Background
Methods
Data sources and search strategy
Eligibility criteria
Study selection
Risk of bias and quality of evidence assessment
Data extraction
Statistical analysis
Ethics
Results
Study selection
Evidence from randomized controlled trials
RCTs reporting heart failure
Study | International study | Number of countries involved | Number of study sites | Study phase | Total number of patients randomized | Length of follow up (weeks) | Male (n,%) | Mean age (years) | Mean BMI (kg/m2) | Mean HbA1c (%) | Mean FPG (mmol/L) | Mean diabetes duration (years) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Trials reporting heart failure | ||||||||||||
No | 1 | NR | III | 427 | 26 | 290 (67.9) | 56.8 | 26.1 | 8.5 | NR | 9.0 | |
Yes | 2 | 138 | III | 746 | 104 | 371 (49.7) | 53.0 | 33.1 | 8.3 | 9.4 | 5.4 | |
Yes | 21 | 170 | III | 1091 | 104 | 635 (58.2) | 56.7 | 31.0 | 8.4 | 10.0 | 7.6 | |
NCT00360334 2009 [45] | No | 1 | 35 | III | 235 | 26 | 160 (68.4) | 56.6 | NR | NR | NR | 6.0 |
NCT00614120 2010 [46] | Yes | 3 | 51 | III | 929 | 16 | 514 (55.3) | 53.3 | 25.6 | NR | NR | 7.5 |
NCT00701935 2013 [47] | Yes | 2 | 17 | II | 80 | 26 | 42 (52.5) | 58.1 | NR | NR | NR | NR |
Yes | 10 | 289 | III | 1049 | 164 | 482 (47.6) | 54.5 | 32.6 | 8.1 | 9.2 | 6.0 | |
Yes | 4 | 222 | III | 779 | 164 | 418 (56.1) | 55.5 | 33.1 | 8.3 | 9.5 | 8.8 | |
NCT00839527 2014 [52] | Yes | 9 | 358 | III | 685 | 164 | 353 (53.2) | 55.2 | NR | NR | NR | NR |
NCT00849017 2014 [53] | Yes | 3 | 262 | III | 309 | 164 | 166 (55.1) | 52.9 | NR | NR | NR | NR |
NCT00849056 2014 [54] | Yes | 6 | 331 | III | 310 | 156 | 180 (59.8) | 55.0 | NR | NR | NR | NR |
NCT00855439 2015 [55] | No | 1 | 1 | NR | 46 | 82 | 26 (56.5) | 53.0 | NR | NR | NR | NR |
Yes | 17 | 108 | III | 637 | 30 | 261 (51.2) | 59.5 | 32.5 | 8.2 | 7.1 | 11.5a | |
NCT01064687 2015 [58] | Yes | 3 | 89 | III | 978 | 26 | 570 (58.4) | 55.7 | 33.2 | 8.1 | 9.0 | 8.8 |
NCT01075282 2015 [59] | Yes | 20 | 78 | III | 810 | 78 | 353 (51.3) | 56.7 | 31.6 | 8.1 | 9.1 | 9.1 |
Yes | 19 | 91 | III | 807 | 56 | 353 (43.7) | 55.6 | 33.3 | 7.6 | 9.0 | 2.6 | |
NCT01191268 2014 [62] | Yes | 16 | 101 | III | 884 | 52 | 473 (53.5) | 59.4 | 32.5 | 8.5 | NR | 12.7 |
NCT01512108 2014 [63] | No | 1 | 36 | III | 363 | 52 | 262 (72.8) | 59.5 | NR | 8.1 | 8.8 | NR |
NCT01620489 2014 [64] | Yes | 6 | 50 | III | 277 | 26 | 140 (50.5) | 67.2 | NR | NR | NR | NR |
Pratley 2013 [65] | Yes | 17 | 130 | III | 760 | 24 | 362 (48.9) | 56.4 | 32.7 | 8.3 | 10.0 | 8.8 |
Trials reporting hospitalization for heart failure | ||||||||||||
Yes | 49 | NR | III | 6068 | 108b | 4207 (69.3) | 60.3 | 30.2 | 7.7 | 8.2 | 9.3 |
Study | Medications used across groups | Incretin | Control | Duration of treatment (weeks) | ||
---|---|---|---|---|---|---|
Type | Events | Type | Events | |||
Trials reporting heart failure | ||||||
BG or BG + TZD | Exenatide | 1/215 | Insulin glargine | 0/212 | 26 | |
None | Liraglutide | 1/497 | Glimepiride | 0/248 | 104 | |
Metformin | Liraglutide | 1/724 | Placebo | 0/121 | 104 | |
Liraglutide | 1/724 | Glimepiride | 0/242 | |||
NCT00360334 2009 [45] | OADs | Exenatide | 0/118 | Insulin glargine | 1/116 | 26 |
NCT00614120 2010 [46] | Merformin | Liraglutide | 1/697 | Glimepiride | 0/231 | 16 |
NCT00701935 2013 [47] | None | Exenatide | 0/43 | Placebo | 1/37 | 26 |
Metformin | Albiglutide | 2/302 | Placebo | 0/101 | 156 | |
Albiglutide | 2/302 | Glimepiride | 1/307 | |||
Metformin ± SU | Albiglutide | 2/504 | Insulin glargine | 2/241 | 156 | |
NCT00839527 2014 [52] | Metformin + glimepiride | Albiglutide | 0/271 | Placebo | 1/115 | 164 |
Albiglutide | 0/271 | Pioglitazone | 4/277 | |||
NCT00849017 2014 [53] | None | Albiglutide | 1/200 | Placebo | 2/101 | 164 |
NCT00849056 2014 [54] | Pioglitazone ± Metformin | Albiglutide | 0/150 | Placebo | 1/151 | 156 |
