European Heart Journal

Niessner, Alexander; Tamargo, Juan; Koller, Lorenz; Saely, Christoph H; Schmidt, Thomas Andersen; Savarese, Gianluigi; Wassmann, Sven; Rosano, Giuseppe; Ceconi, Claudio; Torp-Pedersen, Christian; Kaski, Juan Carlos; Kjeldsen, Keld Per; Agewall, Stefan; Walther, Thomas; Drexel, Heinz; Lewis, Basil S

doi: 10.1093/eurheartj/ehx625pmid: 29126266

The aim of antidiabetic pharmacotherapy in patients with type 2 diabetes and cardiovascular disease Patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) have a particularly high risk for recurrent major adverse cardiovascular events (MACE).1 Compared with patients with CVD only, the risk for MACE increases by about 1.7-fold in those with CVD and T2DM.1 Type 2 diabetes mellitus is a stronger risk factor for MACE than the angiographic severity of coronary heart disease (CHD).2 Reducing the T2DM-associated risk is therefore of utmost importance. Antidiabetic pharmacotherapy reduces plasma glucose and dosing is adjusted according to HbA1c concentration. European Society of Cardiology (ESC) guidelines recommend HbA1c values <7% for patients with CVD.3 While controlling HbA1c levels is important to prevent both microvascular disease and atherosclerosis progression, the association between HbA1c and short to mid-term cardiovascular events is less well defined. Albeit early trials showed a trend towards MACE reduction with glucose lowering agents,4,5 recent data indicates that only specific antidiabetic therapies reduce MACE,6,–9 and this effect appears to be independent of baseline HbA1c level or HbA1c reduction.6,7 Of note, these recent outcome trials were primarily designed as non-inferiority trials to test for cardiovascular safety with subsequent hierarchical testing for superiority only. Furthermore, in most of these trials it was possible to add other glucose-lowering therapies after randomization to achieve adequate glycaemic control resulting in an imbalance of other antidiabetic therapies between intervention and control arm which may have influenced study results. This position paper will critically appraise emerging evidence regarding antidiabetic pharmacotherapy in patients with T2DM and mostly stable CVD. While patients with acute coronary syndrome (ACS) have been excluded from recent studies, the ELIXA and the EXAMINE trials specifically recruited patients post ACS.10,11 We have critically assessed: (i) the relevance of the study population, the presence of CVD, statistical power, concomitant cardiovascular treatments, and exclusion criteria (Table 1, Supplementary material online, Table S1), (ii) the effects of antidiabetic pharmacotherapy on cardiovascular endpoints (Figure 1, Table 2, Supplementary material online, Table S2), and (iii) the occurrence of specific adverse effects (Table 2, Supplementary material online, Table S2).12–15 In this article, we report relative risk reduction (RRR) for comparability of trial results and number needed to treat/harm (NNT/NNH) and absolute risk reduction (ARR) for the duration of the respective study follow-up to show the magnitude of the effect (Supplementary material online, Table S2). Based on current data, this article summarizes the positions of the ESC WG on Cardiovascular Pharmacotherapy on the selection of antidiabetic pharmacotherapy and potential drug combinations. The mechanisms of specific antidiabetic therapies16 and insulin therapy (including insulin analogues) will not be discussed. Table 1 Relevance of studies for patients with type 2 diabetes and established cardiovascular disease Study Class of drug Drug Power (n of patients with primary endpoint) Established cardiovascular disease Concomitant cardiovascular medication Relevant exclusion criteria Relevance of study EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin Adequate (772) 99% Vast majority Recent ACS, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD CANVAS Program Canagliflozin Strong (1011) 66% Majority Recent ACS, NYHA IV, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD LEADER GLP-1 receptor agonist Liraglutide Strong (1302) 81% Majority Recent ACS, NYHA IV, malignant neoplasm Highly relevant for stable CVD SUSTAIN-6 Semaglutide Moderate (254) 59% Majority Recent ACS, NYHA IV, malignant neoplasm, pancreatitis Relevant for stable CVD EXSCEL Exenatide Strong (1744) 73% Majority eGFR < 30 mL/min, personal or family history of medullary thyroid cancer, history of pancreatitis Highly relevant for stable CVD ELIXA Lixisenatide Adequate (805) 100% (ACS) Vast majority eGFR < 30 mL/min, pancreatitis, gastrointestinal disease, personal or family history of medullary thyroid cancer Highly relevant for ACS PROACTIVE Thiazolidinedione Pioglitazone Strong (1086) 100% Majority Recent ACS, symptomatic heart failure, ketoacidosis Highly relevant for stable CVD SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin Strong (1222) 79% Majority Recent ACS Highly relevant for stable CVD EXAMINE Alogliptin Adequate (621) 100% (ACS within the previous 15–90 days) Vast majority Recent ACS, NYHA IV Highly relevant for ACS TECOS Sitagliptin Strong (1690) 74% Majority eGFR < 30 mL/min, ketoacidosis Highly relevant for stable CVD UKPDS 34 Biguanide Metformin Moderate (139 during follow-up of > 10 years) NR Limited use >65 years of age Limited relevance for CVD STOP-NIDDM Alpha-glucosidase inhibitor Acarbose (compared to sulfonylurea) Hypothesis generating study (47) <5% Limited use Any cardiovascular event within the last 6 months Limited relevance for CVD Study Class of drug Drug Power (n of patients with primary endpoint) Established cardiovascular disease Concomitant cardiovascular medication Relevant exclusion criteria Relevance of study EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin Adequate (772) 99% Vast majority Recent ACS, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD CANVAS Program Canagliflozin Strong (1011) 66% Majority Recent ACS, NYHA IV, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD LEADER GLP-1 receptor agonist Liraglutide Strong (1302) 81% Majority Recent ACS, NYHA IV, malignant neoplasm Highly relevant for stable CVD SUSTAIN-6 Semaglutide Moderate (254) 59% Majority Recent ACS, NYHA IV, malignant neoplasm, pancreatitis Relevant for stable CVD EXSCEL Exenatide Strong (1744) 73% Majority eGFR < 30 mL/min, personal or family history of medullary thyroid cancer, history of pancreatitis Highly relevant for stable CVD ELIXA Lixisenatide Adequate (805) 100% (ACS) Vast majority eGFR < 30 mL/min, pancreatitis, gastrointestinal disease, personal or family history of medullary thyroid cancer Highly relevant for ACS PROACTIVE Thiazolidinedione Pioglitazone Strong (1086) 100% Majority Recent ACS, symptomatic heart failure, ketoacidosis Highly relevant for stable CVD SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin Strong (1222) 79% Majority Recent ACS Highly relevant for stable CVD EXAMINE Alogliptin Adequate (621) 100% (ACS within the previous 15–90 days) Vast majority Recent ACS, NYHA IV Highly relevant for ACS TECOS Sitagliptin Strong (1690) 74% Majority eGFR < 30 mL/min, ketoacidosis Highly relevant for stable CVD UKPDS 34 Biguanide Metformin Moderate (139 during follow-up of > 10 years) NR Limited use >65 years of age Limited relevance for CVD STOP-NIDDM Alpha-glucosidase inhibitor Acarbose (compared to sulfonylurea) Hypothesis generating study (47) <5% Limited use Any cardiovascular event within the last 6 months Limited relevance for CVD ACS, acute coronary syndrome; CVD, cardiovascular disease; NA, not applicable; NR, not reported. Table 1 Relevance of studies for patients with type 2 diabetes and established cardiovascular disease Study Class of drug Drug Power (n of patients with primary endpoint) Established cardiovascular disease Concomitant cardiovascular medication Relevant exclusion criteria Relevance of study EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin Adequate (772) 99% Vast majority Recent ACS, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD CANVAS Program Canagliflozin Strong (1011) 66% Majority Recent ACS, NYHA IV, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD LEADER GLP-1 receptor agonist Liraglutide Strong (1302) 81% Majority Recent ACS, NYHA IV, malignant neoplasm Highly relevant for stable CVD SUSTAIN-6 Semaglutide Moderate (254) 59% Majority Recent ACS, NYHA IV, malignant neoplasm, pancreatitis Relevant for stable CVD EXSCEL Exenatide Strong (1744) 73% Majority eGFR < 30 mL/min, personal or family history of medullary thyroid cancer, history of pancreatitis Highly relevant for stable CVD ELIXA Lixisenatide Adequate (805) 100% (ACS) Vast majority eGFR < 30 mL/min, pancreatitis, gastrointestinal disease, personal or family history of medullary thyroid cancer Highly relevant for ACS PROACTIVE Thiazolidinedione Pioglitazone Strong (1086) 100% Majority Recent ACS, symptomatic heart failure, ketoacidosis Highly relevant for stable CVD SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin Strong (1222) 79% Majority Recent ACS Highly relevant for stable CVD EXAMINE Alogliptin Adequate (621) 100% (ACS within the previous 15–90 days) Vast majority Recent ACS, NYHA IV Highly relevant for ACS TECOS Sitagliptin Strong (1690) 74% Majority eGFR < 30 mL/min, ketoacidosis Highly relevant for stable CVD UKPDS 34 Biguanide Metformin Moderate (139 during follow-up of > 10 years) NR Limited use >65 years of age Limited relevance for CVD STOP-NIDDM Alpha-glucosidase inhibitor Acarbose (compared to sulfonylurea) Hypothesis generating study (47) <5% Limited use Any cardiovascular event within the