Updates on cardiovascular outcome trials in diabetes.

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Term Occurence Count Dictionary
type 1 diabetes mellitus 1 endocrinologydiseases
Insulin 32 endocrinologydiseasesdrugs
acarbose 19 endocrinologydiseasesdrugs
dapagliflozin 3 endocrinologydiseasesdrugs
diabetes mellitus 2 endocrinologydiseases
metformin 11 endocrinologydiseasesdrugs
sitagliptin 1 endocrinologydiseasesdrugs
Albiglutide 4 endocrinologydiseasesdrugs
Exenatide 3 endocrinologydiseasesdrugs
Liraglutide 2 endocrinologydiseasesdrugs
dulaglutide 2 endocrinologydiseasesdrugs
pioglitazone 8 endocrinologydiseasesdrugs
type 2 diabetes mellitus 1 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Albiglutide 6091 100 mg vs. canagliflozin 300 mg vs. placeboCV death, MI or stroke10,1421.512.2009–02.2017NCT01032629 Albiglutide trialOngoing, not recruitingAlbiglutideGLP-1 receptor agonistAlbiglutide 30 mg vs. albiglutide 50 mg
Albiglutide 6131 placeboCV death, MI or stroke10,1421.512.2009–02.2017NCT01032629Albiglutide trialOngoing, not recruiting Albiglutide GLP-1 receptor agonistAlbiglutide 30 mg vs. albiglutide 50 mg vs. placeboCV death, MI or stroke9400–07.2015–02.2018NCT02465515ACECompletedAcarboseα-Glucosidase
Albiglutide 6164 stroke10,1421.512.2009–02.2017NCT01032629Albiglutide trialOngoing, not recruitingAlbiglutideGLP-1 receptor agonist Albiglutide 30 mg vs. albiglutide 50 mg vs. placeboCV death, MI or stroke9400–07.2015–02.2018NCT02465515ACECompletedAcarboseα-Glucosidase
Albiglutide 7998 AHA≥ 18CANVAS program≥ 40T2DM(7.0, 10.5%)Pre-existing CVD or high CV riskDrug naive or AHA– Albiglutide trial≥ 40T2DM> 7.0%CVD––ACE≥ 65Prediabetes5.9%CV event within the last 3 monthDrug naive25Table 3Concomitant
Exenatide 4603 semaglutide 1.0 mg vs. placeboCV death, MI, or stroke32991.902.2013–01.2016NCT01720446EXSCELCompleted Exenatide GLP-1 receptor agonistExenatide once-weekly vs. placeboCV death, MI, or stroke14,7523.206.2010–04.2017NCT01144338CAROLINAOngoing,
Exenatide 4634 death, MI, or stroke32991.902.2013–01.2016NCT01720446EXSCELCompletedExenatideGLP-1 receptor agonist Exenatide once-weekly vs. placeboCV death, MI, or stroke14,7523.206.2010–04.2017NCT01144338CAROLINAOngoing,
Exenatide 5047 agonistDulaglutide vs. placeboCV death, MI, or stroke9622–07.2011–07.2018NCT01394952ITCA650Completed Exenatide in DUROSGLP-1 receptor agonistITCA 650 (exenatide in DUROS) vs. placeboCV death, MI, UA, or stroke4000–03.2013–03.2016NCT01455896DECLARE-TIMIOngoing,
Insulin 990 summarizes the results of the DEVOTE, CANVAS, EXSCEL and ACE trials that tested cardiovascular safety of Insulin degludec, canagliflozin, once-weekly exenatide and acarbose and were published in 2017. We provide
Insulin 2692 OUTCOME) as well as GLP-1 receptor agonist (RA; 3 studies: ELIXA, LEADER and SUSTAIN6) classes [[8]]. Also Insulin glargine and Insulin degludec had been subjected to be tested for CV safety [[9]–[11]].The previously
Insulin 2713 receptor agonist (RA; 3 studies: ELIXA, LEADER and SUSTAIN6) classes [[8]]. Also Insulin glargine and Insulin degludec had been subjected to be tested for CV safety [[9]–[11]].The previously published CVOTs determined
Insulin 5504 inhibitorLinagliptin vs. placeboCV death, MI, UA, or stroke8000–07.2013–12.2017NCT01897532DEVOTECompleted Insulin degludecBasal insulinsInsulin degludec vs. insulin glargineCV death, MI, or stroke76371.910.2013–10.2016NCT01959529MK-3102TerminatedMK-3102DPP-4
Insulin 5534 death, MI, UA, or stroke8000–07.2013–12.2017NCT01897532DEVOTECompletedInsulin degludecBasal insulins Insulin degludec vs. insulin glargineCV death, MI, or stroke76371.910.2013–10.2016NCT01959529MK-3102TerminatedMK-3102DPP-4
Insulin 8272 to in the textConcomitant medication @baselineAntihyperglycaemic medication N (%)CV treatment N (%) Insulin MetforminSulphonyl-ureaAspirinStatinsAntiplatelet/anticoagulantBeta-blockerACEI/ARBOther anti-hypertensivesSAVOR-TIMI536757