NCT00855439 2015 [55] | Other diabetes medications | Exenatide | 1/22 | Glargine | 1/24 | 78 |
Insulin glargine + metformin | Exenatide | 0/315 | Insulin lispro | 1/312 | 30 | |
NCT01064687 2015 [58] | Metformin and pioglitazone | Dulaglutide | 1/559 | Placebo | 0/141 | 26 |
Exenatide | 0/278 | Placebo | 0/141 | |||
NCT01075282 2015 [59] | Metformin and glimepiride | Dulaglutide | 3/545 | Insulin glargine | 1/262 | 78 |
None | Dulaglutide | 1/539 | Metformin | 0/268 | 52 | |
NCT01191268 2014 [62] | Insulin lispro | Dulaglutide | 0/588 | Insulin glargine | 1/296 | 52 |
NCT01512108 2014 [63] | None | Liraglutide | 1/240 | Additional OAD | 0/120 | 52 |
NCT01620489 2014 [64] | OAD and/or insulin | Liraglutide | 1/140 | Placebo | 0/137 | 26 |
Pratley 2013 [65] | SU ± metformin | Taspoglutide | 0/494 | Pioglitazone | 2/257 | 24 |
Trials reporting hospitalization for heart failure | ||||||
Metformin, SU, glinide, TZD, insulin, metformin and SU, insulin and OADs, or other diabetes medications | Lixisenatide | 122/3034 | Placebo | 127/3034 | 100 |
Quality assessment | Summary of findings | Quality of evidence | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Study event rates | Relative risk (95 % CI) | Anticipated absolute effects (5-year time frame) | |||||||||
No of participants (studies) Follow-up time | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | With control | With GLP-1 agonists | Risk with control | Risk difference with GLP-1 agonists (95 % CI) | ||
Heart failure | |||||||||||
11758 (20) 16-164 weeks | Serious limitation due to risk of biasa | No serious limitations | No serious limitations | Serious limitation, confidence interval includes important benefit and harm | Undetected | 19/4317 (0.44 %) | 17/7441 (0.23 %) | OR 0.62 (0.31 to 1.22) | 50 per 1000b | 19 fewer per 1000 (34 fewer to 11 more) | ⊕ ⊕ ΟΟ Low due to risk of bias and imprecision |
Hospitalization for heart failure | |||||||||||
6068 (1) 2.1 years | No serious limitations | No serious limitations | No serious limitations | Serious limitation, confidence interval includes important benefit and harm | Undetected | 127/3034 4.2 % | 122/3034 4 % | HR 0.96 (0.75 to 1.23) | 100 per 1000c | 4 fewer per 1000 (25 fewer to 23 more) | ⊕ ⊕ ⊕Ο Moderate due to imprecision |
Trials reporting hospitalization for heart failure
Evidence from observational studies
Studies reporting heart failure
Study | Study design | Data source | Countries involved | Funding | Total number of patients | Follow up (years) | Male (n, %) | Mean age (years) | Mean BMI (kg/m2) | Mean HbA1c (%) | Mean FPG (mmol/L) | Mean diabetes duration (years) | CVD at baseline |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Studies reporting heart failure | |||||||||||||
NCT01060059 2013 [66] | Prospective cohort study | Real world data | Italy | Private for-profit funding | 882 | 1 | 493 (55.9) | 62.5 | NR | 8.9 | NR | NR | NR |
Kannan 2015 [17]a | Retrospective cohort study | Electronic health records | U.S. | No funding | 13,185 | 4b | 7827 (54.6) | 60.6 | 32.6c | NR | NR | NR | Included patients had no history of CVD or congestive heart failure at baseline |
Paul 2015 [18] | Retrospective cohort study | Claims data | U.S. | NR | 39,225 | 3.5b | 18093 (46.1) | 58.2 | 35.3 | 7.9 | NR | 1.3 | Included patients had CVD or no CVD at baseline |
Studies reporting hospitalization for heart failure | |||||||||||||
Yu 2015 [19]a | Nested case–control study | Electronic medical records | UK | Public funding | 57,737 | NA | 32795 (56.8) | 61.6 | NR | NR | NR | 2.3 | Included patients had CVD or no CVD at baseline |
Study | Exposure of interest | Control group | Number of events or cases | Total number of analyzed patients | Adjusted estimates (95 % CI) | Adjusted covariate |
