Table 2. Summary of Clinical Trials in Which the Cardiovascular Effects of GLP-1 RAs Were Non-Primary Outcomes.
| Study | Duration, wk | No. of patients | Background+Comparator | Intervention | ΔBW, kg | ΔHR, bpm | ΔSystolicBP, mm Hg | ΔCVD risk markers, mmol/L (for lipid profiles) |
|---|---|---|---|---|---|---|---|---|
| Exenatide BID | ||||||||
| Blevins et al. (2011) [51] (DURATION-5) | 24 | 252 | (None, 1 or combination of Met, SU, TZD)+exenatide QW | Exenatide 10 µg BID | –1.4 | 2.1a (4.1a for exenatide QW) | –1.2 | 0.07 LDL-C |
| 0.03 HDL-C | ||||||||
| 0.01 TG | ||||||||
| Bunck et al. (2010) [48] | 52 | 69 | Met+insulin glargine | –3.9a | b | b | –61% hs-CRPa | |
| Buse et al. (2009) [54] (LEAD-6) | 26 | 464 | (Met±SU)+liraglutide | –2.9 | 0.69a (+3.28a for liraglutide) | –2.0 | –0.40 LDL-C | |
| –0.05 HDL-C | ||||||||
| –0.23 TGc | ||||||||
| –0.10 FFAc | ||||||||
| –0.03 g/L ApoB | ||||||||
| Davies et al. (2009) [55] | 26 | 235 | 2 or 3 OADs+insulin glargine | –2.73a | b | –2.9 | –0.25 LDL-Ca | |
| 0.01 HDL-C | ||||||||
| –0.33 TG | ||||||||
| DeFronzo et al. (2010) [56] | 20 | 137 | Met+TZD | –2.8a | b | b | –0.05 LDL-Ca | |
| 0.02 HDL-C | ||||||||
| –0.34 TGa | ||||||||
| Derosa et al. (2010) [49] | 52 | 128 | Met+SU | –8.0a | b | b | ↓hs-CRP (VNR)a | |
| Drucker et al. (2008) [57] (DURATION-1) | 30 | 295 | (Met, SU, TZD or any two combined)+exenatide QW | –3.6 | b | –3.4 | +0.03 LDL-Cc | |
| –0.03 HDL-C | ||||||||
| –11% TG | ||||||||
| Klonoff et al. (2008) [58] | 3 years | 217 | (Met±SU)+placebo | –5.3a | b | –3.5a | –6% LDL-Ca | |
| 24% HDL-Ca | ||||||||
| –12% TG-Ca | ||||||||
| Moretto et al. (2008) [59] | 24 | 232 | None+placebo | –3.1a | b | –3.7a | –0.07 LDL-C | |
| 0.02 HDL-C | ||||||||
| Exenatide QW | ||||||||
| Drucker et al. (2008) [57] (DURATION-1) | 30 | 295 | (Met, SU, TZD, or any two combined)+exenatide BID | Exenatide QW | –3.7 | b | –4.7 | –0.13 LDL-Ca |
| –0.02 HDL-C | ||||||||
| –15% TG | ||||||||
| Buse et al. (2010) [60] (DURATION-1 extension) | +22 (52 in total) | 295 | (Met, SU, TZD, or any two combined)+exenatide BID or QW from DURATION-1 studies | –4.1 (QW)–4.5 (BID→QW) | b | –6.2a (QW)–3.8 (BID→QW) | –9.6 mg/dL TC | |
| –0.7 mg/dL HDL-C | ||||||||
| –3.4 mg/dL LDL-C | ||||||||
| –15% TG | ||||||||
| MacConell et al. (2013) [61] (DURATION-1 extension) | 3 years | 295 | (Met, SU, TZD, or any two combined)+exenatide BID→exenatide QW | –2.3a | b | –2.1 | –0.26 TC | |
| –0.18 LDL-C | ||||||||
| 0.03 HDL-C | ||||||||
| –12% TG | ||||||||
| Bergenstal et al. (2010) [50] (DURATION-2) | 26 | 491 | Met+(Sit or TZD) | –2.3a | b | ↓(VNR)a | ↑HDL-Ca | |
| –5% TG | ||||||||
| ↓hs-CRPa | ||||||||
| ↓BNPa | ||||||||