Insulin 9624 present an update of this publication, including the most recent CVOTs on GLP-1 RAs, SGLT-2 inhibitors, Insulin degludec and acarbose and discuss their implications for the medication of type 2 diabetes mellitus
Insulin 10234 inhibitor MK-3102 was terminated in March 2017. The DEVOTE study compared the CVO of the ultra-long-acting Insulin degludec with Insulin glargine U100 in T2DM patients with a high risk of CV events. The trial was designed
Insulin 10256 terminated in March 2017. The DEVOTE study compared the CVO of the ultra-long-acting Insulin degludec with Insulin glargine U100 in T2DM patients with a high risk of CV events. The trial was designed to continue until
Insulin 17018 ACE study additionally included UA and HF into the primary composite endpoint.In the DEVOTE study, Insulin degludec was non-inferior to Insulin glargine. Primary MACE occurred in 8.5% of the degludec group vs.
Insulin 17055 and HF into the primary composite endpoint.In the DEVOTE study, Insulin degludec was non-inferior to Insulin glargine. Primary MACE occurred in 8.5% of the degludec group vs. 9.3% of the glargine group (HR 0.91;
Insulin 19319 difference in the occurrence of CV death comparing the two study groups confirming non-inferiority of Insulin degludec towards Insulin glargine (3.6% vs. 3.7%; HR 0.96; 95% CI 0.76–1.21; p = 0.71 [[10]]). Participants
Insulin 19344 occurrence of CV death comparing the two study groups confirming non-inferiority of Insulin degludec towards Insulin glargine (3.6% vs. 3.7%; HR 0.96; 95% CI 0.76–1.21; p = 0.71 [[10]]). Participants treated with
Insulin 20276 non-fatal MIRegarding the second component of the primary outcome, non-fatal MI, non-inferiority of Insulin degludec to Insulin glargine was confirmed (3.8% vs. 4.4%; HR 0.85; 95% CI 0.68–1.06; p = 0.15 [[10]]).
Insulin 20296 MIRegarding the second component of the primary outcome, non-fatal MI, non-inferiority of Insulin degludec to Insulin glargine was confirmed (3.8% vs. 4.4%; HR 0.85; 95% CI 0.68–1.06; p = 0.15 [[10]]). In the CANVAS
Insulin 21221 95% CI 0.87–1.46; p = 0.38 [[23]]).Fatal and/or non-fatal strokeNon-inferiority was confirmed for Insulin degludec regarding the primary endpoint non-fatal stroke. 1.9% of patients in the degludec and 2.1%
Insulin 23810 the DEVOTE study (3.8% vs. 4.5%) Acute kidney injury occurred in 1.8% of participants treated with Insulin degludec and in 2.5% of participants treated with Insulin glargine [[10]]. As the CANVAS program includes
Insulin 23868 occurred in 1.8% of participants treated with Insulin degludec and in 2.5% of participants treated with Insulin glargine [[10]]. As the CANVAS program includes CANVAS-R, renal outcomes were specifically analysed.
Insulin 25773 the number of nocturnal severe hypoglycaemic events was significantly reduced in participants in the Insulin degludec group compared to the Insulin glargine group (4.9% vs. 6.6% of patients with severe hypoglycaemia;
Insulin 25812 hypoglycaemic events was significantly reduced in participants in the Insulin degludec group compared to the Insulin glargine group (4.9% vs. 6.6% of patients with severe hypoglycaemia; rate ratio 0.73; 95% CI 0.60–0.89;
Insulin 28174 inhibitor canagliflozin, the GLP-1 RA once-weekly exenatide and the α-glucosidase inhibitor acarbose. Insulin degludec was compared to Insulin glargine U100. Since 2015 the new longer-acting Insulin glargine U300
Insulin 28207 RA once-weekly exenatide and the α-glucosidase inhibitor acarbose. Insulin degludec was compared to Insulin glargine U100. Since 2015 the new longer-acting Insulin glargine U300 has been approved for the European
Insulin 28263 acarbose. Insulin degludec was compared to Insulin glargine U100. Since 2015 the new longer-acting Insulin glargine U300 has been approved for the European market, after initiation of DEVOTE. The DEVOTE study
Insulin 28461 DEVOTE study could confirm non-inferiority in terms of CV events. With regard to hypoglycaemic risks Insulin degludec was superior to Insulin glargine, both in rates of severe and nocturnal severe hypoglycaemia.
