aspart Insulin glargine Glinides Thiazolidinediones Insulin lispro Human insulin Metformin Sulfonylurea Animal insulin s

4 The ominous Octet in the Pathogenesis and Treatment of T2DM TZDs GLP-1 DPP-4 SU Decreased Insulin Secretion Decreased Incretin Effect GLP-1 Increased Lipolysis TZDs Islet -cells GLP-1 Dpp-4 H Y P E R G L Y C E M I A Increased Glucose Reabsorption Increased Glucagon Secretion SGLT2- Inhibitors Met GLP-1 TZDs Increased HGP Neurotransmitter Dysfunction GLP-1 Decreased Glucose Uptake TZDs GLP1 Modified after DeFronzo RA. Diabetes 2009; 58:773

5 Effects of Sodium-Glucose Cotransporter 2 Inhibitors on 24-Hour Ambulatory Blood Pressure: A Systematic Review and Meta-Analysis Methods and Results: Meta-analysis of 6 randomized, double-blind, placebo-controlled trials to investigate the effects of SGLT2 inhibitors on 24-hour ambulatory BP SGLT2 inhibitors significantly reduce 24-hour ambulatory systolic and diastolic BP by 3.76 mm Hg (95% CI, 4.23 to 2.34) and 1.83 mm Hg (95% CI, 2.35 to 1.31) respectively. Significant reductions in daytime and nighttime systolic and diastolic BP were also found. No Association between baseline BP or change in body weight were observed Conclusions: (1) This meta-analysis shows that the reduction in 24-hour ambulatory BP observed with SGLT2 inhibitors is a class effect. (2) The diurnal effect of SGLT2 inhibitors on 24-hour ambulatory BP may contribute to their favorable effects on cardiovascular outcomes. Baker LA et al. J Am Heart Assoc. 2017;6:e

6 Effect of different SGLT2 inhibitors on 24-hour systolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

7 Effect of diiferent SGLT2 inhibitors on 24-hour diastolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

8 Effect of different SGLT2 inhibitors on daytime systolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

9 Effect of different SGLT2 inhibitors on daytime diastolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

10 Effect of different SGLT2 inhibitors on nighttime systolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

11 Effect of different SGLT2 inhibitors on nighttime diastolic blood pressure Baker LA et al. J Am Heart Assoc. 2017;6:e

12 Change from baseline in mean 24-hour SBP at week 12 by number of antihypertensive medications at baseline (ANCOVA, FAS, LOCF); P=0.448 for interaction between SBP reduction and number of antihypertensive medications at baseline. Change from baseline in mean 24-h DBP at week 12 by number of antihypertensive medications at baseline (ANCOVA, FAS, LOCF); P=0.498 for interaction between DBP reduction and number of antihypertensive medications at baseline. Mancia G et al. Hypertension 2016;68:

13 Change from baseline in mean 24-hour SBP at week 12 by use of diuretics at baseline (ANCOVA, FAS, LOCF); P=0.380 for interaction between SBP reduction and use of diuretics at baseline. Change from baseline in mean 24-hour DBP at week 12 by use of diuretics at baseline (ANCOVA, FAS, LOCF); P=0.240 for interaction between DBP reduction and use of diuretics at baseline. Mancia G et al. Hypertension 2016;68:

14 Change from baseline in mean 24-hour SBP at week 12 by ACE inhibitors/arbs at baseline (ANCOVA, FAS, LOCF); P=0.900 for interaction between SBP reduction and use of ACE inhibitors/arbs at baseline. Change from baseline in mean 24-hour DBP at week 12 by ACE inhibitors/arbs at baseline (ANCOVA, FAS, LOCF); P=0.359 for interaction between DBP reduction and use of ACE inhibitors/arbs at baseline. Mancia G et al. Hypertension 2016;68:

15 <30 Change from baseline at week 24 with empagliflozin compared with placebo in egfr subgroups in HbA1c in Weight in SBP Unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease in DBP Cherney et al. Kidney International 2018: 93,

