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  • Review Article
  • OPEN ACCESS

Pharmacotherapy for Non-alcoholic Fatty Liver Disease Associated with Diabetes Mellitus Type 2

  • Emmanouil S. Koullias*  and
  • John Koskinas
 Author information  Cite
Journal of Clinical and Translational Hepatology   2022;10(5):965-971

doi: 10.14218/JCTH.2021.00564

Abstract

Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus type 2 commonly coexist as a manifestation of metabolic syndrome. The presence of diabetes promotes the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis, and the presence of NAFLD increases the risk of diabetic complications. This coexistence affects a large part of the population, imposing a great burden on health care systems worldwide. Apart from diet modification and exercise, recent advances in the pharmacotherapy of diabetes offer new prospects regarding liver steatosis and steatohepatitis improvement, enriching the existing algorithm and supporting a multifaceted approach to diabetic patients with fatty liver disease. These agents mainly include members of the families of glucagon-like peptide-1 analogues and the sodium-glucose co-transporter-2 inhibitors. In addition, agents acting on more than one receptor simultaneously are presently under study, in an attempt to further enhance our available options.

Graphical Abstract

Keywords

NAFLD/NASH, Diabetes mellitus type 2, Steatosis, SGLT2, GLP1

Introduction

Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus type 2 (DM2) constitute two very common entities, around the globe, being especially prevalent in the Western hemisphere. NAFLD can progress to non-alcoholic steatohepatitis (NASH) and subsequently to cirrhosis and hepatocellular carcinoma (HCC). NAFLD leads to a 2-3-fold increased risk of DM2 development,1,2 since liver fat accumulation is a crucial pathogenetic component.3 The coexistence of DM2 in a patient with NAFLD increases the risk of developing the aforementioned outcomes disproportionately and contributes to deterioration of kidney and cardiovascular functions as well.4 It is estimated that 25–35% of patients with obesity and diabetes also have NASH.5,6

It is widely recognized that obesity and insulin resistance are major determinants for the development of both DM2 and NAFLD.6 Various mechanisms could be involved, both in the early and later stages of NAFLD, from lipid metabolite accumulation and mounting oxidative stress to the release of several pro-inflammatory cytokines.6 The coexistence of underlying predisposing genes, such as PNPLA3, TM6SF2 and others, seems to increase the risk for development of DM2 as well as of NAFLD.7

The emergence of very efficient antiviral regimens for the treatment of chronic hepatitis B and C infections has brought to the forefront the need for tackling the most common and most commonly ignored NAFLD-related liver disease. Multiple therapeutic approaches are in the pipeline for NASH itself; however, while outcomes are still awaited, the treatment strategies followed for DM2 seem to provide some means to treat NASH and, certainly, prevent or improve it to some degree, by targeting the molecular mechanisms underpinning NAFLD.8,9

Current and future treatment approaches for NAFLD/NASH associated with DM2

Currently, the most effective way to improve NAFLD and NASH is through weight loss. This can be achieved through diet and lifestyle modifications, such as adoption of the Mediterranean diet/lifestyle10–12 and bariatric surgery.13–17 Several, if not all, antidiabetic medications have been utilized as possible NAFLD treatments. Metformin was a major candidate, but multiple trials showed no improvement regarding steatosis, inflammation or fibrosis, despite a significant reduction of liver enzymes;18,19 thus, this therapeutic option was rejected for NASH, despite its possible beneficial effects on HCC prevention.20 Additionally, various dipeptidyl peptidase IV inhibitors have been utilized, such as sitagliptin, which was found not to improve liver enzymes, liver fat content or liver fibrosis in patients with NAFLD.21,22 Similarly unimpressive results were published from the J-LINK study, regarding linagliptin.23 Saxagliptin was found, in a randomized trial vs. glimepiride, to exhibit encouraging results, as far as liver steatosis reduction was concerned. However, the independence of this effect this medication’s hypoglycemic action could not be established.24

On the other hand, the use of antidiabetic agents such as thiazolidinediones, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 analogues (GLP1a) are examples of pharmacologic attempts to combine glycemic control and weight loss with improvement of liver steatosis and inflammation. The efficacy of these drugs, as well as a few more under development, will be summarized and discussed in this review.