Insulin 28494 non-inferiority in terms of CV events. With regard to hypoglycaemic risks Insulin degludec was superior to Insulin glargine, both in rates of severe and nocturnal severe hypoglycaemia. Glycaemic control did not differ
Insulin 28692 did not differ between the two groups. Also adverse events did not occur in different rates comparing Insulin degludec and Insulin glargine. Interestingly, it was reported that fasting glucose variability during
Insulin 28713 the two groups. Also adverse events did not occur in different rates comparing Insulin degludec and Insulin glargine. Interestingly, it was reported that fasting glucose variability during the study was associated
Insulin 29449 standard care medication like insulin, metformin or sulfonylurea. The ORIGIN trial compared CV outcomes of Insulin glargine with standard care and did not observe any differences between the two groups [[9]].The CANVAS
Insulin 34716 study [[23]].The recent CVOT results summarized in this overview indicate, that the utilization of Insulin degludec as glucose-lowering medication is safe in regard to CVOs and adverse events. Even though canagliflozin
Insulin 38148 drug classes (SGLT-2 inhibitors, GLP-1 RAs, DPP-4 inhibitors, Thiazolidinedione, Sulfonylureas and Insulin ) could give further insight into this question. This study is estimated to be completed by the end of
Insulin 42726 outcomes and confirmed previous studies that indicated no increased CV risk of glucose-lowering drugs. Insulin degludec showed non-inferiority to Insulin glargine (DEVOTE). The CANVAS program demonstrated superiority
Insulin 42769 indicated no increased CV risk of glucose-lowering drugs. Insulin degludec showed non-inferiority to Insulin glargine (DEVOTE). The CANVAS program demonstrated superiority of canagliflozin to placebo in the primary
Liraglutide 4310 empagliflozin 25 mg vs. placeboCV death, MI, or stroke70003.107.2010–04.2015NCT01131676LEADERCompleted Liraglutide GLP-1 receptor agonistLiraglutide vs. placeboCV death, MI, or stroke93403.808.2010–12.2015NCT01179048SUSTAIN-6CompletedSemaglutideGLP-1
Liraglutide 4343 death, MI, or stroke70003.107.2010–04.2015NCT01131676LEADERCompletedLiraglutideGLP-1 receptor agonist Liraglutide vs. placeboCV death, MI, or stroke93403.808.2010–12.2015NCT01179048SUSTAIN-6CompletedSemaglutideGLP-1
acarbose 1049 trials that tested cardiovascular safety of Insulin degludec, canagliflozin, once-weekly exenatide and acarbose and were published in 2017. We provide context on these results by comparing them with earlier trials
acarbose 9645 publication, including the most recent CVOTs on GLP-1 RAs, SGLT-2 inhibitors, Insulin degludec and acarbose and discuss their implications for the medication of type 2 diabetes mellitus (T2DM) patients.Summary
acarbose 11377 mini pump (DUROS®). Additionally, the ACE trial investigated whether the α-glucosidase inhibitor acarbose could reduce CV events in a population with established coronary heart disease and newly detected impaired
acarbose 17983 non-inferiority; p = 0.06 for superiority [[24]]). A total of 470 of 3272 (14.4%) participants of the acarbose group in the ACE trial had a primary outcome event compared to 479 of 3250 (14.7%) in the placebo group
acarbose 19029 0.77–0.97 [[24]]. The ACE study could not demonstrate a significant difference between the treatment with acarbose or placebo with regard to all-cause mortality (216 (7%) of 3272 vs. 219 (7%) of 3250; HR 0.98; 95% CI
acarbose 20001 related deaths in the ACE study was similar to EXSCEL. 4.4% of patients died due to CV causes in the acarbose group and 5.0% in the placebo group. This between group difference was not considered to be significant
acarbose 21088 non-fatal MI were 122 (3.7%) vs. 108 (3.3%), indicating no significant difference in the treatment with acarbose and placebo (HR 1.12; 95% CI 0.87–1.46; p = 0.38 [[23]]).Fatal and/or non-fatal strokeNon-inferiority
acarbose 21995 statistically different between the two groups (HR 0.85; 95% CI 0.70–1.03 [[24]]). Similarly, treatment with acarbose did not reveal a reduction of stroke events compared to placebo (2.3% vs. 2.4%; HR 0.97; 95% CI, 0.70–1.33;
acarbose 22648 investigated as a secondary outcome. 174 participants (5.3%) were hospitalized for UA after being treated with acarbose and 170 participants of the placebo group (5.2%; HR 1.02; 95% CI 0.82–1.26; p = 0.87) revealing
acarbose 23353 (3.1%) when given placebo (HR 0.94; 95% CI 0.78–1.13 [[24]]). In ACE, 65 participants (2.0%) of the acarbose group were hospitalized for HF and 73 participants (2.2%) of the placebo group. This difference was