| Diamant et al. (2010) [53] (DURATION-3) | 26 | 456 | (Met±SU)+insulin glargine | –2.6a | 4.0a | –3.0a | –0.05 LDL-C | |
| 0.0 HDL-C | ||||||||
| –2.0 mg/dL hs-CRPa | ||||||||
| Diamant et al. (2012) [52] (DURATION-3 extension) | 84 | 456 | (Met±SU)+insulin glargine | –2.1a | 1.97a | –4.2a | –0.12 TC | |
| 0.95 TG | ||||||||
| –2.05 mg/dL hs-CRP | ||||||||
| Diamant et al. (2014) [62] (DURATION-3 extension) | 3 years | 456 | (Met±SU)+insulin glargine | –2.49a | 2 | –2 | –0.13 TCa | |
| –0.17 LDL-Ca | ||||||||
| 0.05 HDL-Ca | ||||||||
| 1.02 TG | ||||||||
| –2.00 mg/dL CRPa | ||||||||
| Russell-Jones et al. (2012) [63] (DURATION-4) | 26 | 820 | None+(Met, TZD or Sit) | –2.0 | 1.5 | –1.3 | No change in fasting serum lipids (VNR) | |
| Blevins et al. (2011) [51] (DURATION-5) | 24 | 252 | (None, 1, or combination: Met, SU, TZD)+exenatide BID | –2.3a | 4.1a (2.1a for exenatide BID) | –2.9a | –0.17 LDL-Ca | |
| 0.0 HDL-C | ||||||||
| 0.01 TG | ||||||||
| Buse et al. (2013) [64] (DURATION-6) | 26 | 911 | (Met, SU, Met+SU, or Met+TZD)+liraglutide | –2.68 | b | –2.48 (–3.45 for liraglutide) | –0.06 TC | |
| 0.02 HDL-C | ||||||||
| –0.05 LDL-C | ||||||||
| –2.19 nmol/L hs-CRP | ||||||||
| –4.45 ng/L BNP | ||||||||
| Liraglutide | ||||||||
| Marre et al. (2009) [65] (LEAD-1) | 26 | 1,041 | SU+(TZD or TZD placebo) | 1.2 mg/day | +0.3a | 2–4a | –2.6–2.8 | b |
| 1.8 mg/day | –0.2a | 2–4a | –2.6–2.8 | b | ||||
| Nauck et al. (2009) [66] (LEAD-2) | 26 | 1,091 | Met+(SU or placebo) | 1.2 mg/day | –2.6a | 2–3a | –2–3a | b |
| 1.8 mg/day | –2.8a | 2–3a | –2–3a | b | ||||
| Garber et al. (2009) [67] (LEAD-3) | 52 | 746 | None+SU | 1.2 mg/day | –2.1a | 3.2a | –2.1 | b |
| 1.8 mg/day | –2.5a | 1.6 | –3.6a | b | ||||
| Garber et al. (2011) [68] (LEAD-3 extension) | 2 years | 746 | None+SU | 1.2 mg/day | –1.89a | 2.04 | –1.35 | b |
| 1.8 mg/day | –2.70a | 0.92 | –2.37 | b | ||||
| Zinman et al. (2009) [69] (LEAD-4) | 26 | 533 | (Met+TZD)+placebo | 1.2 mg/day | –1.0a | b | –6.7a | –0.21 TC |
| –0.28 LDL-Ca | ||||||||
| –0.03 HDL-C | ||||||||
| –0.38 TGa | ||||||||
| –0.03 FFAa | ||||||||
| 1.8 mg/day | –2.0a | b | –5.6a | –0.20 TC | ||||
| –0.23 LDL-C | ||||||||
| –0.04 HDL-C | ||||||||
| –0.32 TG | ||||||||
| –0.05 FFAa | ||||||||
| Russell-Jones et al. (2009) [70] (LEAD-5) | 26 | 581 | (Met+SU)+(insulin glargine or placebo) | 1.8 mg/day | –1.8a | b | –4.0a | b |
| Buse et al. (2009) [54] (LEAD-6) | 26 | 464 | (Met±SU)+exenatide | 1.8 mg/day | –3.2 | 3.28 (0.69 for exenatide BID) | –2.5 | –0.44 LDL-C |
| –0.04 HDL-C | ||||||||
| –0.41 TGa | ||||||||
| –0.17 FFAa | ||||||||
| –0.06 g/L ApoB | ||||||||
| Buse et al. (2010) [71] (LEAD-6 extension) | +14 (40 in total) | 376 | (Met±SU)+exenatideBID→liraglutide | 1.8 mg/day | –0.9a | b | –3.8a | b |