Thiazolidinediones-peroxisome proliferator-activated receptor γ (PPARγ) agonists

PPARs are nuclear hormone receptors with various functions in metabolic homeostasis, lipid metabolism, and the inflammation process. Pioglitazone (a PPARγ agonist) is an anti-diabetic medication that modulates the transcription of genes involved in glucose and lipid metabolism in the adipose tissue, muscle, and liver. Treatment with pioglitazone at 30 mg/day has led to statistically important improvement of inflammation in patients with NASH, with or without diabetes.25 It has been used successfully in the PIVENS study-National Clinical Trial number (NCT): 00063622, on non-diabetic patients with NASH. This study, which recruited 247 patients, showed that pioglitazone caused significant reductions in steatosis, inflammation, hepatocellular ballooning and improvement in insulin resistance and liver-enzyme levels, despite failing to achieve the primary outcome of improvement in standardized scoring of liver biopsies.26 Furthermore, a single-center, parallel-group, randomized, placebo-controlled study, which included 101 patients with biopsy-proven NASH and prediabetes or DM2 (NCT00994682), showed significant improvement of nonalcoholic fatty liver disease activity score in 58% of the patients in the pioglitazone group (vs. 17% in the placebo group) after 18 months of treatment. A reduction in fibrosis progression was also observed in the same group.27 This is the first antidiabetic agent to achieve relative success in treating NAFLD in both diabetic and non-diabetic patients. Currently, a randomized clinical trial (RCT) is going to examine the effect of pioglitazone and empagliflozin combination in patients with NAFLD and DM2 (NCT03646292). Pioglitazone is a cheap alternative for the treatment of NASH, with or without DM2, but must be used with caution, considering the long-term adverse effects of weight gain, osteopenia, and aggravation of congestive heart failure.28

Other PPAR agonists

Multiple agents of this family have been used in trials regarding NAFLD. The most well-known examples, apart from pioglitazone, are fenofibrate, pemafibrate, seladelpar, elafibranor and lanifibranor, which have been studied in various trials regarding their effect on liver inflammation and fibrosis, without particular success, with the exception of lanifibranor, a pan-PPAR agonist, which was shown in a phase 2b RCT (NATIVE-NCT03008070) to improve ballooning and inflammation, without worsening of fibrosis.29,30 The focus of those trials was on the presence and possible positive effects on NAFLD, irrespectively of the coexistence of DM2, although 103 out of 247 patients included in the NATIVE RCT with lanifibranor were diabetic. Further evaluation of possible NASH resolution and improvement of liver fibrosis in the case of lanifibranor will be conducted in the phase 3 study NATiV3 (NCT04849728), which will include both diabetic and non-diabetic patients, as well.

Another member of this drug family, saroglitazar, a PPARα/γ agonist, has shown promise in diabetic patients with dyslipidemia, while it has also been utilized in experimental models and clinical trials for the treatment of NASH in India,31,32 exhibiting promising results.33

GLP-1 analogues

GLP-1 is an incretin hormone that stimulates insulin secretion and inhibits glucagon secretion, after ingestion of glucose.34 Other actions include reduction of gastrointestinal motility and appetite. It is a 30-amino acid peptide produced by the intestinal epithelial endocrine L-cells and subsequently inactivated by dipeptidyl peptidase IV.34 GLP-1 analogues, with a longer duration of action than the original enzyme, offer a potent option for the treatment of DM2. Numerous drugs of this class have been developed in recent years, including exenatide, lixisenatide, dulaglutide, liraglutide and semaglutide. As far as NASH is concerned, liraglutide has been most studied, demonstrating significant improvement of steatohepatitis (histological resolution of NASH in 39% of the patients in the treatment group vs. 9% in the placebo group) and reduced frequency of progression of fibrosis during the phase 2 RCT (LEAN study-NCT01237119), irrespectively of the presence of diabetes mellitus (9% of patients in the treatment group exhibited worsening of fibrosis vs. 36% in the placebo group).35 Furthermore, the RCT LIGHT-ON (NCT02147925) compared the effect of liraglutide, sitagliptin and insulin glargine, when added to metformin in diabetic patients, exhibiting statistically significant results, in favor of liraglutide and sitagliptin, regarding body weight, visceral adipose tissue and liver fat content reduction.36 Liraglutide seems to offer a body-weight loss of 4–6 kg compared to placebo,37 while the protective effect on cardiovascular outcomes (lower rates of myocardial infarction, stroke and death) is notable,38 as is the lower rates of diabetes nephropathy development and progression.39 As shown in the LEADER study (NCT01179048), the secondary composite outcome of persistent doubling of the serum creatinine level, new-onset persistent macroalbuminuria, end-stage renal disease or death due to renal disease occurred significantly less frequently in the treatment group than in the placebo group, with a hazard ratio of 0.78.39

Dulaglutide is currently being tested in the single-blind RCT REALIST (NCT03648554) in patients with NASH and DM2. Patients will be randomized to receive either dulaglutide at 1.5 mg in combination with dietary monitoring or dietary monitoring alone for 52 weeks. The primary outcome consists of histological improvement of NASH (≥2 points of NASH activity score). An additional study will assess the combined effect of dulaglutide and empagliflozin on noninvasive liver steatosis and fibrosis markers on patients with NAFLD and DM2 (NCT05140694).