acarbose 25075 0.9% [[24]]). In the ACE trial the incidence of impaired renal function was not different between the acarbose and the placebo groups (rate ratio 0.81; 95% CI 0.54–1.23; p = 0.33 [[23]]).Pancreatic effectsPancreatic
acarbose 28164 SGLT-2 inhibitor canagliflozin, the GLP-1 RA once-weekly exenatide and the α-glucosidase inhibitor acarbose . Insulin degludec was compared to Insulin glargine U100. Since 2015 the new longer-acting Insulin glargine
acarbose 33386 trial was conducted in China, trial population consisted to 97% of Han Chinese. It was shown, that acarbose was more effective in individuals consuming “Eastern” diets compared to “Western” diets. This
acarbose 33555 diets compared to “Western” diets. This might be a reason for the high number of prescriptions of acarbose in China, where it is the most common oral glucose-lowering medication. It is also prescribed as preventative
acarbose 33993 (adding hospitalization for HF and UA) as primary outcome. The primary endpoint was not reduced comparing acarbose with placebo. Also most secondary outcomes did not show a difference between the two treatment groups.
acarbose 34221 participants which developed diabetes during the follow-up of the ACE study was reduced by 18% in the acarbose group compared to the placebo group. This risk reduction of incident diabetes in the high CV risk population
acarbose 34363 group. This risk reduction of incident diabetes in the high CV risk population supports the fact, that acarbose is frequently prescribed as prevention for individuals with impaired glucose tolerance [[23]]. Anyhow,
acarbose 35094 Once-weekly exenatide demonstrated safety with regard to CVOs and adverse events. ACE could confirm, that acarbose can be used without safety concerns.One major strength of the CANVAS program is that it is, so far,
acarbose 42930 superiority of canagliflozin to placebo in the primary endpoint. Once-weekly exenatide (EXSCEL) and acarbose (ACE) were non-inferior to placebo and no safety concerns were raised by the presented results. Many
dapagliflozin 31165 [[30]–[33]]. The currently ongoing DECLARE-TIMI study will provide information on safety issues of dapagliflozin , enabling comparison with further SGLT-2 inhibitors. The contemporary analysis of real-world clinical
dapagliflozin 31583 drugs. The SGLT-2 inhibitors varied according to countries included (canagliflozin, empagliflozin and dapagliflozin ). This epidemiological study showed that the analysed SGLT-2 inhibitors can—in a real-world setting—reduce
dapagliflozin 42111 Therefore, several trials on CVO are currently running and will be completed in 2019 (DECLARE-TIMI— dapagliflozin and VERTIS—ertugliflozin) to add new information on further agents to the results obtained in the
dulaglutide 32939 No safety concerns were risen by any adverse events observed in the EXSCEL trial. A fifth GLP-1 RA, dulaglutide is currently tested for CV safety in the REWIND study, which is estimated to be completed in July 2018.The
dulaglutide 41884 Two currently ongoing studies will present the results for further agents in the next year: REWIND ( dulaglutide ) and the albiglutide trial (albiglutide). SGLT-2 inhibitors are a relatively new class of glucose-lowering
metformin 29381 only the second completed trial investigating CV effects of standard care medication like insulin, metformin or sulfonylurea. The ORIGIN trial compared CV outcomes of Insulin glargine with standard care and did
metformin 35896 acute and chronic heart failure” commented that in patients with HF the treatment of choice should be metformin , especially because no CV data were available for DPP-4 inhibitors and GLP-1 RAs. The positive results
metformin 37058 [[38]].Efforts are made to provide CVO information on the standard glucose-lowering agents insulin, metformin and sulfonylurea. A meta-analysis concluded, that a CV risk of metformin in T2DM patients could not
metformin 37131 glucose-lowering agents insulin, metformin and sulfonylurea. A meta-analysis concluded, that a CV risk of metformin in T2DM patients could not be determined mainly due to the low amount of information currently available
metformin 37311 of information currently available [[39]]. The REMOVAL trial recently investigated the influence of metformin on atherosclerosis progression in long-standing type 1 diabetes mellitus (T1DM) patients with high CV
metformin 37436 atherosclerosis progression in long-standing type 1 diabetes mellitus (T1DM) patients with high CV risk. Adding metformin to the insulin therapy and standard of care did not significantly affect atherosclerosis progression.