| Pratley et al. (2010) [72] | 26 | 658 | Met+Sit | 1.2 mg/day | –2.86a | 2.32 | –0.55 | –0.08 LDL-C |
| 0.00 HDL-C | ||||||||
| –0.19 TG | ||||||||
| –0.03 FFA | ||||||||
| –0.06 g/L ApoB | ||||||||
| 1.8 mg/day | –3.38a | 3.94 | –0.72 | –0.05 LDL-C | ||||
| 0.00 HDL-C | ||||||||
| –0.43 TG | ||||||||
| –0.07 FFA | ||||||||
| –0.07 g/L ApoB | ||||||||
| Pratley et al. (2011) [73] extension | +26 (52 in total) | 436 | Met+Sit | 1.2 mg/day | –2.78a | 1.72 | –0.37 | 0.09 LDL-C |
| –0.10 TG | ||||||||
| –0.07 FFA | ||||||||
| –0.03 g/L ApoB | ||||||||
| 1.8 mg/day | –3.68a | 3.09 | –2.55 | 0.09 LDL-C | ||||
| –0.32 TG | ||||||||
| –0.10 FFA | ||||||||
| –0.03 g/L ApoB | ||||||||
| Lixisenatide | ||||||||
| Rosenstock et al. (2013) [74] (GetGoal-X) | 24 | 634 | Met+exenatide BID | 20 µg QD | –2.8 | 0.1 | –2.9 | b |
| Rosenstock et al. (2014) [75] (GetGoal-S) | 24 | 859 | (SU±Met)+placebo | 20 µg QD | –1.76a | –0.1 | Slight decrease (VNR) | No relevant change in lipid levels (VNR) |
| Albiglutide | ||||||||
| Nauck et al. (2016) [76] (HARMONY 2) | 52 | 309 | None+placebo | 30 mg QW | –0.39 | 2.5 | –2.8 | –0.312 TC |
| –0.278 LDL-C | ||||||||
| 0.051 HDL-C | ||||||||
| –0.379 TG | ||||||||
| –0.038 FFA | ||||||||
| 50 mg QW | –0.86 | 0.8 | –1.3 | –0.101 TC | ||||
| –0.130 LDL-C | ||||||||
| 0.042 HDL-C | ||||||||
| 0.014 TG | ||||||||
| –0.007 FFA | ||||||||
| Ahren et al. (2014) [77] (HARMONY 3) | 104 | 1,049 | Met+(Sit, SU or placebo) | 30 mg QW | –1.21a | 1.3 | –1.0 | –0.07 TC |
| –0.03 LDL-C | ||||||||
| 0.04 HDL-C | ||||||||
| –0.20 TG | ||||||||
| Weissman et al. (2014) [78] (HARMONY 4) | 52 | 779 | (Met±SU)+insulin glargine | 30 mg QW | –1.06 | 1.0 | –1.4 | –2.1 mg/dL TC |
| –1.8 mg/dL LDL-C | ||||||||
| 2.1 mg/dL HDL-C | ||||||||
| –17.3 mg/dL TG | ||||||||
| Pratley et al. (2014) [79] (HARMONY 7) | 32 | 841 | (Met, TZD, SU, or any combination)+liraglutide 1.8 mg QD | 30 mg→ 50 mg QW at week 6 | –0.64 | 5.7 at week 4 (max) | <±1.0 | Investigator-assessed cardiovascular AE: 8.2% (forliraglutide: 10.5%) |
| Returned to baseline within study period | ||||||||
| Dulaglutide | ||||||||
| Wysham et al. (2014) [80] (AWARD-1) | 52 | 976 | (Met±TZD)+(exenatide BID or placebo→dulaglutide at week 26) | 0.75 mg/day | –0.20a | 1.56 (2.80a at week 26) | 1.62 (–0.36a at week 26) | –0.09 TC |
| –0.08 LDL-C | ||||||||
| 0.00 HDL-C | ||||||||
| 0.04 TG | ||||||||
| 1.5 mg/day | –1.30a | 1.68 (2.80a at week 26) | 0.83 (0.11a at week 26) | –0.12 TC | ||||
| –0.06 LDL-C | ||||||||
| 0.05 HDL-C | ||||||||
| –0.26 TGa | ||||||||
| Giorgino et al. (2015) [81] (AWARD-2) | 78 | 810 | (Met±SU)+insulin glargine | 0.75 mg/day | –1.33a | 0.61a | –0.59 | 0.03 TC |