Similarly, a recently approved antidiabetic agent of the same drug family, semaglutide, has been assessed in a double-blind phase 2 RCT in 320 patients with NASH without DM2, given subcutaneously once daily, at various doses, for 72 weeks (NCT02970942). Semaglutide proved to be significantly superior to placebo, as far as resolution of NASH was concerned (59% achieved this outcome in the maximum dose group vs. 17% in the placebo group), but without achieving improvement of fibrosis.40 A dose-dependent pattern of body-weight reduction was observed, with the patients receiving the maximum dose of 0.4mg per day achieving a mean 13% weight loss, while the Placebo group exhibited a mean loss of 1%. Two phase 3 RCTs (STEP1 and STEP 2) regarding overweight or obese patients with diabetes mellitus, proved that semaglutide 2.4mg subcutaneously weekly was superior to placebo, as far as body-weight reduction is concerned,41,42 while similar results were derived from another phase 3 trial, comparing oral semaglutide with liraglutide in diabetic overweight patients, where semaglutide achieved significantly greater weight reduction than liraglutide or placebo (NCT02863419-PIONEER 4).43 On the same note, semaglutide was deemed superior to dulaglutide in a phase 3 open-label trial (SUSTAIN 7) regarding weight and glycated hemoglobin (HbA1c) reduction in diabetic patients.44 Due to these promising results, as well as its established cardiovascular safety,42,45 investigational interest around this agent is intense, with multiple randomized trials exploring its effects on liver fibrosis and steatosis of diabetic and nondiabetic patients, when administered alone, in combination or in comparison with other agents, such as empagliflozin (on diabetics-NCT04639414), efinopegdutide (on diabetics and non-diabetics-NCT04944992), cilofexor and firsocostat (on diabetics and non-diabetics-NCT04971785). The largest one is a phase 3, double-blind trial, by Novo Nordisk, aspiring to recruit 1,200 patients with NASH, with or without DM2, expected to be completed in 2028 (NCT04822181).

Experimental agents

GLP-1/glucagon receptor (GLP1R/GCR) and GLP-1/glucose-dependent insulinotropic peptide receptor (GLP1R/GIPR) dual agonists

Various drugs, as noted above, originally created for the treatment of DM2, have shown promise for the treatment of NAFLD and NASH, due to their metabolic effects in lipid and glucose metabolism. Following the same principle, a more recent example is the development of GLP1R/GCR dual agonists,46 such as MEDI0382 (cotadutide) or oxyntomodulin. The latter, a peptide secreted by the L-cells of the digestive track, has shown greater potency regarding weight loss, fatty acid oxidation, liver steatosis and anti-hyperglycemic activity compared to equal GLP1R agonism in obese mice.47 MOD-6031, a long-acting, pegylated molecule of oxyntomodulin, has been tested in a phase 1 single-blinded RCT (NCT02692781) on overweight or obese patients, but further investigations have not taken place. On the other hand, MEDI0382 has been more extensively examined in multiple phase 2 RCTs, on diabetic obese patients, exhibiting significant reductions in blood glucose and body weight,48–50 alone or in combination with other antihyperglycemic agents (NCT02548585, NCT03444584, NCT03645421, NCT03244800, NCT03235050, NCT03745937, NCT03596177, NCT04019561). Further evaluation in patients with NAFLD/NASH is warranted, with outcome measures such as steatosis or inflammation reduction. SAR425899, which has yielded early promising results regarding weight and hyperglycemia,51,52 has undergone a phase 2 study, where it was administered in combination with metformin vs, placebo plus metformin and liraglutide plus metformin, in diabetic obese patients (NCT02973321). Another GLP1R/GCR dual agonist, named BI456906, is going to be tested in a phase 2 RCT in patients with NASH with or without diabetes (NCT04771273). Additionally, other molecules, such as pegapamodutide and efinopegdutide (GLP1R/GCR agonists), among others, are under study, for possible application in NASH and DM2 patients.53

