Background
-
For outcome clinical trials, in order to exclude unacceptable CV risk, a two-sided 95 % CI upper boundary of 1.8 risk ratio (pre-approval) and/or 1.3 risk ratio (post-approval) for major adverse events (MACE) versus control group is required.
-
To satisfy the new statistical requirements, CV event analysis might include a meta-analysis of all placebo-controlled, add-on (drug vs. placebo, plus standard therapy) and active-controlled trials, and/or an additional single, large, safety CVOT can be conducted. This, alone or in addition to other trials, needs to satisfy the upper bound mentioned above before approval.
-
Patient selection should focus on high-risk populations, including those with advanced disease, elderly and those with renal impairment.
-
Trials must include at least 2 years of CV safety data.
-
A prospective independent adjudication of CV events in phase 2 and 3 studies must also be performed. These CV events include CV mortality, myocardial infarction (MI) and stroke, and possibly hospitalization for ACS, urgent revascularization and other end-points.
Summary of results of recently completed CVOTs
Study status | Drug | Drug class | Intervention | Primary Outcome | N | Follow-up (years) | Start and estimated end date | Clinicaltrials.gov ID | |
---|---|---|---|---|---|---|---|---|---|
SAVOR-TIMI53 | Completed | Saxagliptin | DPP-4 inhibitor | Addition of saxagliptin vs. placebo to usual diabetes care | CV death, MI, or stroke | 18,206 | 2.1 | 05.2010–05.2013 | NCT01107886 |
EXAMINE | Completed | Alogliptin | DPP-4 inhibitor | Addition of alogliptin vs. placebo to usual diabetes care | CV death, MI, or stroke | 5380 | 1.5 | 10.2009–06.2013 | NCT00968708 |
TECOS | Completed | Sitagliptin | DPP-4 inhibitor | Sitagliptin vs. placebo | CV death, MI, UA, or stroke | 14,724 | 3 | 12.2008–03.2015 | NCT00790205 |
ELIXA | Completed | Lixisenatide | GLP-1 inhibitor | Lixisenatide vs. placebo | CV death, MI, UA, or stroke | 6076 | 2.1 | 06.2010–02.2015 | NCT01147250 |
EMPA-REG OUTCOME | Completed | Empagliflozin | SGLT-2 inhibitor | Empagliflozin 10 mg vs. empagliflozin 25 mg vs. placebo | CV death, MI, or stroke | 7000 | 3.1 | 07.2010–04.2015 | NCT01131676 |
LEADER | Completed | Liraglutide | GLP-1 inhibitor | Liraglutide vs. placebo | CV death, MI, or stroke | 9340 | 3.8 | 08.2010–12.2015 | NCT01179048 |
SUSTAIN-6 | Completed | Semaglutide | GLP-1 inhibitor | Semaglutide 0.5 mg vs. semaglutide 1.0 mg vs. placebo | CV death, MI, or stroke | 3299 | 1.99 | 02.2013–01.2016 | NCT01720446 |
EXSCEL | Ongoing, not recruiting | Exenatide | GLP-1 inhibitor | Exenatide once weekly vs. placebo | CV death, MI, or stroke | 14,000 | 06.2010–04.2018 | NCT01144338 | |
CAROLINA | Ongoing, not recruiting | Linagliptin | DPP-4 inhibitor | Liraglutide vs. placebo | CV death, MI, UA, or stroke | 6000 | 10.2010–09.2018 | NCT01243424 | |
REWIND | Ongoing, not recruiting | Dulaglutide | GLP-1 inhibitor | Dulaglutide vs. placebo | CV death, MI, or stroke | 9622 | 07.2011–01.2016 | NCT01394952 | |
ITCA650 | Ongoing, not recruiting | Exenatide in DUROS | GLP-1 inhibitor | ITCA 650 (exenatide in DUROS) vs. placebo | CV death, MI, UA, or stroke | 4000 | 03.2013–07.2018 | NCT01455896 | |
DECLARE-TIMI | Ongoing, not recruiting | Dapagliflozin | SGLT-2 inhibitor | Dapagliflozin 10 mg vs. placebo | CV death, MI, or stroke | 17,276 | 01.2013–04.2019 | NCT01730534 | |
