Table 1.
Potential effect of anti-diabetic agents on NAFLD and cardiovascular outcomes
| Glucose-lowering agent | NAFLD | CV outcomes | ||
|---|---|---|---|---|
| Hepatic steatosis | NASH | Liver fibrosis | ||
| Metformin | Neutral | Neutral | Neutral | Reduction/neutral |
| Meta-analysis [68, 69] | Several RCTs [70,71,72,73] | Meta-analyses [68, 69] | -UKPDS [14, 74]: ↓MI Design: metformin vs conventional dietary measures Population: newly diagnosed T2DM and overweight -HOME TRIAL [75]: ↓ macrovascular events Design: metformin vs placebo Population: T2DM patients with insulin -SPREAD-DIMCAD [76]: ↓ recurrent CV events Design: metformin vs glipizide Population: T2DM with CAD -Meta-analysis [77, 78]: neutral * * ↑ CV risk when metformin is combined with sulfonylurea |
|
| DPP-4 inhibitors | Neutral/improved | Unknown | Unknown | Neutral |
|
- Neutral [79]: MRI-PDFF Design: RCT Sitagliptin vs placebo Population: Pre-T2DM or T2DM with NAFLD - Improved [80]: ↓MRI-PDFF Design: RCT vildaglitin vs placebo Population: T2DM with NAFLD |
-SAVOR-TIMI 53 [81]: neutral* Design: RCT saxagliptin vs placebo Population: T2DM with high CV risk * ↑ Hospitalizations for HF in patients with history of HF -TECOS [82]: neutral Design: RCT sitagliptin vs placebo Population: T2DM with CVD -EXAMINE [83]: neutral* Design: RCT alogliptin vs placebo Population: T2DM with CVD * ↑ HF incidence in patients already symptomatic at baseline [84] -CARMELINA [85]: neutral Design: RCT linagliptin vs placebo Population: T2DM with high CV risk -Meta-analyses [86, 87]: neutral |
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| Pioglitazone | Improved | Improved | Neutral/improved | Reduction/THF |
| Several RCTs and meta-analysis [68] | Several RCTs and meta-analysis [88] | -Neutral Several RCTs and Meta-analysis [68] -Improved* in patients with advanced fibrosis (F3F4) Meta-analysis [88] |
- PROactive [89]: neutral * Design: RCT pioglitazone vs placebo Population: T2DM with high CV risk * ↓ all-cause mortality, nonfatal MI, and stroke (secondary endpoint) -IRIS trial 2016 [90]: ↓strokes or MI Design: RCT pioglitazone vs placebo Population: non-diabetic with history of stroke or TIA - Meta-analyses: ↓MACE [91], ↑ HF incidence ↓ MACE and MI* [87], ↑ HF incidence ↓ All-cause mortality, MI or stroke [92] |
|
| GLP-1 receptor agonist | Improved | Improved | Neutral | Reduction |
|
LEAN trial: ↓hepatic steatosis in liver biopsy [93], Design: RCT liraglutide vs placebo Population: overweight patients with NASH with or without T2DM |
- LEAN trial: resolution of definite NASH with no worsening of fibrosis [93] Design: RCT liraglutide vs placebo Population: overweight patients with NASH with or without T2DM - resolution of definite NASH with no worsening of fibrosis [94] Design: semaglutide vs placebo Population: patient with NASH and fibrosis F1, F2 or F3 with or without T2DM |
Neutral: [94] Design: semaglutide vs placebo Population: patient with NASH and fibrosis F1, F2 or F3 with or without T2DM |
-LEADER [95]: ↓ 3-point MACE Design: RCT liraglutide vs placebo Population: T2DM high CV risk -SUSTAIN6 [96]: neutral* Design: RCT semaglutide vs placebo Population: T2DM with high CV risk *↓composite endpoint (CV death , nonfatal MI, stroke) -REWIND [97]: ↓composite endpoint (non fatal MI, non fatal stroke, CV death) Design: RCT dulaglutide vs placebo Population: T2DM at high CV risk -ELIXA [98]: neutral MACE Design: RCT lixisenatide versus placebo Population: T2DM with CVD -EXSCEL [99]: neutral MACE Design: RCT exenatide vs placebo Population: T2DM with or without CVD -HARMONY [100]: ↓ 3-point MACE Design: RCT albiglutide vs placebo Population: T2DM and CVD -Meta-analyses: ↓MACE in secondary CV prevention [101•: ↓ MACE , ↓ HF [87] |
|
| SGLT2 inhibitors | Neutral/improved | Unknown | Unknown | Reduction |
|
-Improved [102]: ↓MRI-PDFF Design: RCT empaglifozin vs standard of care. Population: T2DM with NAFLD -Improved [103]: ↓ MRI-PDFF Design: RCT dapagliflozin vs placebo Population: T2DM -Neutral [104]: proton-magnetic resonance spectroscopy Design: RCT canagliflozin vs placebo Population: uncontrolled T2DM |
-EMPA-REG OUTCOME [105] ↓ MACE empagliflozin vs placebo T2DM patients at high CV risk -CANVAS [106]: ↓ composite endpoint (CV death, non-fatal MI, non-fatal stroke) canagliflozin vs placebo T2DM and high CV risk -DECLARE-TMI 58 [107]: ↓CV death and HF hospitalization Dapagliflozin vs placebo T2DM with and without CVD -DAPA HF [108]: ↓composite endpoint (CV death/hospitalization or urgent visit for HF) dapagliflozin 10 mg/d vs placebo T2DM and non-diabetic patients, with HFrEF -Meta-analyses [87, 101•, 109] ↓ MACE in patients with CVD ↓ hospitalization for HF |
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MACE major adverse cardiac events, CAD coronary artery disease, CVD cardiovascular disease, HF heart failure, HFrEF heart failure and reduced ejection fraction, MI myocardial infarction, MRI-PDFF magnetic resonance imaging proton-density fat fraction, RCT randomized control trial, TIA transient ischemic attack, T2DM type 2 diabetes mellitus