last 6 months Limited relevance for CVD Study Class of drug Drug Power (n of patients with primary endpoint) Established cardiovascular disease Concomitant cardiovascular medication Relevant exclusion criteria Relevance of study EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin Adequate (772) 99% Vast majority Recent ACS, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD CANVAS Program Canagliflozin Strong (1011) 66% Majority Recent ACS, NYHA IV, eGFR < 30 mL/min, medical history of cancer Highly relevant for stable CVD LEADER GLP-1 receptor agonist Liraglutide Strong (1302) 81% Majority Recent ACS, NYHA IV, malignant neoplasm Highly relevant for stable CVD SUSTAIN-6 Semaglutide Moderate (254) 59% Majority Recent ACS, NYHA IV, malignant neoplasm, pancreatitis Relevant for stable CVD EXSCEL Exenatide Strong (1744) 73% Majority eGFR < 30 mL/min, personal or family history of medullary thyroid cancer, history of pancreatitis Highly relevant for stable CVD ELIXA Lixisenatide Adequate (805) 100% (ACS) Vast majority eGFR < 30 mL/min, pancreatitis, gastrointestinal disease, personal or family history of medullary thyroid cancer Highly relevant for ACS PROACTIVE Thiazolidinedione Pioglitazone Strong (1086) 100% Majority Recent ACS, symptomatic heart failure, ketoacidosis Highly relevant for stable CVD SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin Strong (1222) 79% Majority Recent ACS Highly relevant for stable CVD EXAMINE Alogliptin Adequate (621) 100% (ACS within the previous 15–90 days) Vast majority Recent ACS, NYHA IV Highly relevant for ACS TECOS Sitagliptin Strong (1690) 74% Majority eGFR < 30 mL/min, ketoacidosis Highly relevant for stable CVD UKPDS 34 Biguanide Metformin Moderate (139 during follow-up of > 10 years) NR Limited use >65 years of age Limited relevance for CVD STOP-NIDDM Alpha-glucosidase inhibitor Acarbose (compared to sulfonylurea) Hypothesis generating study (47) <5% Limited use Any cardiovascular event within the last 6 months Limited relevance for CVD ACS, acute coronary syndrome; CVD, cardiovascular disease; NA, not applicable; NR, not reported. Table 2 Outcome for patients with type 2 diabetes and established cardiovascular disease Study Class of drug Drug Median follow-up (years) Reduction of (NNT) Specific adverse effects (NNHa) Evidence for benefit/harm of investigational drug Primary composite cardiovascular endpoint Secondary cardiovascular endpoints All-cause mortality EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin 3.1 Yes (61) Cardiovascular death (45), heart failure hospitalization (72) Yes (39) Genital infection (22), volume depletion in patients ≥75 years, ketoacidosis Relevant benefit, particularly for patients at risk or with HF CANVASa Program Canagliflozin 2.4 Yes (72)a Heart failure hospitalization (104a, exploratory analysis) No Amputation (115a), low-trauma fractures, male genitalia infection (14a) Relevant benefit at the cost of increased risk of amputations LEADER GLP-1 receptor agonist Liraglutide 3.8 Yes (55) Cardiovascular death (79) Yes (71) Injection site reaction with once daily sc injection (233), drug discontinuation due to nausea (79), acute gallstone disease (85) Relevant benefit SUSTAIN-6 Semaglutide 2.1 Yes (43) Non-fatal stroke (97) No Retinopathy (78), gastrointestinal disorders (66) Relevant benefit EXSCEL Exenatide 3.2 No No No [exploratory analysis yes (100)] Thyroid papillary carcinomas (n = 10 vs. 4) Non-significant trend for benefit ELIXA Lixisenatide 2.1 No No No Gastrointestinal disorders leading to drug discontinuation (27) No benefit PROACTIVE Thiazolidinedione Pioglitazone 2.9 No Composite endpoint of all-cause mortality, non-fatal MI and stroke (49), increase of HF hospitalization (NNH = 62) No Oedema wo heart failure (12) Potential benefit, increased risk of HF hospitalization SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin 2.1 No Increase of HF hospitalization (NNH = 140) No Increased (but very rare) occurrence of non-fatal angioedema No benefit, increased risk of HF hospitalization EXAMINE Alogliptin 2.1 No No No NR No benefit TECOS Sitagliptin 3.0 No No No NR No benefit UKPDS 34 Biguanide Metformin 10.7 Yes (11) Non-fatal MI (16) Yes (11) NR Potential cardiovascular benefit in patients wo CVD STOP-NIDDM Alpha- glucosidase inhibitor Acarbose (compared to sulfonylurea) 3.38 Yes (40) Non-fatal MI (62) NR Premature study drug discontinuation (8) Hypothesis generation for potential cardiovascular benefit in patients wo CVD Study Class of drug Drug Median follow-up (years) Reduction of (NNT) Specific adverse effects (NNHa) Evidence for benefit/harm of investigational drug Primary composite cardiovascular endpoint Secondary cardiovascular endpoints All-cause mortality EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin 3.1 Yes (61) Cardiovascular death (45), heart failure hospitalization (72) Yes (39) Genital infection (22), volume depletion in patients ≥75 years, ketoacidosis Relevant benefit, particularly for patients at risk or with HF CANVASa Program Canagliflozin 2.4 Yes (72)a Heart failure hospitalization (104a, exploratory analysis) No Amputation (115a), low-trauma fractures, male genitalia infection (14a) Relevant benefit at the cost of increased risk of amputations LEADER GLP-1 receptor agonist Liraglutide 3.8 Yes (55) Cardiovascular death (79) Yes (71) Injection site reaction with once daily sc injection (233), drug discontinuation due to nausea (79), acute gallstone disease (85) Relevant benefit SUSTAIN-6 Semaglutide 2.1 Yes (43) Non-fatal stroke (97) No Retinopathy (78), gastrointestinal disorders (66) Relevant benefit EXSCEL Exenatide 3.2 No No No [exploratory analysis yes (100)] Thyroid papillary carcinomas (n = 10 vs. 4) Non-significant trend for benefit ELIXA Lixisenatide 2.1 No No No Gastrointestinal disorders leading to drug discontinuation (27) No benefit PROACTIVE Thiazolidinedione Pioglitazone 2.9 No Composite endpoint of all-cause mortality, non-fatal MI and stroke (49), increase of HF hospitalization (NNH = 62) No Oedema wo heart failure (12) Potential benefit, increased risk of HF hospitalization SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin 2.1 No Increase of HF hospitalization (NNH = 140) No Increased (but very rare) occurrence of non-fatal angioedema No benefit, increased risk of HF hospitalization EXAMINE Alogliptin 2.1 No No No NR No benefit TECOS Sitagliptin 3.0 No No No NR No benefit UKPDS 34 Biguanide Metformin 10.7 Yes (11) Non-fatal MI (16) Yes (11) NR Potential cardiovascular benefit in patients wo CVD STOP-NIDDM Alpha- glucosidase inhibitor Acarbose (compared to sulfonylurea) 3.38 Yes (40) Non-fatal MI (62) NR Premature study drug discontinuation (8) Hypothesis generation for potential cardiovascular benefit in patients wo CVD NNT/NNH number needed to treat/harm was calculated only for significant results with the formula 100/absolute difference of endpoint in % for the given follow-up period. ACS, acute coronary syndrome; NR, not reported. a NNTs/NNHs were calculated based on the given event rates per 1000 patient years and transformed for a follow-up of 3 years. Table 2 Outcome for patients with type 2 diabetes and established cardiovascular disease Study Class of drug Drug Median follow-up (years) Reduction of (NNT) Specific adverse effects (NNHa) Evidence for benefit/harm of investigational drug Primary composite cardiovascular endpoint Secondary cardiovascular endpoints All-cause mortality EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin 3.1 Yes (61) Cardiovascular death (45), heart failure hospitalization (72) Yes (39) Genital infection (22), volume depletion in patients ≥75 years, ketoacidosis Relevant benefit, particularly for patients at risk or with HF CANVASa Program Canagliflozin 2.4 Yes (72)a Heart failure hospitalization (104a, exploratory analysis) No Amputation (115a), low-trauma fractures, male genitalia infection (14a) Relevant benefit at the cost of increased risk of amputations LEADER GLP-1 receptor agonist Liraglutide 3.8 Yes (55) Cardiovascular death (79) Yes (71) Injection site reaction with once daily sc injection (233), drug discontinuation due to nausea (79), acute gallstone disease (85) Relevant benefit SUSTAIN-6 Semaglutide 2.1 Yes (43) Non-fatal stroke (97) No Retinopathy (78), gastrointestinal disorders (66) Relevant benefit EXSCEL Exenatide 3.2 No No No [exploratory analysis yes (100)] Thyroid papillary carcinomas (n = 10 vs. 4) Non-significant trend for benefit ELIXA Lixisenatide 2.1 No No No Gastrointestinal disorders leading to drug discontinuation (27) No benefit PROACTIVE Thiazolidinedione Pioglitazone 2.9 No Composite endpoint of all-cause mortality, non-fatal MI and stroke (49), increase of HF hospitalization (NNH = 62) No Oedema wo heart failure (12) Potential benefit, increased risk of HF hospitalization SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin 2.1 No Increase of HF hospitalization (NNH = 140) No Increased (but very rare) occurrence of non-fatal angioedema No benefit, increased risk of HF hospitalization EXAMINE Alogliptin 2.1 No No No NR No benefit TECOS Sitagliptin 3.0 No No No NR No benefit UKPDS 34 Biguanide Metformin 10.7 Yes (11) Non-fatal MI (16) Yes (11) NR Potential cardiovascular benefit in patients wo CVD STOP-NIDDM Alpha- glucosidase inhibitor Acarbose (compared to sulfonylurea) 3.38 Yes (40) Non-fatal MI (62) NR Premature study drug discontinuation (8) Hypothesis generation for potential cardiovascular benefit in patients wo CVD Study Class of drug Drug Median follow-up (years) Reduction of (NNT) Specific adverse effects (NNHa) Evidence for benefit/harm of investigational drug Primary composite cardiovascular endpoint Secondary cardiovascular endpoints All-cause mortality EMPA-REG OUTCOME SGLT2 inhibitor Empagliflozin 3.1 Yes (61) Cardiovascular death (45), heart failure hospitalization (72) Yes (39) Genital infection (22), volume depletion in patients ≥75 years, ketoacidosis Relevant benefit, particularly for patients at risk or with HF CANVASa Program Canagliflozin 2.4 Yes (72)a Heart failure hospitalization (104a, exploratory analysis) No Amputation (115a), low-trauma fractures, male genitalia infection (14a) Relevant benefit at the cost of increased risk of amputations LEADER GLP-1 receptor agonist Liraglutide 3.8 Yes (55) Cardiovascular death (79) Yes (71) Injection site reaction with once daily sc injection (233), drug discontinuation due to nausea (79), acute gallstone disease (85) Relevant benefit SUSTAIN-6 Semaglutide 2.1 Yes (43) Non-fatal stroke (97) No Retinopathy (78), gastrointestinal disorders (66) Relevant benefit EXSCEL Exenatide 3.2 No No No [exploratory analysis yes (100)] Thyroid papillary carcinomas (n = 10 vs. 4) Non-significant trend for benefit ELIXA Lixisenatide 2.1 No No No Gastrointestinal disorders leading to drug discontinuation (27) No benefit PROACTIVE Thiazolidinedione Pioglitazone 2.9 No Composite endpoint of all-cause mortality, non-fatal MI and stroke (49), increase of HF hospitalization (NNH = 62) No Oedema wo heart failure (12) Potential benefit, increased risk of HF hospitalization SAVOR-TIMI 53 Dipeptidyl peptidase 4 inhibitor Saxagliptin 2.1 No Increase of HF hospitalization (NNH = 140) No Increased (but very rare) occurrence of non-fatal angioedema No benefit, increased risk of HF hospitalization EXAMINE Alogliptin 2.1 No No No NR No benefit TECOS Sitagliptin 3.0 No No No NR No benefit UKPDS 34 Biguanide Metformin 10.7 Yes (11) Non-fatal MI (16) Yes (11) NR Potential cardiovascular benefit in patients wo CVD STOP-NIDDM Alpha- glucosidase inhibitor Acarbose (compared to sulfonylurea) 3.38 Yes (40) Non-fatal MI (62) NR Premature study drug discontinuation (8) Hypothesis generation for potential cardiovascular benefit in patients wo CVD NNT/NNH number needed to treat/harm was calculated only for significant results with the formula 100/absolute difference of endpoint in % for the given follow-up period. ACS, acute coronary syndrome; NR, not reported. a NNTs/NNHs were calculated based on the given event rates per 1000 patient years and transformed for a follow-up of 3 years. Figure 1 View largeDownload slide Primary cardiovascular composite endpoint of randomized controlled trials on non-insulin antidiabetic pharmacotherapies. (A) Studies with stable cardiovascular disease or patients at high risk for cardiovascular disease. (B) Studies with acute coronary syndrome; The bars show the event rate of the primary cardiovascular composite endpoint during the study follow-up in the intervention and control group. Numbers indicate the relative risk reduction. *P < 0.05. Figure 1 View largeDownload slide Primary cardiovascular composite endpoint of randomized controlled trials on non-insulin antidiabetic pharmacotherapies. (A) Studies with stable cardiovascular disease or patients at high risk for cardiovascular disease. (B) Studies with acute coronary syndrome; The bars show the event rate of the primary cardiovascular composite endpoint during the study follow-up in the intervention and control group. Numbers indicate the relative risk reduction. *P < 0.05. Non-insulin antidiabetic pharmacotherapy and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease—a critical appraisal of emerging clinical data Antidiabetic pharmacotherapy with beneficial effects on primary cardiovascular outcome The effects of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (using two different dosages) were compared to placebo in 7020 patients with T2DM and established CVD—including 76% of patients with CHD—in the EMPA-REG OUTCOME trial.7 Relevant exclusion criteria were ACS within 2 months and glomerular filtration rate (GFR) < 30 mL/min. The primary composite endpoint of non-fatal (excluding silent) myocardial infarction (MI), non-fatal stroke, and cardiovascular death was significantly reduced by 14% RRR in a pooled analysis of the two empagliflozin dosages during a median follow-up time of 3.1 years. This equals to an ARR from 12.1% to 10.5% (NNT = 61). The reduction in the primary endpoint was driven by a RRR of cardiovascular death by 38% (NNT = 45) with a further RRR of all-cause mortality by 32% (NNT = 39). In parallel, hospitalization for heart failure (HF) was reduced by 35% RRR corresponding to an ARR from 4.1% to 2.7% (NNT = 72). Empagliflozin therapy was associated with genital infections (NNH = 22). Recently, the results of the CANVAS Program assessing the effects of canagliflozin, another SGLT2 inhibitor, were published.9 The CANVAS Program analysed 10 142 patients with T2DM who had a history of (66%) or were at risk for CVD from the CANVAS and CANVAS-R trial with identical main inclusion criteria but differences with regard to the study design such as the duration of follow-up (median 2.4 years) and usage of low and high dose of canagliflozin. The primary composite endpoint of non-fatal MI, non-fatal stroke, and cardiovascular death was significantly reduced by 14% RRR equalling to an ARR from 9.5% to 8.1% for a 3-year period (NNT = 72). While there was no significant reduction of all-cause mortality, a further exploratory analysis indicated an reduction of hospitalization for HF by 33% corresponding to an estimated ARR from 2.6% to 1.7% (NNT = 104). Canagliflozin therapy was associated with an increased risk of amputation (NNH = 115), low-trauma fractures (P = 0.06), and infections of male genitalia (NNH = 14). A pharmacovigilance analysis of the FDA confirms that the use of canagliflozin is associated with an increased risk of amputations.17 As highlighted by the European Medicines Agency (EMA), in elderly patients the risk of adverse effects related to volume-depletion increases with SGLT2 inhibitors, particularly with the higher dose. Furthermore, empagliflozin and canagliflozin should be interrupted in patients who are hospitalized for major surgical procedures and serious medical illness due to an increased risk of ketoacidosis.18 Retrospective real-world data generate the hypothesis that the effect on hospitalization for HF and death might be generalizable to other SGLT2 inhibitors.19 However, the results of ongoing randomized controlled trials with the SGLT2 inhibitors dapagliflozin (DECLARE-TIMI58, NCT01730534) and ertugliflozin (VERTIS CV, NCT01986881) are needed to prove beneficial cardiovascular effects of these SGLT2 inhibitors. The glucagon-like peptide-1 (GLP-1) receptor agonist (RA) liraglutide given once daily subcutaneously was compared to placebo in 9340 patients with T2DM and established CVD (81%) or an age ≥ 60 years with at least one cardiovascular risk factor suggesting end organ damage, in the LEADER study.6 The primary composite endpoint including non-fatal MI, non-fatal stroke, and cardiovascular death was significantly reduced by 13% RRR during a median follow-up of 3.8 years equalling to an ARR from 14.9% to 13.0% (NNT = 55). The reduction was driven by a 22% RRR of cardiovascular death (NNT = 79) with an additional RRR of all-cause mortality by 15% (NNT = 71). While there was no significant overall increase of adverse effects there was a significantly increased rate of drug discontinuation due to gastrointestinal symptoms (NNH = 79) and acute gallstone disease (NNH = 85). Semaglutide, another GLP-1 RA, given once weekly subcutaneously, reduced the primary composite endpoint of cardiovascular death, non-fatal MI, or non-fatal stroke by 26% RRR in the SUSTAIN-6 study in patients (n = 3297) with T2DM who had a history of (59%) or were at risk for CVD during a median follow-up time of 3.8 years, corresponding to an ARR from 8.9% to 6.6% (NNT = 43).8 This lower risk was mainly driven by a RRR of non-fatal stroke by 39% (NNT = 97). Long-term glycaemic control with semaglutide in the SUSTAIN-6 trial was particularly pronounced with a dose-dependent lower HbA1c of 0.7–1.0% than in the control group after 2 years. While fewer serious adverse events and a lower rate of new or worsening nephropathy occurred with semaglutide, more patients discontinued treatment mainly because of gastrointestinal disorders (NNH = 66). Retinopathy rates were significantly higher with semaglutide (NNH = 78). In the recently published EXSCEL trial, the GLP1 RA exenatide (extended-release) given once weekly was compared to placebo in 14 752 patients with T2DM including 73% of patients with established CVD.20 There was a non-significant trend for a reduction of the primary composite endpoint including non-fatal MI, non-fatal stroke, and cardiovascular death (P = 0.06). A further exploratory analysis indicated a reduction of all-cause mortality by 14% corresponding to an estimated ARR from 7.9% to 6.9% (NNT = 100). In the exenatide arm there was a higher number of thyroid papillary carcinomas (n = 10 vs. 4). In patients with T2DM and ACS, no benefit was observed with the GLP-1 RA lixisenatide with a shorter half-life in the ELIXA study.10 Additionally, more patients in the lixisenatide arm stopped treatment due to gastrointestinal disorders during the follow-up of median 2.1 years (NNH = 27). Antidiabetic pharmacotherapy with neutral effects on primary cardiovascular outcome The thiazolidinedione pioglitazone was compared with placebo in 5238 