metformin 37557 insulin therapy and standard of care did not significantly affect atherosclerosis progression. However, metformin treatment had a positive effect on HbA1c, body weight and LDL-cholesterol [[40], [41]]. In addition
metformin 37737 LDL-cholesterol [[40], [41]]. In addition to REMOVAL, the EMERALD study currently investigates the influence of metformin on CV function in adolescent T1DM patients and is bound to be completed in 2018 (NCT01808690).Sulfonylureas
metformin 38617 initiated to compare the efficacy of pioglitazone, a PPAR-γ agonist, and sulfonylurea as add-ons to metformin on CV outcomes. 3028 participants with inadequately controlled metformin monotherapy were randomized.
metformin 38690 sulfonylurea as add-ons to metformin on CV outcomes. 3028 participants with inadequately controlled metformin monotherapy were randomized. The trial was designed as a Prospective Randomised Open Blinded Evaluation
metformin 39399 sulfonylurea group. These results suggest, that both drugs are suitable options as add-on treatment to metformin , with benefits for hypoglycaemia and LDL-cholesterol when using pioglitazone [[43]]. A previous CVOT
pioglitazone 38425 published TOSCA-IT and the still running CAROLINA provide a head-to-head comparison of sulfonylureas with pioglitazone and the DDP-4 inhibitor linagliptin [[42]].The large-scale study TOSCA-IT was initiated to compare the
pioglitazone 38553 inhibitor linagliptin [[42]].The large-scale study TOSCA-IT was initiated to compare the efficacy of pioglitazone , a PPAR-γ agonist, and sulfonylurea as add-ons to metformin on CV outcomes. 3028 participants with
pioglitazone 39072 or urgent coronary revascularization. No significant differences between the two treatment groups— pioglitazone vs. sulfonylurea—could be observed in regard of the primary and secondary outcomes. The number of
pioglitazone 39271 The number of hypoglycaemic events was significantly lower and LDL-cholesterol levels higher in the pioglitazone than in the sulfonylurea group. These results suggest, that both drugs are suitable options as add-on
pioglitazone 39473 options as add-on treatment to metformin, with benefits for hypoglycaemia and LDL-cholesterol when using pioglitazone [[43]]. A previous CVOT with pioglitazone (PROactive) described a significant reduction of non-fatal
pioglitazone 39515 benefits for hypoglycaemia and LDL-cholesterol when using pioglitazone [[43]]. A previous CVOT with pioglitazone (PROactive) described a significant reduction of non-fatal MI and stroke in patients with T2DM and a
pioglitazone 39742 macrovascular events. However, other end-points like heart failure showed a drastic increase in the pioglitazone group [[44]]. These results could not be confirmed by the TOSCA-IT study. Vaccaro and colleagues suggest,
pioglitazone 40066 of comparator. The low risk population of TOSCA-IT (only 11% with CVD) could mask minor benefits of pioglitazone . Indeed, post hoc on-treatment results are in agreement with previous findings [[43], [44]].Not only
sitagliptin 2890 [[9]–[11]].The previously published CVOTs determined safety of the DPP-4 inhibitors saxagliptin, alogliptin and sitagliptin as well as the GLP-1 RA lixisenatide with regard to CV outcomes [[12]–[15]]. Additionally, LEADER,
Select Disease Character Offset Disease Term Instance
diabetes mellitus 9714 inhibitors, Insulin degludec and acarbose and discuss their implications for the medication of type 2 diabetes mellitus (T2DM) patients.Summary of recently completed CVOTsIn the past year, several CVOTs were completed, among
diabetes mellitus 37376 recently investigated the influence of metformin on atherosclerosis progression in long-standing type 1 diabetes mellitus (T1DM) patients with high CV risk. Adding metformin to the insulin therapy and standard of care did
type 1 diabetes mellitus 37369 trial recently investigated the influence of metformin on atherosclerosis progression in long-standing type 1 diabetes mellitus (T1DM) patients with high CV risk. Adding metformin to the insulin therapy and standard of care did
type 2 diabetes mellitus 9707 SGLT-2 inhibitors, Insulin degludec and acarbose and discuss their implications for the medication of type 2 diabetes mellitus (T2DM) patients.Summary of recently completed CVOTsIn the past year, several CVOTs were completed, among

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