16 Proposed mechanisms for antihypertensive action of SGLT2 inhibitors Osmotic diuresis Increase natriuresis Weight loss after a week Improve arterial stiffness Reduce sympathetic system activity Improve circadian rhythm and BP variability Suppress renal renin angiotensin system Reduce oxidative stress Improve endothelial dysfunction? Briasoulis A, Al Dhaybi, Bakris GL. Current Cardiology Reports 2018; 20:1

17 Summary of meta-analyses of GLP-1 therapies on Blood Pressure Lowering Good et al- Curr Hypertens Rep 2016; 18: 16

18 Forest plot illustrating systolic blood pressure (SBP) changes between (A) Exenatide and placebo treatment (B) Exenatide and insulin glargine treatment (C) Exenatide and Sitagliptin (D) Exenatide and Pioglitazone Wang et al. Diabetes, Obesity and Metabolism 2013:15:

19 Forest plot illustrating systolic BP blood changes between (A) 1.2 mg liraglutide treatment/day and placebo treatment or (B) 1.2 mg liraglutide treatment/day and glimepiride treatment Forest plot illustrating systolic BP changes between (A) 1.8 mg liraglutide treatment/day and placebo treatment or (B) 1.8 mg liraglutide treatment/day and glimepiride treatment Wang et al. Diabetes, Obesity and Metabolism 2013:15:

20 Effect of DPP-4 inhibitors versus different types of comparators on Systolic Blood Pressure GLP-1 RAS SGLT-2 Inhibitors Placebo Other antidiabetic agents Sulfonylureas Zhang & Zhao. J Hypertens 2016; 34: Effects of DPP-4 inhibitors on blood pressure in patients with type 2 diabetes: A systematic review and meta-analysis

21 Effect of DPP-4 inhibitors versus different types of comparators on diastolic Blood Pressure GLP-1 RAS SGLT-2 Inhibitors Placebo Other antidiabetic agents Sulfonylureas Zhang & Zhao. J Hypertens 2016; 34: Effects of DPP-4 inhibitors on blood pressure in patients with type 2 diabetes: A systematic review and meta-analysis

22 Model of blood pressure lowering with GLP-1R activation The BP-lowering effects of GLP-1 R agonists are rapid and occur within 2 3 weeks. Meta-analysis of six trials of liraglutide (n = 1363 for 1.8 mg, n = 896 for 1.2 mg) have shown an SBP reduction of 2.5 mmhg within 2 weeks of treatment, prior to any changes in weight. These effects typically plateau by 8 12 weeks and are seen in follow-up of up to 2 years GLP-1 glucagon-like peptide-1, ANP atrial natriuretic peptide, cgmp cyclic guanosine monophosphate, NO nitric oxide, NTS nucleus tractus solitarius, RVLM rostral ventral lateral medulla, Arc arcuate nucleus, VMH ventromedial hypothalamus, PVN paraventricular nucleus Good et al- Curr Hypertens Rep 2016; 18: 16

23 Potential Mechanisms regulating the anti-hypertensive effects of GLP-1 agonist therapy ANP secretion via atrial GLP-1R-mediated camp-epac-anp pathways and vasorelaxation Sodium excretion via the ANP-Na+/H+ exchanger dependent and independent mechanisms in the PCT Smooth muscle relaxation and vasodilation via NO-independent cgmp-dependent pathways Endothelial nitric oxide release through Akt-eNOS pathways. NO-independent mechanisms of vasodilation in the endothelium may also participate Promoting weight loss by suppressing appetite, delaying gastric emptying GLP glucagon-like peptide-1, camp cyclic adenosine monophosphate, EPAC exchange protein activated by camp, ANP atrial natriuretic peptide, PCT proximal convoluted tubule, cgmp cyclic guanosine monophosphate, enos endothelial nitric oxide Good et al- Curr Hypertens Rep 2016; 18: 16

24 Effect of TZDs on Systolic Blood pressure (pre-post study design) A total of 37 clinical trials that reported a change in BP were included in the metaanalysis. When compared with baseline, TZDs lowered systolic BP by 4.70 mm Hg (95% CI to -3.27) and diastolic BP by 3.79 mm Hg (95% CI to -1.77) When compared with placebo, TZDs lowered systolic BP by 3.47 mm Hg (95% CI to -2.02) and diastolic BP by 1.84 mm Hg (95% CI to -0.25). Qayyum R, Adomaityte J. J Clin Hypertens 2006; 8:19-28