Finally, tirzepatide is a GLP1R/GIPR dual agonist, currently being evaluated in phase 3 trials; in diabetic patients, alone or in combination with other agents, such as SGLT2 agonists and metformin, or vs. insulin glargine, insulin degludec or a GLP1R agonist (GLP1Ra) (SURPASS program: NCT03861039, NCT03861052, NCT03954834, NCT04039503, NCT04093752, NCT03987919, NCT03730662, NCT03882970) and in obese but not diabetic patients (SURMOUNT-1, NCT04184622). The primary outcomes are HbA1c and body-weight reduction, respectively, seeking to confirm the impressive results of phase 2 studies,54 especially in comparison with established treatments such as dulaglutide and semaglutide. This drug, with promising results for NASH-related biomarkers,55 is under evaluation in a phase 2 study (SYNERGY-NASH, NCT04166773), with the primary outcome being the absence of NASH and no worsening of fibrosis on liver histology after 1 year of treatment. Recruitment addresses patients with or without DM2.

SGLT2 inhibitors

The SGLT2i family represents anti-hyperglycemic agents acting independently of insulin. Their effectiveness, regarding reduction of hyperglycemia, has been demonstrated in multiple trials and the class is extensively utilized in the treatment of patients with DM2 and cardiovascular disease.56–59 The currently approved drugs are empagliflozin, dapagliflozin, ertugliflozin, tofogliflozin, and canagliflozin. Inhibition of SGLT2 emerges as a potential approach for NAFLD/NASH treatment both by reduction of hyperglycemia and body weight and, possibly, through reduction of oxidative stress and inflammation.60–63 Members of the SGLT2i family exhibit cardioprotective effects for patients with atherosclerotic cardiovascular disease. This was shown by the reduced rate of relevant events in large studies, such as the EMPA-REG OUTCOME, among others.64 Similar results of significant reduction in a composite of cardiovascular death or heart failure-associated hospitalization of patients, with or without diabetes, receiving an SGLT2i, were observed in the EMPEROR-Reduced, EMPEROR-Preserved (empagliflozin) and the DAPA-HF (dapagliflozin) studies.65–67 Furthermore, these agents have been shown to exhibit renal benefits in patients with chronic kidney disease.68,69 Therefore, an extra incentive exists for using them in patients suffering from multiple comorbidities.

Regarding NAFLD, empagliflozin, in particular, has shown positive effects regarding liver fat content, as measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) and Control Attenuation Parameter (CAP),60,61 and liver fibrosis, as measured by liver stiffness determination63 and various indexes, such as the FIB4 index and NAFLD fibrosis score.70 Of note is that the benefits of this agent were shown both in diabetic and non-diabetic patients.

The combination of this particular class with thiazolidinediones presents an interesting concept, currently under trial in a phase-4, open-label study, where empagliflozin is being evaluated alone and in conjunction with pioglitazone on diabetic patients, with the primary outcome being the measurement of liver fat content by MRI-PDFF (NCT03646292). It has already been mentioned that empagliflozin is currently being studied as adjunct to GLP1a, as well as tirzepatide.

Another drug of this class, dapagliflozin, is being examined in the DEAN trial, a phase 3 RCT addressing NASH in patients with DM2. A Japanese open-label trial, with dapagliflozin, showed positive effects regarding steatosis and fibrosis, measured with non-invasive techniques, through liver stiffness measurement (especially in patients with stiffness equal or greater than 8 kPa),71 while similar results were reported from the double-blind EFFECT-II study (NCT02279407).72 Both studies addressed only patients with DM2.

Lastly, tofogliflozin treatment was associated with reduction of liver steatosis, as measured by MRI-PDFF, in a Japanese randomized open-label trial (ToPiND study) that compared it with pioglitazone treatment in diabetics. Patients that took tofogliflozin exhibited weight and liver fat content reduction, although steatosis improvement was greater in the pioglitazone group.73 Tofogliflozin was also selected for a phase 4 trial, vs. glimepiride, where the improvement in histological features of NAFLD in diabetic patients will be measured (NCT02649465). Results from this trial have not yet been published.74 Histologically proven improvement of fibrosis has not yet been presented.