patients with T2DM and established CVD in the PROACTIVE study.5 The comprehensive primary endpoint including peripheral artery disease, ACS, coronary interventions, and all-cause mortality in addition to non-fatal MI and stroke was not significantly affected by pioglitazone. However, the secondary composite endpoint of all-cause mortality (in contrast to cardiovascular mortality used for the primary composite endpoint in most other trials), non-fatal MI and stroke was significantly reduced by 16% RRR corresponding to an ARR from 13.6% to 11.6% during a mean follow-up of 34.5 months (NNT = 49). Hospitalization for HF was increased with pioglitazone by 40% equalling to an absolute increase from 4.1% to 5.7% (NNH = 62). The main adverse effect was oedema without HF (NNH = 12). Moreover, in the IRIS study pioglitazone was tested in 3876 patients with insulin resistance (but without established T2DM) and ischaemic stroke or TIA within 6 months. In this study, pioglitazone decreased the primary composite endpoint of non-fatal and fatal MI as well as stroke by 24% RRR during a median follow-up time of 4.8 years equalling to an ARR from 11.8% to 9.0% (NNT = 36).21 Pioglitazone, however, was associated with a significantly higher frequency of oedema (NNH = 9.3) and bone fractures (NNH = 53). The dipeptidyl peptidase 4 (DPP-4) inhibitor saxagliptin was compared to placebo in the SAVOR-TIMI 53 study22 in 16 492 patients with T2DM who had a history of (78%) or were at risk for CVD. The study showed non-inferiority (but not superiority) for saxagliptin regarding the primary composite endpoint including MI, ischaemic stroke, and cardiovascular death during a median follow-up of 2.1 years. Hospitalization for HF significantly increased by 27% equalling to an absolute increase from 2.8% to 3.5% (NNH = 140). This increased risk was limited to the first 12 months of follow-up.23 This surprising but critical result of a secondary endpoint without a priori adjustment for multiple comparisons was not confirmed in observational studies and needs to be verified in a further randomized controlled trial. The DPP-4 inhibitor alogliptin was investigated in 5380 patients with T2DM who had a recent ACS in the EXAMINE trial.11 The primary composite endpoint of death from cardiovascular causes, non-fatal MI, or non-fatal stroke showed non-inferiority but not superiority for alogliptin during a median follow-up time of 18 months. The DPP-4 inhibitor sitagliptin was investigated in 14 671 patients with T2DM and CVD in the TECOS trial during a median follow-up of 3 years.24 Sitagliptin showed non-inferiority but not superiority with regard to the composite of cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization for unstable angina. Overall, rates of HF hospitalization were not significantly different between treatment arms in the EXAMINE and the TECOS trials. The effect of the DDP-4 inhibitor linagliptin on cardiovascular events is tested in the ongoing CAROLINA study (NCT01243424) compared to the sulfonylurea glimepiride while there is no published plan for a randomized controlled trial about the effect of the DDP-4 inhibitor vildagliptin on cardiovascular outcome. Antidiabetic pharmacotherapy with hypothesis-generating studies with regard to a beneficial effect on cardiovascular outcomes In a predefined sub-analysis of the UKPDS 34 study, the biguanide metformin was compared to conventional care primarily consisting of diet in 753 overweight patients (>120% ideal bodyweight) with newly diagnosed diabetes and a mean age of 53 years.4 Concomitant therapy consisted of antihypertensive therapy in 15%, ‘more than one aspirin daily’ in 1.8% and lipid lowering therapy in 0.1% of patients. The primary outcome measures included aggregates of any diabetes-related events, diabetes-related death and all-cause mortality. These endpoints were significantly reduced by 32% to 42% RRR within a long-term follow-up of median 10.7 years. With regard to cardiovascular endpoints MI was significantly reduced by 39% RRR compared to conventional therapy (but not compared to intensive therapy with sulfonylurea or insulin) equalling to an ARR from 17.8% to 11.4% (NNT = 16). There was no significant difference with regard to stroke or peripheral artery disease. As mentioned by EMA lactic acidosis is a rare but relevant complication of metformin therapy particularly in situations of hypoxia. Metformin is contraindicated in patients with severe chronic kidney disease (GFR < 30 mL/min, Supplementary material online, Table S3). In the STOP-NIDDM trial, the alpha-glucosidase inhibitor acarbose was compared to placebo in 1429 patients with impaired glucose tolerance and without a cardiovascular event within the last 6 months.25 The mean age was 55 years, with 5% of patients having a history of CVD and 21% taking cardiovascular medications. Early drug discontinuation was observed in 31% of subjects in the acarbose arm, mostly due to gastrointestinal side effects, compared to 19% in the placebo arm (NNH = 8). During a mean follow-up of 3.3 years cardiovascular events, defined as secondary endpoint, were reduced by 49% RRR in the acarbose arm equalling to an ARR from 4.7% to 2.2% (NNT = 40). While only 13 clinical cases of MI were observed there was a statistically significant RRR of 91% with acarbose (NNT = 62). Methodological aspects such as a modified intention-treat-analysis omitting the follow-up of 4.3% of originally randomized patients further limit the results of this hypothesis-generating study. While sulfonylureas are widely used no data about their safety in patients with CVD are available. In addition they promote weight gain, and cause hypoglycaemia—mainly with first generation sulfonylureas and immediate release formulations—, the latter two adverse effects being associated with increased cardiovascular risk.26 Patients at risk for heart failure The EMPA-REG OUTCOME, CANVAS Program, LEADER, SUSTAIN-6, EXSCEL, ELIXA, SAVOR-TIMI 53, EXAMINE, and TECOS study report on the proportion of patients with a diagnosis of HF at randomization which ranges from 10% in the EMPA-REG OUTCOME trial to 28% in the EXAMINE study (Supplementary material online, Table S4). Specific data regarding HF are limited to NYHA functional class in two studies.6,24 The CANVAS Program, LEADER, SUSTAIN-6, EXSCEL, ELIXA, SAVOR-TIMI 53, EXAMINE, and TECOS trial analysed whether the presence of HF affected the primary outcome but did not find any significant interaction. Heart failure hospitalization was significantly increased in the SAVOR-TIMI 53 study with saxagliptin and in the PROACTIVE study with pioglitazone. Thus, they should not be used in patients at risk for HF or with established HF. According to an analysis of the SAVOR-TIMI 53 study patients with elevated Nt-proBNP or chronic kidney disease (GFR < 60 mL/min) may be at risk for HF.23 On the contrary, this endpoint was significantly reduced in the EMPA-REG OUTCOME study with empagliflozin and in an exploratory analysis of the CANVAS Program trial. Aiming at improving cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease—positions based on current trials data In patients with T2DM and CVD, antidiabetic pharmacotherapy should be chosen based on beneficial effects on cardiovascular events in Phase III and post-marketing trials (Figure 2). Accordingly, EMA has recently stated that improvement of glycaemic control and reduction of cardiovascular morbidity and mortality should be major goals in the treatment of T2DM (SmPC of empagliflozin). So far, the SGLT2 inhibitors empagliflozin and canagliflozin, and the GLP-1 RAs liraglutide and semaglutide reduced cardiovascular events in adequately powered studies with contemporary concomitant cardiovascular treatment in patients with established CVD, mainly stable CHD and with the exclusion of recent ACS. For canagliflozin the net benefit is restricted by an increased rate of amputations. For semaglutide approval of EMA is pending. Hence, currently the SGLT2 inhibitor empagliflozin, and the GLP-1 RA liraglutide may be considered preferred treatment choices. So far, the 2016 European Guidelines on CVD prevention recommended that in patients with T2DM and CVD, an SGLT2 inhibitor should be considered early in the therapeutic process to reduce cardiovascular and total mortality (Class IIa recommendation).3 In patients above 75 years of age, the use of the lower dose of empagliflozin is recommended to avoid adverse events related to volume depletion. While the power of outcome data for metformin is limited, economic reasons, ample clinical experience, and safe use in combination with other antidiabetic therapies (see Supplementary material online, Table S5) are reasons to continue to use this drug as first choice. Figure 2 View largeDownload slide Positions on non-insulin antidiabetic pharmacotherapies and potential combinations in patients with type 2 diabetes and stable cardiovascular disease. The positions about the choice of antidiabetic pharmacotherapy are based on current data on reduction of cardiovascular events. SGLT2, sodium glucose cotransporter 2; GLP1, glucagon-like peptide-1; RA, receptor agonist. Figure 2 View largeDownload slide Positions on non-insulin antidiabetic pharmacotherapies and potential combinations in patients with type 2 diabetes and stable cardiovascular disease. The positions about the choice of antidiabetic pharmacotherapy are based on current data on reduction of cardiovascular events. SGLT2, sodium glucose cotransporter 2; GLP1, glucagon-like peptide-1; RA, receptor agonist. When these preferred