CARMELINA | Ongoing, not recruiting | Linagliptin | DPP-4 inhibitor | Linagliptin vs. placebo | CV death, MI, UA, or stroke | 8000 | 07.2013–01.2018 | NCT01897532 | |
DEVOTE | Ongoing, not recruiting | Insulin degludec | Basal insulins | Insulin degludec vs. insulin glargine | CV death, MI, or stroke | 7637 | 10.2013–09.2016 | NCT01959529 | |
MK-3102 | Ongoing, not recruiting | MK-3102 | DPP-4 inhibitor | MK-3102 vs. placebo | CV death, MI, UA, or stroke | 4202 | 10.2012–12.2020 | NCT01703208 | |
Ertugliflozin trial | Ongoing, not recruiting | Ertugliflozin | SGLT-2 inhibitor | Ertugliflozin 5 mg vs. ertugliflozin 15 mg vs. placebo | CV death, MI, or stroke | 3900 | 11.2013–06.2020 | NCT01986881 | |
TOSCA-IT | Ongoing, not recruiting | Pioglitazone | PPAR-γ agonists | Pioglitazone vs. sulfonylurea | Death, MI, stroke or coronary revascularisation | 3371 | 09.2008–12.2018 | NCT00700856 | |
CANVAS | Ongoing, not recruiting | Canagliflozin | SGLT-2 inhibitor | Canagliflozin 100 mg vs. canagliflozin 300 mg vs. placebo | CV death, MI, UA, or stroke | 4418 | 12.2009–06.2017 | NCT01032629 |
Age | Diabetes type | HbA1c levels | Cardiovascular status | Prior antihyperglycemic treatment | BMI (kg/m2) | |
---|---|---|---|---|---|---|
SAVOR-TIMI53 | ≥40 | T2DM | ≥6.5 % | CVD OR high CV risk | AHA | 31.1 |
EXAMINE | ≥18 | T2DM | (6.5, 11.0 %) | ACS (15, 90) days before | AHA | 28.7 |
TECOS | ≥50 | T2DM | (6.5, 11.0 %) | preexisting CVD | AHA | 30.2 |
ELIXA | ≥30 | T2DM | ≥7.0 % | ACS min. 180 days before | AHA | 30.2 |
EMPA-REG OUTCOME | ≥18 | T2DM | (7.0, 10.0 %) | Preexisting CVD | Drug näive OR AHA | ≤45 |
LEADER | ≥50 | T2DM | ≥7.0 % | Preexisting CVD/cerebrovascular disease/vascular disease/renalORheart failure at ≥50 OR CV risk at ≥60 | Drug näive OR AHA | 32.5 |
SUSTAIN-6 | ≥50 | T2DM | ≥7.0 % | Preexisting CVD at ≥50 OR preCVD at ≥60 | Drug näive OR AHA | 31.1 |
EXSCEL | ≥18 | T2DM | (7.0, 10.0 %) | Specific AHA | ||
CAROLINA | ≥40 ≤85 | T2DM | (6.5, 7.5–8.5 %) | CVD OR specified diabetes end-organ damage OR age ≥70 years OR ≥2 specified CV risk factors | ≤45 | |
REWIND | ≥50 | T2DM | ≤9.5 % | Preexisting vascular disease OR ≥CV risk factors | AHA | |
ITCA650 | ≥40 | T2DM | ≥6.5 % | Preexisting coronary, cerebrovascular or peripheral artery disease | ||
DECLARE-TIMI | ≥40 | T2DM | High risk CV events | |||
CARMELINA | ≥18 | T2DM | (6.5, 10.0 %) | High risk CV events | Drug näive OR specific AHA | ≤45 |
DEVOTE | ≥50 | T2DM | ≤7.0 % | CVD OR renal disease OR ≥60 CV risk | Specific AHA | |
MK-3102 | ≥40 | T2DM | (6.5, 10.0 %) | Preexisting vascular disease | ||
Ertugliflozin trial | ≥40 | T2DM | (7.0, 10.5 %) | Preexisting vascular disease | Drug näive OR AHA | ≥18 |
TOSCA-IT | ≥50 ≤75 | T2DM | (7.0, 9.0 %) | Specific AHA | 20–45 | |
CANVAS | ≥40 | T2DM | (7.0, 10.5 %) | Preexisting CVD OR high CV risk | Drug näive OR AHA |
Concomitant medication @baseline | Antihyperglycemic medication N (%) | CV treatment N (%) | |||||||
---|---|---|---|---|---|---|---|---|---|
Insulin | Metformin | Sulphonylurea | Aspirin | Statins | Antiplatelet/anticoagulant | Beta-blocker | ACEI/ARB | Other anti-hypertensives | |
SAVOR-TIMI53 | 6757 (40.9) | 11,094 (67.4) | 6332 (38.5) | 12,390 (75.2) | 12,892 (78.3) | 13,386 (81.3) | 10,117 (61.4) | 12,935 (78.5) | 6730 (40.9) |
EXAMINE | 1605 (29.8) | 3562 (66.2) | 2503 (69.9) | 4881 (90.7) | 4866 (90.4) | 5232 (97.2) | 4411 (81.9) | 4411 (81.9) | 1197 (22.2) |