Conclusions and thoughts for the future of NASH treatment in diabetic patients

The current scarcity of effective treatments for NASH in combination with its rising prevalence worldwide led to an extraordinary interest for related research. An exponentially expanding discovery of lipid metabolism mechanisms contributed to the development of multiple candidate drugs under trial in various populations with NASH. The available approaches focus on metabolic pathway modifiers (e.g., the Farnesoid X-receptor agonists obeticholic acid and cilofexor, the acetyl-CoA carboxylase inhibitor firsocostat, the PPAR agonist elafibranor) on the one hand, and agents with anti-inflammatory and/or antifibrotic action (e.g., the CCR2/5 inhibitor cenicriviroc and the ASK-1 inhibitor selonsertib) on the other.

However, none have yet been approved for the treatment of NASH, while many others have already been deemed ineffective (e.g., elafibranor, seladelpar, emricasan, selonsertib and elobixibat). Despite high hopes that new agents will soon be added to the few available drugs for the treatment of NASH, antidiabetic agents remain the sole alternative, apart from vitamin E, offering a multi-target and relatively effective approach to the treatment of patients with both NAFLD/NASH and DM2.

For the time being, the proposed treatment algorithm for patients with DM2 and NAFLD/NASH focuses on caloric restriction, especially those acquired by ingestion of fructose and alcohol, and initiation of aerobic exercise, targeting an overall body-weight reduction of 7–10%. Treatment with pioglitazone is a logical approach in patients with histologically proven NASH; however, it is associated with weight gain and deterioration of congestive heart failure. The emergence of the most effective GLP1Ra and the SGLT2i agents offers a safer approach in tackling patients with NAFLD and DM2 (Tables 1 and 2), through a variety of molecular mechanisms (Fig. 1).75–78 Treatment with a combination of these agents, as add-on to metformin, along with proper control of cardiovascular risk factors (e.g., hypertension, hyperlipidemia and smoking), is widely adopted for overweight diabetic patients who are diagnosed with a fatty liver, even more when their cardioprotective effects are taken into account.79 Efficient control of DM2 along with their effect on body mass index reduction and improvement of liver steatosis and steatohepatitis make them, for nonce, very attractive.

Table 1

Suggested algorithm for medical treatment of diabetic patients with NAFLD/NASH

1. Baseline CBC, LFTs, INR, Cr, U, HbA1c, liver U/S, FibroScan
2. Avoidance of alcohol
3. Caloric restriction (especially fructose) and aerobic exercise, e.g., by adopting the Mediterranean diet/lifestyle (target body-weight loss: 7–10%)
4. Initiation of drugs
  A. GLP1Ra (e.g., liraglutide or semaglutide, especially on patients with CVD) as add-on to metformin, or
  B. SGLT2i (e.g., empagliflozin, especially on patients with HF or CVD) as add-on to metformin, or
  C. Both GLP1Ra and SGLT2i
  D. Pioglitazone as an alternative or add-on, in selected patients, without osteopenia/osteoporosis or CHF
5. Regular follow-up every 3 months until diabetes control and target weight loss achievement
6. Consider enrollment in clinical trial involving dual GLP1R/GCPR or GLP1R/GIPR agonists
7. If target weight is unachievable, consider bariatric surgery for patients with BMI >30 kg/m2

BMI, body mass index; CBC, complete blood cell count; CHF, congestive heart failure; Cr, creatinine; CVD, cardiovascular disease; HF, heart failure; INR, international normalized ratio; LFTs, liver function tests; U, urea; U/S, ultrasound.

Table 2

Proposed and experimental drugs for patients with DM2 and NAFLD/NASH

DrugMechanism of actionEffect as shown from trials so far
PioglitazonePPARγ agonistReduction of steatosis and inflammation
SaroglitazarPPARα/γ agonistReduction of steatosis and inflammation
LanifibranorpanPPAR agonistReduction of steatosis and inflammation
EmpagliflozinSGLT2iReduction of steatosis, possible positive effect on fibrosis
DapagliflozinSGLT2iReduction of steatosis, possible positive effect on fibrosis
TofogliflozinSGLT2iReduction of steatosis
DulaglutideGLP1aUnder investigation
LiraglutideGLP1aReduction of steatosis and inflammation, possible positive effect on fibrosis
SemaglutideGLP1aReduction of steatosis and inflammation
Experimental agents
  TirzepatideGLP1R/GIPR dual agonistPossible reduction of steatosis and inflammation
  MEDI0382GLP1R/GCR dual agonistFurther evaluation in NASH warranted
  BI456906GLP1R/GCR dual agonistFurther evaluation in NASH warranted
Examples of possible mechanisms of NAFLD amelioration through current antidiabetic treatment.
Fig. 1  Examples of possible mechanisms of NAFLD amelioration through current antidiabetic treatment.75-78

AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; FAO, fatty acid oxidation; HSL, hormone-sensitive lipase; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; TG, triglycerides; TNF-α, tumor necrosis factor-alpha.