treatments are not sufficient to achieve therapeutic goals or are contraindicated, the thiazolidinedione pioglitazone, the GLP1 RA exenatide, and DPP-4 inhibitors may be further choices due to their neutral or potentially beneficial effects on cardiovascular events in adequately powered, contemporary trials. While pioglitazone did not reduce the primary cardiovascular endpoint in the PROACTIVE trial it reduced the secondary composite endpoint of cardiovascular events.5 Exenatide showed a non-significant reduction of the primary composite endpoint by 9%. DPP-4 inhibitors may be considered for treatment of patients with T2DM and stable CVD based on their favourable safety profile. Contemporary trials have shown a neutral effect of the DPP-4 inhibitors saxagliptin and sitagliptin on the primary cardiovascular endpoint in patients with stable CVD or at risk for CVD. There is no evidence supporting a combination of DPP-4 inhibitors with a GLP1 RA. Future clinical trials should pursue the possible benefit of antidiabetic pharmacotherapy on hard cardiovascular endpoints in various specified types of CVD. A reduction of HF hospitalization with the SGLT2 inhibitors empagliflozin and canagliflozin prompts ad hoc trials in patients with HF. While post-ACS trials with the GLP-1 RA lixisenatide and the DPP-4 inhibitor alogliptin have shown a neutral effect on the clinical outcome, further specific post-ACS trials are needed with antidiabetic drugs having shown a benefit in patients with stable CVD. Supplementary material Supplementary material is available at European Heart Journal online. Conflict of interest: Dr A.N. reports grants and personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, outside the submitted work. Dr J.T. has nothing to disclose. Dr L.K. has nothing to disclose. Dr C.H.S. reports personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, personal fees from Eli-Lilly, personal fees from Genericon, personal fees from Merck, personal fees from MSD, personal fees from Novo Nordisc, personal fees from Pfizer, personal fees from Sanofi-Aventis, personal fees from Takeda, during the conduct of the study. Dr T.A.S. holds Novo Nordisk stock. Dr G.S. reports grants from MSD Italia, grants from Heart and Lung Foundation, grants from Italian Society of Cardiology, outside the submitted work. Dr S.W. reports personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Astra Zeneca, outside the submitted work. Dr G.R. has nothing to disclose. Dr C.C. has nothing to disclose. Dr C.T-P. reports grants and personal fees from Bayer, grants from Biotronics, outside the submitted work. Dr K.K. has nothing to disclose. Dr J.C.K. has nothing to disclose. Dr S.A. has nothing to disclose. Dr T.W. reports grants and personal fees from Tarix Pharmaceutical, outside the submitted work. Dr H.D. has nothing to disclose. Dr B.S.L. reports grants and personal fees from AstraZeneca, grants from Pfizer, outside the submitted work. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. References 1 Stam-Slob MC , van der Graaf Y , de Borst GJ , Cramer MJ , Kappelle LJ , Westerink J , Visseren FL. Group SS . Effect of type 2 diabetes on recurrent major cardiovascular events for patients with symptomatic vascular disease at different locations . Diabetes Care 2015 ; 38 : 1528 – 1535 . Google Scholar CrossRef Search ADS PubMed 2 Chirinos JA , De Marchena E , Veerani A , Peter A , Khan N , Schob A , Ferreira A , Chakko S. IS diabetes a stronger predictor of recurrent cardiovascular events than the angiographic severity of coronary artery disease? Chest 2006 ; 130 : 198S . Google Scholar CrossRef Search ADS 3 Piepoli MF , Hoes AW , Agewall S , Albus C , Brotons C , Catapano AL , Cooney MT , Corra U , Cosyns B , Deaton C , Graham I , Hall MS , Hobbs FD , Lochen ML , Lollgen H , Marques-Vidal P , Perk J , Prescott E , Redon J , Richter DJ , Sattar N , Smulders Y , Tiberi M , van der Worp HB , van Dis I , Verschuren WM ; Authors/Task Force Members . 2016 European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European Society of Cardiology and other societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) . Eur Heart J 2016 ; 37 : 2315 – 2381 . Google Scholar CrossRef Search ADS PubMed 4 UK Prospective Diabetes Study (UKPDS) Group Writing committee—Turner RC , Holman RR , Stratton IM , Cull CA , Matthews DR , Manley SE , Frighi V , Wright D , Neil A , Kohner E , McElroy H , Fox C , Hadden D . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group . Lancet 1998 ; 352 : 854 – 865 . Google Scholar CrossRef Search ADS PubMed 5 Dormandy JA , Charbonnel B , Eckland DJ , Erdmann E , Massi-Benedetti M , Moules IK , Skene AM , Tan MH , Lefebvre PJ , Murray GD , Standl E , Wilcox RG , Wilhelmsen L , Betteridge J , Birkeland K , Golay A , Heine RJ , Koranyi L , Laakso M , Mokan M , Norkus A , Pirags V , Podar T , Scheen A , Scherbaum W , Schernthaner G , Schmitz O , Skrha J , Smith U , Taton J , Investigators PR. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial . Lancet 2005 ; 366 : 1279 – 1289 . Google Scholar CrossRef Search ADS PubMed 6 Marso SP , Daniels GH , Brown-Frandsen K , Kristensen P , Mann JF , Nauck MA , Nissen SE , Pocock S , Poulter NR , Ravn LS , Steinberg WM , Stockner M , Zinman B , Bergenstal RM , Buse JB ; LEADER Steering Committee and Investigators . Liraglutide and cardiovascular outcomes in type 2 diabetes . N Engl J Med 2017 ; 377 : 839 – 848 . Google Scholar CrossRef Search ADS PubMed 7 Zinman B , Wanner C , Lachin JM , Fitchett D , Bluhmki E , Hantel S , Mattheus M , Devins T , Johansen OE , Woerle HJ , Broedl UC , Inzucchi SE , Investigators E-RO. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes . N Engl J Med 2015 ; 373 : 2117 – 2128 . Google Scholar CrossRef Search ADS PubMed 8 Marso SP , Bain SC , Consoli A , Eliaschewitz FG , Jodar E , Leiter LA , Lingvay I , Rosenstock J , Seufert J , Warren ML , Woo V , Hansen O , Holst AG , Pettersson J , Vilsboll T ; SUSTAIN-6 Investigators . Semaglutide and cardiovascular outcomes in patients with type 2 diabetes . N Engl J Med 2016 ; 375 : 1834 – 1844 . Google Scholar CrossRef Search ADS PubMed 9 Neal B , Perkovic V , Mahaffey KW , de Zeeuw D , Fulcher G , Erondu N , Shaw W , Law G , Desai M , Matthews DR. Group CPC . Canagliflozin and cardiovascular and renal events in type 2 diabetes . N Engl J Med 2017 ; 377 : 644 – 657 . Google Scholar CrossRef Search ADS PubMed 10 Pfeffer MA , Claggett B , Diaz R , Dickstein K , Gerstein HC , Kober LV , Lawson FC , Ping L , Wei X , Lewis EF , Maggioni AP , McMurray JJ , Probstfield JL , Riddle MC , Solomon SD , Tardif JC , Investigators E. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome . N Engl J Med 2015 ; 373 : 2247 – 2257 . Google Scholar CrossRef Search ADS PubMed 11 White WB , Cannon CP , Heller SR , Nissen SE , Bergenstal RM , Bakris GL , Perez AT , Fleck PR , Mehta CR , Kupfer S , Wilson C , Cushman WC , Zannad F. Investigators E . Alogliptin after acute coronary syndrome in patients with type 2 diabetes . N Engl J Med 2013 ; 369 : 1327 – 1335 . Google Scholar CrossRef Search ADS PubMed 12 Kumar R , Kerins DM , Walther T. Cardiovascular safety of anti-diabetic drugs . Eur Heart J Cardiovasc Pharmacother 2016 ; 2 : 32 – 43 . Google Scholar CrossRef Search ADS PubMed 13 Turner JR , Caveney E , Gillespie BS , Karnad DR , Kothari S , Metz A , Keller LH. With regard to the papers by Kumar et al. and de Leeuw and de Boer addressing the cardiovascular safety and efficacy of anti-diabetic drugs . Eur Heart J Cardiovasc Pharmacother 2017 ; 3 : 75 – 76 . Google Scholar PubMed 14 Turner JR , Karnad DR , Kothari S , Metz A , Patel H , Caveney E. With regard to the paper by Zannad et al. entitled Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment versus risk aversion . Eur Heart J Cardiovasc Pharmacother 2017 ; 3 : 7 – 8 . Google Scholar CrossRef Search ADS PubMed 15 Zannad F , Stough WG , Lipicky RJ , Tamargo J , Bakris GL , Borer JS , Alonso García M. D L A , Hadjadj S , Koenig W , Kupfer S , McCullough PA , Mosenzon O , Pocock S , Scheen AJ , Sourij H , Van der Schueren B , Stahre C , White WB , Calvo G. Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion . Eur Heart J Cardiovasc Pharmacother 2016 ; 2 : 200 – 205 . Google Scholar CrossRef Search ADS PubMed 16 de Leeuw AE , de Boer RA. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects . Eur Heart J Cardiovasc Pharmacother 2016 ; 2 : 244 – 255 . Google Scholar CrossRef Search ADS PubMed 17 Fadini GP , Avogaro A. SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System . Lancet Diabetes Endocrinol 2017 ; 5 : 680 – 681 . Google Scholar CrossRef Search ADS PubMed 18 Bonora BM , Avogaro A , Fadini GP. Sodium-glucose co-transporter-2 inhibitors and diabetic ketoacidosis: An updated review of the literature . Diabetes Obes Metab 2017 ; doi: 10.1111/dom.13012. 19 Kosiborod M , Cavender MA , Fu AZ , Wilding JP , Khunti K , Holl RW , Norhammar A , Birkeland KI , Jorgensen ME , Thuresson M , Arya N , Bodegard J , Hammar N , Fenici P ; CVD-REAL Investigators Group . Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors) . Circulation 2017 ; 136 : 249 – 259 . Google Scholar CrossRef Search ADS PubMed 20 Holman RR , Bethel MA , Mentz RJ , Thompson VP , Lokhnygina Y , Buse JB , Chan JC , Choi J , Gustavson SM , Iqbal N , Maggioni AP , Marso SP , Ohman P , Pagidipati NJ , Poulter N , Ramachandran A , Zinman B , Hernandez AF ; EXSCEL Study Group . Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes . N Engl J Med 2017 ; 377 : 1228 – 1239 . Google Scholar CrossRef Search ADS PubMed 21 Kernan WN , Viscoli CM , Furie KL , Young LH , Inzucchi SE , Gorman M , Guarino PD , Lovejoy AM , Peduzzi PN , Conwit R , Brass LM , Schwartz GG , Adams HP , Berger L , Carolei A , Clark W , Coull B , Ford GA , Kleindorfer D , O’Leary JR , Parsons MW , Ringleb P , Sen S , Spence JD , Tanne D , Wang D , Winder TR ; for the IRIS Trial Investigators . Pioglitazone after ischemic stroke or transient ischemic attack . N Engl J Med 2016 ; 374 : 1321 – 1331 . Google Scholar CrossRef Search ADS PubMed 22 Scirica BM , Bhatt DL , Braunwald E , Steg PG , Davidson J , Hirshberg B , Ohman P , Frederich R , Wiviott SD , Hoffman EB , Cavender MA , Udell JA , Desai NR , Mosenzon O , McGuire DK , Ray KK , Leiter LA , Raz I. Committee S-TS, Investigators . Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus . N Engl J Med 2013 ; 369 : 1317 – 1326 . Google Scholar CrossRef Search ADS PubMed 23 Scirica BM , Braunwald E , Raz I , Cavender MA , Morrow DA , Jarolim P , Udell JA , Mosenzon O , Im K , Umez-Eronini AA , Pollack PS , Hirshberg B , Frederich R , Lewis BS , McGuire DK , Davidson J , Steg PG , Bhatt DL ; SAVOR TIMI-53 Steering Committee and Investigators . Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial . Circulation 2014 ; 130 : 1579 – 1588 . Google Scholar CrossRef Search ADS PubMed 24 Green JB , Bethel MA , Armstrong PW , Buse JB , Engel SS , Garg J , Josse R , Kaufman KD , Koglin J , Korn S , Lachin JM , McGuire DK , Pencina MJ , Standl E , Stein PP , Suryawanshi S , Van de Werf F , Peterson ED , Holman RR ; TECOS Study Group . Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes . N Engl J Med 2015 ; 373 : 232 – 242 . Google Scholar CrossRef Search ADS PubMed 25 Chiasson JL , Josse RG , Gomis R , Hanefeld M , Karasik A , Laakso M , Group S-NTR. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial . Lancet 2002 ; 359 : 2072 – 2077 . Google Scholar CrossRef Search ADS PubMed 26 Del Prato S , Pulizzi N. The place of sulfonylureas in the therapy for type 2 diabetes mellitus . Metabolism 2006 ; 55 : S20 – S27 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. 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Khan, Safi U; Duran, Crystal A; Rahman, Hammad; Lekkala, Manidhar; Saleem, Muhammad A; Kaluski, Edo

doi: 10.1093/eurheartj/ehx597pmid: 29069399

AimsTo assess whether continuous positive airway pressure (CPAP) therapy reduces major adverse cardiovascular events (MACE) in patients with moderate-to-severe obstructive sleep apnoea (OSA).Methods and resultsA total of 235 articles were recovered using MEDLINE, EMBASE and Cochrane library (inception–December 2016) and references contained in the identified articles. Seven randomized controlled trials (RCTs) were selected for final analysis. Analysis of 4268 patients demonstrated non-significant 26% relative risk reduction in MACE with CPAP [risk ratio (RR) 0.74; 95% confidence interval (CI) 0.47–1.17; P = 0.19, I 2 = 48%]. A series of sensitivity analyses suggested that increased CPAP usage time yielded significant risk reduction in MACE. and stroke. Subgroup analysis revealed that CPAP adherence time ≥4 hours (h)/night reduced the risk of MACE by 57% (RR 0.43; 95% CI 0.23–0.80; P = 0.01, I 2 = 0%). CPAP therapy showed no beneficial effect on myocardial infarction (MI), all-cause mortality, atrial fibrillation/flutter (AF), or heart failure (HF) (P > 0.05). CPAP had positive effect on mood and reduced the daytime sleepiness [Epworth Sleepiness Scale (ESS): mean difference (MD) −2.50, 95% CI − 3.62, −1.39; P < 0.001, I 2 = 81%].ConclusionCPAP therapy might reduce MACE and stroke among subjects with CPAP time exceeding 4 h/night. Additional randomized trials mandating adequate CPAP time adherence are required to confirm this impression.

Cowie, Martin R; Gallagher, Angela M; Simonds, Anita K

doi: 10.1093/eurheartj/ehx678pmid: 29182739

Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea’†, by S.U. Kahn et al., on page 2291. Obstructive sleep apnoea (OSA) is often found in patients with, or at risk of, cardiovascular or cerebrovascular disease. It can be associated with many symptoms, including daytime sleepiness, memory loss, nocturia, and morning headache. There is a strong association between untreated moderate-to-severe OSA (apnoea–hypopnoea index during sleep of at least 15/h) and cardiovascular events in epidemiological studies.1,2 Potential mechanisms linking OSA with the heart and vascular system are intermittent hypoxaemia, increased negative intra-thoracic pressure swings, sympathetic activation, sleep fragmentation and deprivation, systemic inflammation, hypercoaguability, endothelial dysfunction, metabolic dysregulation, myocardial fibrosis, arrhythmia, and ischaemia3 (Take home figure). Take home figure View largeDownload slide Pathophysiology of obstructive sleep apnoea Take home figure View largeDownload slide Pathophysiology of obstructive sleep apnoea The mainstay of treatment of OSA is continuous positive airway pressure (CPAP) therapy, with positive airway pressure being applied through a nasal or oronasal interface in order to splint the upper airway open and prevent obstructive respiratory events. Such therapy, if tolerated, is clearly associated with improvement in sleep quality, daytime sleepiness, and quality of life, and this is the main driver for its usage in clinical practice.4 Untreated OSA is associated with an increased risk of road traffic accidents, and the safety implications of missing the diagnosis or not complying with therapy are clear. In observational studies, those who have their OSA treated with CPAP appear to have a cardiovascular event rate that is similar to those who do not have OSA,2 and this has led many to believe that treatment with CPAP will reduce the risk of such events. However, patients who seek diagnosis and accept mask therapy in the long term differ in many ways from those who do not, and such confounding is difficult, if not impossible, to control for. Randomization protects us from (measured and unmeasured) confounding, if studies are large enough, and should provide a more robust answer to whether treatment of OSA with CPAP therapy improves cardiovascular outcome. The first randomized trial of CPAP therapy to address this issue was performed by the Spanish Sleep and Breathing Network in 723 patients with OSA but with no history of cardiovascular events, and was published in 2012.5 During follow-up that averaged 4 years, with a median adherence to CPAP of 5 h/night, there was no significant reduction in the primary endpoint of the incidence of systemic hypertension or a cardiovascular event. In a post-hoc analysis, the authors divided the patients into good adherence (at least 4 h/night: 64%) and poor adherence (remainder). Without adjusting for baseline differences in these two groups of patients, there was a 28% [95% confidence interval (CI) 2–48%] lower risk of the primary endpoint in those with good adherence compared with the control group (P = 0.04). This comparison was, of course, not randomized, and there were many differences between the patients who had good adherence compared with those who did not. The authors could report the difference for measured variables,5 but not for unmeasured confounders such as attitude to adherence to lifestyle and therapies for co-morbidities. Several other smaller randomized trials were then conducted in patients with cardiovascular disease, or at high risk of this, and these are reviewed in the meta-analysis by Khan and colleagues in this edition of the journal.6 The largest randomized trial included was the Sleep Apnea Cardiovascular Endpoints (SAVE) study, published in 2016.7 A total of 2717 patients aged between 45 and 75 years with coronary or cerebrovascular disease and with moderate-to-severe OSA were randomized to CPAP treatment plus usual care or to usual care alone. After a mean follow-up of 3.7 years, there was no difference in the primary endpoint (death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischaemic attacks) with a hazard ratio of 1.10 (95% CI 0.91–1.32, P = 0.34). One of the potential explanations for the lack of effect was that compliance with therapy was considered suboptimal: a mean (SD) of 3.3 ± 2.3 h/night throughout the trial despite a 1 week run-in phase. In SAVE, knowing the post-hoc analysis from the Spanish Sleep and Breathing Network Study,5 McEvoy and colleagues7 pre-specified an analysis of CPAP therapy by adherence, dichotomizing patients by 4 h/night (42% of their patients had good adherence by this metric). One-to-one propensity score matching was used to compare 561 patients who were adherent to CPAP therapy with 561 patients in the usual care group (as the anthropometric and disease characteristics were different in those who were highly adherent to therapy): in this pre-specified non-randomized analysis, the primary endpoint was not significantly reduced [relative risk reduction 20% (95% CI +7 to –40%, P = 0.13)]. However, there was a borderline reduction in the risk of stroke [relative risk reduction 44% (95% CI 0–68%, P =0 .05)]. In this issue of the journal, Khan and colleagues meta-analyse all of the seven (published) randomized trials of CPAP therapy to treat moderate-to-severe OSA, attempting to determine the true effect of CPAP therapy on cardiovascular outcome, and whether 4 h/night is the critical usage time to demonstrate an effect. Three of the studies do not have more than 100 patients in the intervention arm, and most of the data come from the two studies discussed above. All of the patients in the trials had at least moderate OSA (typically, apnoea–hypopnoea index >15), but many excluded patients who were very sleepy during the day (it being considered unethical to randomize such patients when it is known that they will be much less sleepy with treatment), or hypoxaemic, thus limiting the generalizability of the trials to clinical practice. This also excludes those who may be at most risk, and limits compliance as sleepy patients find CPAP easier to adhere to. The overall cardiovascular event rates appear to be ∼3% per annum across the trials. In the meta-analysis, there was no evidence overall of a reduction in major adverse cardiovascular events with CPAP therapy, despite relatively long-follow up (averaging 37 months).6 The statistical heterogeneity across studies was, however, relatively high. The authors performed several sensitivity analyses: by excluding the largest study (SAVE7), where adherence to therapy was relatively low, they found a statistically borderline reduction in major adverse cardiovascular events (MACE) with little evidence of statistical heterogeneity [relative risk reduction 39% (95% CI 0–63%, P = 0.05)]. By including SAVE, but using the data from those who had good adherence, the effect size is similar, but becomes nominally significant [relative risk reduction 30% [95% CI 2–50%, P = 0.04)]. Examining the individual components of major cardiovascular events, the effect may be driven by a reduction in stroke, something also suggested in post-hoc propensity-matched subgroup analysis from the SAVE study. Residual confounding is impossible to exclude. What should we conclude from the evidence so far? There is no robust evidence that a strategy of treating patients with OSA with (or at high risk of) cardiovascular disease will reduce the risk of cardiovascular events over and above ‘usual’ care. There is good evidence, however, that CPAP therapy will improve daytime sleepiness, anxiety and depression, and quality of life, particularly in those with more severe OSA and higher levels of daytime sleepiness.4 There is a signal that if a patient adheres to therapy for most of their sleep time (or at least 4 h/night, on average) cardiovascular events may be reduced, perhaps more for stroke than other cardiovascular events, but this requires prospective confirmation. This may be challenging, as even in the trial setting and with a run-in phase, SAVE7 could not achieve this level of adherence for many of the enrolled patients, and could not confirm such an effect after adjustment (by propensity matching) for potential confounding between those who did and did not adhere to therapy at this level. Biologically, it makes sense that if OSA is a cyclical stressor on the cardiovascular system, then more consistent long-term control is likely to be necessary to reduce risk. In clinical practice, OSA is common in patients with, or at high risk of, cardiovascular disease and can have a major impact on a patient’s quality of life (and road safety). It is important that cardiologists consider the diagnosis, particularly in those with obesity, resistant hypertension, paroxysmal atrial fibrillation, and daytime sleepiness. The primary therapeutic rationale remains the treatment of symptoms. Effective CPAP therapy with optimal compliance requires individualized titration, good education, problem-solving with mask fit, humidification to reduce the risk of nasal dryness, and modern equipment that is relatively quiet. Collaboration between cardiologists and sleep or respiratory physicians is essential.8 The randomized trial remains King: this is the most robust method for determining whether an intervention has a clinically important effect. Prospective confirmation that CPAP therapy reduces cardiovascular events in patients with OSA (over and above any effect on quality of life and daytime sleepiness) is lacking. Khan and colleagues6 should be congratulated for drawing together the evidence published to date—but this is still only hypothesis generating, and we are left with the conundrum that it is difficult ethically to include the most sleepy and hypoxaemic OSA patients in randomized trials. In the meantime, cardiologists should remember that there are many therapies that have been proven to reduce the risk of cardiovascular events9 and ensure that their patients with OSA also have these considered, and are adherent to them long term. Conflict of interest: M.R.C. was the co-Principal Investigator for the SERVE-HF study, funded by ResMed. He has received research funding and speakers fees from that company. A.M.G.’s salary is funded through a research grant from ResMed to Imperial College London, UK. A.K.S. has no conflicts to declare. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehx597. References 1 Punjabi NM , Caffo BS , Goodwin JL , Gottlieb DJ , Newman AB , O’Connor GT , Rapoport DM , Redline S , Resnick HE , Robbins JA , Shahar E , Unruh ML , Samet JM. Sleep-disordered breathing and mortality: a prospective cohort study . PLoS Med 2009 ; 6 : e1000132 . Google Scholar CrossRef Search ADS PubMed 2 Marin JM , Carizzo SJ , Vincente E , Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study . Lancet 2005 ; 365 : 1046 – 1053 . Google Scholar CrossRef Search ADS PubMed 3 Cowie MR. Sleep-disordered breathing and cardiac disease. In: Fuster V , Harrington R , Narula J , Eapen ZJ , eds. Hurst’s The Heart , 14th ed . New York : McGraw Hill ; 2017 . Chapter 73. 4 Epstein LJ , Kristo D , Strollo PJ , Friedman N , Malhotra A , Patil SP , Ramar K , Rogers R , Schwab RJ , Weaver EM , Weinstein MD. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults . J Clin Sleep Med 2009 ; 5 : 263 – 276 . Google Scholar PubMed 5 Barbe F , Duran-Cantolla J , Sanchez-de-la-Torre M , Martinez-Alonso M , Carmona C , Barcelo A , Chiner E , Masa JF , Gonzalez M , Marín JM , Garcia-Rio F , Diaz de Atauri J , Terán J , Mayos M , de la Peña M , Monasterio C , del Campo F , Montserrat JM ; Spanish Sleep And Breathing Network . Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial . JAMA 2012 ; 307 : 2161 – 2168 . Google Scholar CrossRef Search ADS PubMed 6 Khan SU, , Duran CA, , Rahman H, , Lekkala M, , Saleem MA, , Kaluski E. A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea . Eur Heart J 2018 ; 39 : 2291 – 2297 . 7 McEvoy RD , Antic NA , Heeley E , Luo Y , Ou Q , Zhang X , Mediano O , Chen R , Drager LF , Liu Z , Chen G , Du B , McArdle N , Mukherjee S , Tripathi M , Billot L , Li Q , Lorenzi-Filho G , Barbe F , Redline S , Wang J , Arima H , Neal B , White DP , Grunstein RR , Zhong N , Anderson CS ; SAVE Investigators and Coordinators . CPAP for prevention of cardiovascular events in obstructive sleep apnea . N Engl J Med 2016 ; 375 : 919 – 931 . Google Scholar CrossRef Search ADS PubMed 8 Simonds AK , Cowie MR. Taboo: crossing the specialty barrier . Eur Respir J 2008 ; 31 : 1153 – 1154 . Google Scholar CrossRef Search ADS PubMed 9 Piepoli MF , Hoes AW , Agewall S , Albus C , Brotons C , Catapano AL , Cooney MT , Corrà U , Cosyns B , Deaton C , Graham I , Hall MS , Hobbs FD , Løchen ML , Löllgen H , Marques-Vidal P , Perk J , Prescott E , Redon J , Richter DJ , Sattar N , Smulders Y , Tiberi M , van der Worp HB , van Dis I , Verschuren WM ; Authors/Task Force Members . 2016 European guidelines on cardiovascular disease prevention in clinical practice . Eur Heart J 2016; 37 : 2315 – 2381 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Van Laake, Linda W; Lüscher, Thomas F; Young, Martin E

doi: 10.1093/eurheartj/ehx775pmid: 29309706

The discoveries of the Nobel Prize Awardees 2017 The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for their discoveries of the molecular circadian clock (Figure 1). Figure 1 View largeDownload slide The Nobel Laureates 2017. (From left to right): Jeffrey C. Hall, Michael Rosbash, and Michael W. Young. Figure 1 View largeDownload slide The Nobel Laureates 2017. (From left to right): Jeffrey C. Hall, Michael Rosbash, and Michael W. Young. It has long been recognized that organisms adapt their behaviour to a 24-h time cycle. Already in the 18th century the French astronomer Jean-Jacques d’Ortous de Mairan demonstrated the existence of an internal clock through his observations on the mimosa plant, which opens and closes its leaves in a circadian fashion, even when placed in complete darkness. Two hundred years later Ron Konopka and Seymour Benzer (both Nobel-ineligible because they passed away in the past decade) identified fruit flies (Drosophila) with defective 24-h rhythms; these flies all had a mutation in the same gene. In 1984, Jeffrey Hall and Michael Rosbash molecularly characterized this gene called Period (PER).1 They found that PER protein levels oscillated with a 24-h pattern. In 1994, Michael Young discovered a second core clock protein, TIM, encoded by the gene Timeless.2 This, later supported by discovery of additional clock proteins, such as CLOCK (CLK) and CYCLE (CYC), eventually led the Nobel Prize winners to conclude that a self-sustaining transcription-translation feedback loop governs the 24-h rhythms observed. In this mechanism, PER and TIM proteins accumulate in the cytoplasm, form a heterodimer, and translocate into the nucleus. CLOCK and CYCLE similarly form a heterodimer, activating transcription of particular target genes, including period and timeless. When PER/TIM bind to CLK/CYC, the complex detaches from DNA, thereby terminating transcription of downstream genes. Thus, PER and TIM inhibit their own transcription via CYC and CLK. As PER and TIM protein levels decrease, CYC and CLK are no longer inhibited, allowing reactivation