TECOS | 3408 (23.2) | 11,966 (81.6) | 6645 (45.3) | 11,518 (78.5) | 11,719 (79.9) | 3167 (21.7) | 9322 (63.5) | 11,555 (78.8) | 4961 (33.8) |
ELIXA | 2292 (37.8) | 3834 (63.2) | 1863 (30.7) | 5726 (94.4) | 5621 (92.6) | 480 (7.9) | 5119 (84.4) | 5151 (84.9) | 1327 (21.9) |
EMPA-REG OUTCOME | 2394 (34)a
| 3933 (55.9)a
| 1383 (19.6) | 5990 (85) | 5387 (77) | – | 4537 (64) | 5651 (80) | 2114 (30) |
LEADER | 3905 (41.8)a
| 7136 (76.4) | 4721 (50) | 6523 (69.8) | 6729 (72) | 6322 (67.7) | 5173 (55.4) | 4761 (51) | 920 (9.85) |
SUSTAIN-6 | 1913 (58.0) | 2414 (73.2) | 1410 (42.8) | 2108 (63.9) | 2399 (72.8) | 406 (12.3) | 1894 (57.4) | 1642 (49.8) | 258 (7.8) |
CAROLINA | – | 4982 (82.5) | 1728 (28.6) | 3026 (50.1) | 3872 (64.1) | – | 2344 (38.8) | 2664 (44.1) | 1770 (29.3) |
CANVAS | 2171 (50.1) | 3158 (72.9) | 2032 (46.9) | 3119 (72.0) | 3073 (71.0) |
-
Primary MACE composite end-point Diverse individual elements are included in the primary composite end-point for each CVOT, as shown in Table 1. However, CV death, myocardial infarction and stroke are all common elements to primary composite CVOT end-points. In addition, the TECOS and ELIXA trials included hospitalization for UA in the primary MACE. Corresponding data in Table 4 shows that for saxagliptin (SAVOR-TIMI), sitagliptin (TECOS), lixisenatide (ELIXA) and alogliptin (EXAMINE) treatment, occurrence of the primary composite end-point did not differ from placebo groups, thus confirming non-inferiority of the new treatments in CV safety under the particular conditions of each of the trials. In the EMPA-REG OUTCOME trial, however, the primary outcome occurred in 10.5 % in the pooled empagliflozin group and in 12.1 % of the placebo group (empagliflozin group (HR 0.86; 95 % CI 0.74–0.99; p = 0.04 for superiority), demonstrating therefore not only non-inferiority versus placebo but superiority [49]. A similar result was observed in LEADER, where the primary outcome occurred in significantly fewer patients in the liraglutide group than in the control group (13 vs. 14.9 %; HR 0.87; 95 % CI 0.78–0.97; p = 0.01 for superiority), but only for patients with established CVD (subgroup analysis) [51]. It is important to note, however, that both in LEADER and EMPA-REG OUTCOME, the lesser occurrence in the primary composite end-point was largely driven by a reduction in cardiovascular mortality. Results from the recently published SUSTAIN-6 trial have also shown superiority for semaglutide versus placebo in the primary composite outcome (6.6 vs. 8.9 % of patients, respectively; HR: 0.74, 95 % CI 0.58–0.95; p < 0.001), however, in contrast to EMPA-REG OUTCOME and LEADER, results were not driven by a decrease of risk of cardiovascular death, but of non-fatal stroke occurrence (in 1.6 and 2.7 %, respectively (HR 0.61; 95 % CI 0.38–0.99; p = 0.04) [52].Table 4Comparison of outcome results from terminated CVOTs in comparison to placeboCardiovascular endpointsTECOS [50]ELIXA [44]LEADER [51]SUSTAIN-6 [52]ClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valueClassHazard ratio (95 % CI)p valuePrimary composite MACECV death, MI, or stroke1.00 (0.89-1.12)0.99CV death, MI, or stroke0.96 (≤1.16)0.315CV death, MI, UA, or stroke0.98 (0.89–1.08)0.65CV death, MI, UA, or stroke1.02 (0.89–1.17)0.81CV death, MI, or stroke0.86 (0.74–0.99)0.04aCV death, MI, or stroke0.87 (0.78–0.97)0.01CV death, MI, or stroke0.74 (0.58–0.95)<0.001/0.02aCardiovascular deathPrimary end-point1.03 (0.87–1.22)0.72Primary