| –0.02 LDL-C | ||||||||
| –0.02 HDL-C | ||||||||
| 0.03 TG | ||||||||
| 1.5 mg/day | –1.87a | 1.31a | –0.70 | 0.02 TC | ||||
| 0.00 LDL-C | ||||||||
| 0.00 HDL-C | ||||||||
| 0.05 TG | ||||||||
| Umpierrez et al. (2014) [82] (AWARD-3) | 52 | 807 | None+(Met+placebo) | 0.75 mg/day+oral placebo | –1.36 at week 26 (VNR for week 52) | 1.6 | –2.7 | –1% TCa |
| –2% LDL-Ca | ||||||||
| 2% HDL-C | ||||||||
| –1% TG | ||||||||
| 1.5 mg/day+oral placebo | –2.29 at week 26 (VNR for week 52) | 1.8 | –0.1 | –2% TC | ||||
| –2% LDL-Ca | ||||||||
| 5% HDL-C | ||||||||
| –4% TG | ||||||||
| Blonde et al. (2015 )[83] (AWARD-4) | 52 | 884 | Insulin±OADs→(insulin lispro+Met)+insulin glargine | 0.75 mg/day | +0.18 at week 26 (VNR for week 52) | 2.27 | 1.04 | 0.94% TC |
| –1.02% LDL-C | ||||||||
| 3.54% HDL-Ca | ||||||||
| 5.73% TG | ||||||||
| 1.5 mg/day | –0.87 at week 26 (VNR for week 52) | 2.38a | –0.26 | 0.00% TC | ||||
| –1.95% LDL-C | ||||||||
| 2.44% HDL-Ca | ||||||||
| 2.96% TG | ||||||||
| Nauck et al. (2014) [84] (AWARD-5) | 52 | 1,098 | (None, 1, or combination of OAD)+Sit or placebo (placebo→Sit at week 26) | 0.75 mg/day | –2.60a | 2.1a | –0.5 | –0.03 TC |
| 0.02 LDL-C | ||||||||
| 0.07 HDL-C | ||||||||
| –0.15 TG | ||||||||
| 1.5 mg/day | –3.03a | 2.4a | –0.8 | –0.03 TC | ||||
| –0.06 LDL-Ca | ||||||||
| 0.05 HDL-C | ||||||||
| –0.16 TG | ||||||||
| Weinstock et al. (2015) [85] (AWARD-5 extension) | 2 years | 1,098 | (None, 1, or combination of OAD)+Sit or placebo (placebo→Sit at week 26) | 0.75 mg/day | –2.39 | 2.8a | 1.3 | No significant changes in lipids (VNR) |
| 1.5 mg/day | –2.88a | 2.3a | –0.1 | |||||
| Dungan et al. (2014) [86] (AWARD-6) | 26 | 599 | Met+liraglutide | 1.5 mg/day | –2.90 | 2.37 | –3.36 | b |
GLP-1 RA, glucagon-like peptide-1 receptor agonist; BW, body weight; HR, heart rate; BP, blood pressure; CVD, cardiovascular disease; BID, twice a day; DURATION, Diabetes therapy Utilization: Researching changes in A1c, weight and other factors Through Intervention with exenatide Once weekly; Met, metformin; SU, sulfonylurea; TZD, thiazolidinediones; QW, weekly; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; TG, triglyceride; hs-CRP, high-sensitivity C-reactive protein; LEAD, liraglutide effects and action in diabetes; FFA, free fatty acids; ApoB, apolipoprotein B; OAD, oral antidiabetic drug; Sit, sitagliptin; VNR, value not reported; BNP, B-type natriuretic peptide; QD, daily; AE, adverse event; AWARD, Assessment of Weekly Administration of LY2189265 in Diabetes-1.
aStatistically significant from comparator; bNot determined or not checked; cPerformed significantly more poorly than comparator.