of transcription, such that the loop starts again. Mammalian circadian clocks Like the clock described in Drosophila, the mammalian circadian clock is a transcriptionally-based cell autonomous mechanism,3 comprised of numerous positive (e.g. BMAL1, CLOCK) and negative (e.g. PER, CRY, REV-ERBα) components (Figure 2). One full ‘revolution’ of the core clock components takes approximately 24 h (slightly shorter in rodents and slightly longer in humans). These clocks, which are found in all mammalian cells, can be broadly divided into peripheral and central clocks, based on anatomical location. The central clock (often termed the ‘master’ clock) is found within the suprachiasmatic nucleus (SCN), a specialized region in the hypothalamus consisting of approximately 10 000 neurons. Peripheral clocks (often termed ‘slave’ clocks) are therefore those located elsewhere in the body, including non-SCN regions of the brain. Clocks must be reset on a routine basis, ensuring synchrony both between the organism and the environment, as well as maintaining internal synchrony (i.e. correct temporal alignment of clocks between different cells/organs). For the central clock, the primary ‘Zeitgeber’ (entrainment factor) is light (signal sent via the retinohypothalamic tract), while peripheral clocks are sensitive to neurohumoral modulation. Problems can therefore arise through circadian disruptive behaviours (e.g. shift work, travel through time zones) and disease states (e.g. obesity, diabetes mellitus), when inappropriate timing of Zeitgebers misaligns circadian clocks, invariably augmenting pathogenesis.4 Figure 2 View largeDownload slide The molecular circadian clock and cardiology. The molecular circadian clock, of which a simplified version is schematically depicted in the centre, sustains a 24-h rhythm that has impact on several facets of cardiology. Figure 2 View largeDownload slide The molecular circadian clock and cardiology. The molecular circadian clock, of which a simplified version is schematically depicted in the centre, sustains a 24-h rhythm that has impact on several facets of cardiology. Circadian influence on cardiovascular disease Time-of-day-dependent oscillations have been reported for both physiological cardiovascular (CV) regulation (e.g. heart rate, blood pressure) and disease states (e.g. arrhythmia, sudden cardiac death, myocardial infarction). Such observations have been explained classically by fluctuations in neurohumoral factors (e.g. sympathetic tone, cortisol, etc.), secondary to daily behaviours (e.g. sleep-wake and fasting-feeding cycles). However, both human- and animal-based studies suggest that circadian clocks not only drive rhythms in CV physiology and pathology, but they may be an important therapeutic target for disease prevention and/or treatment (Figure 2). For example, 24-h rhythms in specific cardiovascular regulatory mechanisms [e.g. heart rate, norepinephrine, cortisol, plasminogen activator inhibitor (PAI-1), and platelet activation] persist when individuals are forced to lead either a 20- or 28-h day, indicating mediation by an intrinsic circadian system (i.e. clocks). The clock-driven early morning rise in PAI-1 closely parallels increased risk of myocardial infarction at this time. Myocardial injury as assessed by circulating necrosis markers such as troponin I is also increased in patients during the morning hours, a rhythm that appears to be mediated by circadian clocks (latter evidence based on murine studies). Indeed, disruption of circadian clocks, either through genetic or environmental manipulations, decreases ischaemia tolerance in mice. A similar scenario has emerged for cardiac hypertrophy. For example, disruption of the normal 24-h light/dark cycle augments cardiac dysfunction in mice subjected to aortic constriction.5 More recently, two independent studies have reported that a small molecule agonist of the clock component REV-ERBα decreases cardiac hypertrophy, and improves cardiac function, in mice following pressure overload.6,7 Such studies lead to speculation that pharmacological and non-pharmacological interventions targeting, and/or working in conjunction with, circadian rhythms, may be beneficial in cardiovascular patients (Figure 3). Indeed, lowering nocturnal blood pressure, by treating patients with at least one antihypertension medication prior to bedtime, reduces adverse CV events over an 8-year period.11 Figure 3 View largeDownload slide Crucial impact of circadian rhythms on cardiology: a translational vision. The circadian clock crucially affects stress tolerance in human stem cell-derived cardiomyocytes and progenitor cells (mechanistic platform; figure modified from Dierickx et al.8), mouse cardiomyocytes in an ischaemia-reperfusion model9 (bridging translational step), and human cardiomyocytes in aortic valve replacement surgery10 with impact on clinical outcome (clinical application). MI, myocardial infarction. Figure 3 View largeDownload slide Crucial impact of circadian rhythms on cardiology: a translational vision. The circadian clock crucially affects stress tolerance in human stem cell-derived cardiomyocytes and progenitor cells (mechanistic platform; figure modified from Dierickx et al.8), mouse cardiomyocytes in an ischaemia-reperfusion model9 (bridging translational step), and human cardiomyocytes in aortic valve replacement surgery10 with impact on clinical outcome (clinical application). MI, myocardial infarction. The cardiomyocyte circadian clock Circadian clocks have been described in all CV-relevant cell types, including cardiomyocytes. But what might be the role of this mechanism in the heart? A general concept is that circadian clocks confer the selective advantage of anticipation, temporally partitioning biological processes in a manner that allows a cell/organ to respond appropriately to fluctuations in the environment over the 24-h day. What might the heart need to anticipate? Over the course of the day, the heart must contend with two major behavioural cycles; sleep-wake and fasting-feeding cycles. These cycles are associated with profound fluctuations in energetic demand, neural stimulation, hormones, nutrients, oxygen tension, body temperature, and shear stress. How might the cardiomyocyte clock simultaneously anticipate oscillations in all these factors? Consistent with its transcriptional nature, circadian clocks often govern cellular functions through modulation of genes that are not core clock components (termed clock output genes; CCGs). Selective genetic disruption of the cardiomyocyte circadian clock indicates that this molecular mechanism regulates up to 10% of the cardiac transcriptome; known functions of CCGs in the heart span processes as diverse as signal transduction and ion homeostasis, to metabolism.12 The latter serves as an excellent example, illustrating the importance of temporal partitioning. Metabolic flux analysis reveals that the cardiomyocyte clock promotes oxidative metabolism at the sleep-wake transition (in anticipation of increased energetic demand upon awakening), augments nutrient storage towards the end of the awake period (in anticipation of the upcoming fast during the sleep period), and increases cellular constituent turnover at the beginning of the sleep period (facilitating repair/renewal of the myocardium prior to awakening).13 Moreover, the myocardium exhibits clock-dependent rhythms in responsiveness to various stimuli/stresses, including adrenergic stimulation, insulin, and fatty acids. At a functional level, both time-of-day-dependent oscillations in heart rate and contractility are attenuated in mice following genetic disruption of the cardiomyocyte circadian clock; underscoring the importance of this mechanism in orchestrating critical processes in the heart, these mice develop an age-onset dilated cardiomyopathy and exhibit reduced lifespan.12,14 In addition to the postnatal cardiomyocyte, it was recently shown that both human cardiac progenitor cells15 and in vitro differentiated human pluripotent stem cell-derived cardiomyocytes8 possess an active circadian clock. Correspondingly, cell functions such as stress-induced apoptosis displayed a striking 24-h variation. This may have important implications; from the widespread in vitro (drug) research with these cell types to clinical regenerative therapies16 (Figure 2). Conclusion and perspectives The decision of the Nobel Prize committee to honour Jeffrey C. Hall, Michael Rosbash, and Michael W. Young (Figure 1) emphasizes the importance of the circadian clock in physiology and medicine. The cardiovascular system, including the heart itself, is particularly sensitive to circadian variation. We are only at the beginning of discovering the impact of the circadian clock on all the different aspects of cardiology. Nevertheless, an exciting novel dimension in research and therapy lies ahead of us, with great potential to improve existing therapies and discover new therapeutic targets. Funding L.L. was supported by the Netherlands Heart Foundation (Dekker 2013T056). M.Y. is employed by the University of Alabama at Birmingham. M.Y. was supported by the National Heart, Lung, and Blood Institute (HL106199, HL074259, HL123574, and HL122975). Conflict of interest: none declared. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. 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Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure . Eur Heart J 2016 ; 37 : 1789 – 1798 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2017. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)