end-point0.85 (0.66–1.10)0.212Primary end-point1.03 (0.89–1.19)0.71Primary end-point0.98 (0.78–1.22)0.85Primary end-point0.62 (0.49–0.77)< 0.001Primary end-point0.78 (0.66–0.93)0.007Primary end-point0.98 (0.65–1.48)0.92Myocardial infarctionPrimary end-point0.95 (0.80–1.12)0.52Primary end-point1.08 (0.88–1.33)0.47Primary end-point0.95 (0.81–1.11)0.49Primary end-point1.03 (0.87–1.22)0.71Primary end-point0.87 (0.70–1.09)0.23Primary end-point0.86 (0.73–1.00)0.046Primary end-point0.74 (0.51–1.08)0.12StrokePrimary end-point1.11 (0.88–1.39)0.38Primary end-point0.91 (0.55–1.50)0.71Primary end-point0.97 (0.79–1.19)0.76Primary end-point1.12 (0.79–1.58)0.54Primary end-point1.18 (0.89–1.56)0.26Primary end-point0.86 (0.71–1.06)0.16Primary end-point0.61 (0.38–0.99)0.04Hospitalization for unstable anginaSecondary end-point1.19 (0.89–1.60)0.24Secondary end-point0.90 (0.60–1.37)0.632Primary end-point0.90 (0.70–1.16)0.42Primary end-point1.11 (0.47–2.62)0.81Secondary end-point0.99 (0.74–1.34)0.97ExtendedPrimary end-point0.98 (0.76–1.26)0.87Extended primary end-point0.82 (0.47–1.44)0.49Hospitalization for heart failureSecondary end-point1.27 (1.07–1.51)0.007ExtendedPrimary end-point1.19 (0.90-1.58)0.220Secondary end-point1.00 (0.83–1.20)0.98Secondary end-point0.96 (0.75-1.23)0.75Secondary end-point0.65 (0.50–0.85)0.002ExtendedPrimary end-point0.87 (0.73-1.05)0.14Extended primary end-point1.11 (0.77–1.61)0.57Event rate (%) active groupEvent rate (%) active groupEvent rate (%) active groupEvent rate (%) active groupEvent rate (%) active groupEvent rate (%) active groupEvent rate (%) active groupNo. (%)p valueNo. (%)p valueNo. (%)p valueNo. (%)p valueNo. (%)p valueNo. (%)p valueNo. (%)p valuePrimary composite MACE7.311.39.613.410.513.06.6Non-cardiovascular endpointsRenal event2.0 %0.460.9 %0.881.5 %1.6 %5.2 %5.7 %3.8 %Acute pancreatitis0.3 %0.170.4 %0.50.3 %0.120.2 %0.3 %b0.4 %0.440.54 %Hypoglycemia events0.5 %0.330.7 %0.861.9 %0.330.6 %1.3 %3.3 %0.0222.4 %c
-
Fatal/non-fatal myocardial infarction An important CV outcome to measure given the increased MI risk implied by diabetes [55], therefore its inclusion in all primary composite MACE end-points. Data from the six trials published to date has shown that all glucose-lowering treatments tested are non-inferior to placebo when it comes to MI. For a more detailed comparison of hazard rates, see Table 4.
-
Stroke In general, the third basic element of primary composite MACE end-points. So far, considering the published results of the aforementioned six trials, none of the new glucose-lowering drugs tested increases stroke occurrence in comparison to placebo. However, in EMPA-REG OUTCOME a trend towards an increased stroke incidence was reported [49]. Conversely to EMPA-REG OUTCOME, in SUSTAIN-6, a significant reduction of stroke rates was reported for patients under semaglutide in comparison to the placebo group [52]. For more data on hazard rates, see Table 4.
-
Hospitalization for UA The importance of this end-point varied among trials. While TECOS and ELIXA included UA in their primary end-points; and SAVOR-TIMI, EMPA-REG OUTCOME and EXAMINE included it as part of the secondary composite end-point, LEADER and SUSTAIN-6 included it as part of an extended primary composite end-point. As it happened with MI or stroke risk, UA rates did not increase under any of the treatments investigated when compared to placebo. Extended information is available on Table 4.