25 Effect of Glucose Lowering Drugs on the Combined Endpoint of CV Mortality, Nonfatal Myocardial Infarction and Stroke Antidiabetic Drug HR P-value PROactive Pioglitazone 0.84 (CI ) 0.02 ORIGIN Insulin Glargine 1.02 (CI ) NS SAVOR Saxagliptin 1.00 (CI ) NS EXAMINE Alogliptin 0.96 (CI ) NS ELIXA Lixisenatide 1.02 (CI ) NS TECOS Sitagliptin 0.98 (CI ) NS EMPA-REG Empagliflozin 0.86 (CI ) CANVAS Canagliflozin 0.86 (CI ) 0.02 LEADER Liraglutide 0.87 (CI ) 0.01 SUSTAIN-6 Semaglutide 0.78 (CI ) EXSCEL Exenatide 0.91 (CI ) NS ACE Acarbose 0.95 (CI ) NS Schernthaner G and Sattar N. Journal of Diabetes and Its Complications 2014;28: Schernthaner G et al. Clin Ther 2016;38:

26 EMPA-REG OUTCOME, LEADER and SUSTAIN-6 Key CV and renal outcomes 1 4 3P-MACE CV death All-cause EMPA-REG OUTCOME mortality HHF Composite renal outcomes RRR 14% 38% 32% 35% 39% 44% p-value 0.04 <0.001 < <0.001 <0.001 LEADER RRR 13% 22% 15% 13% 22% 12% p-value NS NS SUSTAIN-6 Doubling of serum creatinine RRR 26% 2% +5% +11% p-value p=0.02 NS NS NS +28% (doubling of serum creatinine) 9% (need for replacement) +28% NS Please note that this is not a head-to-head comparison SUSTAIN-6 was a non-inferiority study, and testing for superiority was not a pre-specified endpoint CV, cardiovascular; HHF, hospitalization for heart failure; MACE, major adverse cardiac event; NS, not significant; RRR, relative risk reduction 1 Zinman B, et al. N Engl J Med 2015;373: ; 2 Wanner C, et al. N Engl J Med 2016;375:323 34; 3 Marso SP, et al. N Engl J Med 2016;375:311 22; 4 Marso SP, et al. N Engl J Med 2016;375:

27 Pioglitazone reduces Risk for Stroke and Myocardial Infarction in Nondiabetic insulin-resistant patients with a history of Stroke/TIA Multicenter, double-blind trial of 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Significant reduction of the primary outcome (fatal or nonfatal stroke or myocardial infarction) after 4.8 year (HR 0.76; 95% [CI], 0.62 to 0.93; P=0.007). IRIS: Insulin Resistance Intervention after Stroke Pioglitazone reduced the risk of ACS (HR, 0.71; 95% ; P=0.02) and the risk of type 1 MI (HR 0.62; 95% CI ; log-rank P=0.03), Kernan WN et al. NEJM : Young LH et al. Circulation 2017; 135:

28 Effect of Glucose lowering drugs on Blood Pressure and Cardiovascular Outcomes Blood Pressure Significant Effects lowering effect on CV Outcomes Metformin? yes (but no CVOT) Sulfonylurea no no Insulin no no (CVOT) Pioglitazone yes yes (CVOT) DPP-4 Inhibitors no no (CVOT) GLP-1 Receptor Agonists yes yes (CVOT SGLT-2 Inhibitors yes yes (CVOT)

29 SUMMARY Some of the modern glucose lowering drugs have clinically relevant effects beyond glucose lowering including blood pressure lowering, weight reduction and antiinflammatory effects SGLT-2 inhibitors, GLP-1 receptor agonists and glitazones reduce significantly systolic and diastolic blood pressure levels It is interesting that drugs of these classes demonstrated positive results in the CVOTs (reduction of CV death, all-cause mortality) and nephroprotection By contrast, sulfonylureas, insulin and DPP-4 inhibitors do not reduce BP and did not show either cardioprotection or nephroprotection Thus, glucose lowering drugs may be preferred which offer blood pressure lowering and other positive effects, which could be involved in the well documented findings of cardioprotection and nephroprotection