---|---|---|---|---|---|---|
Studies reporting heart failure | ||||||
Kannan 2015 [17] | GPL-1 agonists (combined with metformine) | Sulfonylureas (combined with metformine) | 528a | 13,185 (55,110 person years)a | HR 1.10 (0.99 to 1.22) | Age, sex, race, BMI, number of encounters, median household income, smoking status, systolic and diastolic blood pressure, hypertension, dyslipidemia, cerebral vascular event, presence of neuropathy, retinopathy, dementia, chronic obstructive pulmonary disease, cancer, atrial fibrillation, anti-hypertensive medications, lipid lowering agents, anti-platelet agents and propensity for being on metformin and sulfonylureas at baseline, lipid profile, estimated glomerular filtration rate |
Paul 2015 [18] | Exenatide/exenatide + insulin | Insulin | 2338 | 39,225 | Exenatide vs insulin: HR 0.34 (0.22, 0.52) Exenatide + insulin vs insulin: HR 0.40 (0.32, 0.50) Without previous CVD: Exenatide vs insulin: HR 0.34 (0.22, 0.52) Exenatide + insulin vs insulin: HR 0.40 (0.32, 0.50) Without previous CVD & renal diseases: Exenatide vs insulin: HR 0.32 (0.21, 0.50) Exenatide + insulin vs insulin: HR 0.35 (0.28, 0.45) | Gender, ethnicity, age at the start of cohort, BMI, HbA1c, systolic and diastolic blood pressure on the index date, history of cardiovascular disease, any renal disease prior to index date or during follow-up, use of metformin, sulfonylurea, cardioprotective medications or antihypertensive medications, and the duration of diabetes |
NCT01060059 2013 [66] | Exenatide | Basal insulin | 2 | 882 | NR | NR |
Studies reporting hospitalization for heart failure | ||||||
Yu 2015 [19] | GLP-1 agonists (exenatide and liraglutide, alone or incombination with other antidiabetic drugs) | Other oral antidiabetic drugs | 1,118a | 18,744a | OR 0.67 (0.32 to 1.42) | Sex, BMI, excessive alcohol use, smoking status, HbA1c level, comorbidities (neuropathy, renal disease, retinopathy, atrial fibrillation, cancer [other than nonmelanoma skin cancer], chronic obstructive pulmonary disease, coronary artery disease, dyslipidemia, hypertension, previous myocardial infarction, peripheral arteriopathy, previous coronary revascularization, peripheral vascular disease, and previous stroke), number of prescriptions, number of physician visits, and use of the following drugs in the year prior to cohort entry: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, diuretics, fibrates, statins, aspirin, and other nonsteroidal anti-inflammatory drugs |
Comparison | Number of studies (Events or cases, patients) | GLP-1 agonists (events/patients) | Control (events/patients) | Effect Estimate (95%CI) | Cardiovascular morbidities at baseline |
---|---|---|---|---|---|
1. Heart failure | |||||
Randomized controlled trials | |||||
GLP-1 agonists vs. control | 20 (36, 11758) | 17/7441 | 19/4317 | Pooled OR 0.62 (0.31 to 1.22) | Typically without CVD at baseline |
Cohort studies | |||||
GLP-1 agonists vs. SU | 1 (528, 13185) | NR | NR | Adjusted HR 1.10 (0.99 to 1.22) | No history of CVD or congestive heart failure at baseline |
Exenatide vs. insulin Exenatide + insulin vs. insulin | 1 (2338, 39225) | 49/2804 195/7870 | 2094/28551 2094/28551 | Adjusted HR 0.34 (0.22, 0.52) Adjusted HR 0.40 (0.32, 0.50) | With or without CVD at baseline |
Exenatide vs. basal insulin | 1 (2, 882) | 0/444 | 2/438 | Unadjusted OR 0.13 (0.01 to 2.13) | NR |
2. Hospitalization for heart failure | |||||
Randomized controlled trials | |||||
Lixisenatide vs. placebo | 1 (249, 6068) | 122/3034 | 127/3034 | Pooled Adjusted HR 0.96 (0.75, 1.23) | Acute coronary syndrome |
Nested case–control studies | |||||
GLP-1 agonists vs. other OADs | 1 (1118, 18744) | Adjusted OR 0.67 (0.32 to 1.42) | With or without CVD at baseline |