-
Hospitalization for HF As shown in Table 4, rates of hospitalization for HF did not differ between placebo and treatment groups in the EXAMINE, TECOS, ELIXA or SUSTAIN-6 trials, and LEADER showed a non-significant decrease of hospitalization for HF in patients treated with liraglutide [51]. Yet, treatment with saxagliptin (SAVOR-TIMI) was found to increase hospitalization rates for HF (3.5 vs. 2.8 %; HR 1.27; 95 % CI 1.07–1.51; p = 0.007). This effect was independent of age, as confirmed by a later analysis on efficacy and safety in older patients [43]. Conversely, in EMPA-REG OUTCOME treatment with empagliflozin reduced the number of patients hospitalized for HF (2.8 vs. 4.5 %; HR 0.61; 95 % CI 0.47–0.79; p < 0.001) and improved other HF outcomes like the composite endpoint of CV death or hospitalization for HF (5.7 vs. 8.5 %; HR 0.66; 95 % CI 0.55–0.79; p < 0.001) [45, 53].
-
Serious hypoglycemic events As part of the serious adverse event report, the rate of serious hypoglycemic events suffered by patients under treatment with the new glucose lowering drugs was investigated. Even though rates were similar to placebo in all CVOTs, and major hyperglycemia events did not differ between saxagliptin (SAVOR-TIMI) treatment and placebo, hypoglycemia occurrence generally increased with saxagliptin in combination with sulphonylureas or insulin. This effect was consistent across all age ranges analyzed [43]. On the contrary, treatment with liraglutide reduced severe hypoglycemic events in comparison to placebo (rate ratio: 0.69; 95 % CI 0.51–0.93; p = 0.02), which might be due to a reduced need for insulin co-therapy [51]. In SUSTAIN-6, the rates of severe hypoglycemia did not significantly differ between the two semaglutide-dose treatment groups and placebo [semaglutide 0.5 mg and 1.0 mg 191 (23.1 %) and 178 (21.7 %), respectively], placebo 0.5 and 1.0 mg [177 (21.5 %) and 173 (21.0 %)] [52].
-
Pancreatic effects Regarding the possible association between incretin-based therapies and adverse pancreatic effects, CVOTs evaluated whether these new antihyperglycemic agents increased the risk for pancreatitis. Acute pancreatitis occurred slightly more often in the treatment groups than with placebo when employing saxagliptin (SAVOR-TIMI), sitagliptin (TECOS), alogliptin (EXAMINE) or lixisenatide (ELIXA), and even when no significant differences between groups could be found, a meta-analysis on trials on DPP-4 inhibitors showed a marginally higher risk of pancreatitis associated with DPP-4 treatment [56]. In LEADER and SUSTAIN-6, incidence of pancreatitis was lower, even if not statistically significant, in the intervention group than in the placebo group [51, 52].
-
Renal events and/or microvascular effects Definitions for renal events were different for each trial. While in the ELIXA and TECOS trials there is no specification of the type of renal events [44], in EXAMINE only initiation of dialysis is reported [47]. A broader renal end-point including doubling of creatinine level, initiation of dialysis, renal transplantation or creatinine >6.0 mg/dl was used in the SAVOR-TIMI trial [43]. Regardless of end-point definition, none of these trials found differences between treatment and placebo with respect to renal function. Moreover, a further examination of the EMPA-REG OUTCOME trial regarding renal outcomes, found that addition of empagliflozin to standard treatment was associated with a slower progression of kidney disease (empagliflozin HR 0.61; CI 95 % 0.53–0.70; p < 0.001) and lower rates of clinically relevant renal events than placebo [57]. In the LEADER trial, a composite renal and retinal microvascular outcome was investigated. The renal outcome involved the new onset of macroalbuminuria or the doubling of the serum creatinine level and an eGFR ≤45 ml/min/1.73 m2, the need for continuous renal-replacement therapy or death from renal disease. The incidence of the composite microvascular outcome was lower with liraglutide, mainly due to a significantly lower rate of nephropathy events (HR 0.78; 95 % CI 0.67–0.92; p = 0.003) [51]. In SUSTAIN-6, the investigated renal outcome was defined as new or worsening of nephropathy and consisted on persistent macroalbuminuria, persistent doubling of the serum creatinine level and eGFR ≤45 ml/min/1.73 m2, or the need for continuous renal-replacement therapy. Based on that definition, semaglutide treated patients had a significantly lower risk than placebo treated patients (3.8 vs. 6.1 %, respectively; HR 0.64; 95 % CI 0.46–0.88; p = 0.005). Conversely, and somehow unexpectedly, retinopathy-derived complications (blindness, vitreous hemorrhage, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly more often reported in the treatment group as in the placebo (3.0 vs. 1.8 %, respectively; HR 1.76; 95 % CI 1.11–2.78; p = 0.02) [52].