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Non-insulin antidiabetic pharmacotherapy in patients with established cardiovascular disease: a position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy
European Heart Journal ( IF 39.3 ) Pub Date : 2017-11-08 , DOI: 10.1093/eurheartj/ehx625 Alexander Niessner 1 , Juan Tamargo 2 , Lorenz Koller 1 , Christoph H Saely 3, 4, 5 , Thomas Andersen Schmidt 6, 7 , Gianluigi Savarese 8 , Sven Wassmann 9 , Giuseppe Rosano 10, 11 , Claudio Ceconi 12 , Christian Torp-Pedersen 13, 14 , Juan Carlos Kaski 15 , Keld Per Kjeldsen 16, 17, 18 , Stefan Agewall 19, 20 , Thomas Walther 21, 22 , Heinz Drexel 3, 4, 5, 23 , Basil S Lewis 24, 25
European Heart Journal ( IF 39.3 ) Pub Date : 2017-11-08 , DOI: 10.1093/eurheartj/ehx625 Alexander Niessner 1 , Juan Tamargo 2 , Lorenz Koller 1 , Christoph H Saely 3, 4, 5 , Thomas Andersen Schmidt 6, 7 , Gianluigi Savarese 8 , Sven Wassmann 9 , Giuseppe Rosano 10, 11 , Claudio Ceconi 12 , Christian Torp-Pedersen 13, 14 , Juan Carlos Kaski 15 , Keld Per Kjeldsen 16, 17, 18 , Stefan Agewall 19, 20 , Thomas Walther 21, 22 , Heinz Drexel 3, 4, 5, 23 , Basil S Lewis 24, 25
Affiliation
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.
更新日期：2017-11-08
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.
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