Abbreviations

DM2: 

diabetes mellitus type 2

GCR: 

glucagon receptor

GIPR: 

glucose-dependent insulinotropic peptide receptor

GLP-1a: 

glucagon-like peptide-1 analogues

HbA1c: 

glycated hemoglobin

HCC: 

hepatocellular carcinoma

MRI-PDFF: 

Magnetic Resonance Imaging-Proton Density Fat Fraction

NAFLD: 

Non-alcoholic fatty liver disease

NASH: 

non-alcoholic steatohepatitis

NCT: 

National Clinical Trial number

PPAR: 

Peroxisome Proliferator-Activated Receptor

RCT: 

randomized clinical trial

SGLT-2i: 

sodium-glucose co-transporter-2 inhibitors

Declarations

Funding

None to declare.

Conflict of interest

JK has been an editorial board member of Journal of Clinical and Translational Hepatology since 2018. ESK has no conflict of interests related to this publication.

Authors’ contributions

Both authors contributed equally as far as the conception of the article is concerned. Furthermore, the authors participated equally in the relevant research, the drafting of the manuscript and the requested revisions. In conclusion, both authors had an important part in this review and have approved of the final manuscript.

References

  1. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options. JHEP Rep 2019;1(4):312-328 View Article PubMed/NCBI
  2. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol 2021;18(9):599-612 View Article PubMed/NCBI
  3. Radaelli MG, Martucci F, Perra S, Accornero S, Castoldi G, Lattuada G, et al. NAFLD/NASH in patients with type 2 diabetes and related treatment options. J Endocrinol Invest 2018;41(5):509-521 View Article PubMed/NCBI
  4. Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007;191(2):235-240 View Article PubMed/NCBI
  5. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019;71(4):793-801 View Article PubMed/NCBI
  6. Younossi ZM, Tampi RP, Racila A, Qiu Y, Burns L, Younossi I, et al. Economic and Clinical Burden of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes in the US. Diabetes Care 2020;43(2):283-289 View Article PubMed/NCBI
  7. Eslam M, George J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology. Nat Rev Gastroenterol Hepatol 2020;17(1):40-52 View Article PubMed/NCBI
  8. Yu X, Hao M, Liu Y, Ma X, Lin W, Xu Q, et al. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol 2019;864:172715 View Article PubMed/NCBI
  9. Blazina I, Selph S. Diabetes drugs for nonalcoholic fatty liver disease: a systematic review. Syst Rev 2019;8(1):295 View Article PubMed/NCBI
  10. Martín-Peláez S, Fito M, Castaner O. Mediterranean Diet Effects on Type 2 Diabetes Prevention, Disease Progression, and Related Mechanisms. A Review. Nutrients 2020;12(8):E2236 View Article PubMed/NCBI
  11. Plaz Torres MC, Aghemo A, Lleo A, Bodini G, Furnari M, Marabotto E, et al. Mediterranean Diet and NAFLD: What We Know and Questions That Still Need to Be Answered. Nutrients 2019;11(12):E2971 View Article PubMed/NCBI
  12. Anania C, Perla FM, Olivero F, Pacifico L, Chiesa C. Mediterranean diet and nonalcoholic fatty liver disease. World J Gastroenterol 2018;24(19):2083-2094 View Article PubMed/NCBI
  13. Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 2017;67(4):829-846 View Article PubMed/NCBI
  14. van der Windt DJ, Sud V, Zhang H, Tsung A, Huang H. The Effects of Physical Exercise on Fatty Liver Disease. Gene Expr 2018;18(2):89-101 View Article PubMed/NCBI
  15. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients. Gastroenterology 2015;149(2):379-388 View Article PubMed/NCBI
  16. Laursen TL, Hagemann CA, Wei C, Kazankov K, Thomsen KL, Knop FK, et al. Bariatric surgery in patients with non-alcoholic fatty liver disease - from pathophysiology to clinical effects. World J Hepatol 2019;11(2):138-149 View Article PubMed/NCBI
  17. Tan CH, Al-Kalifah N, Ser KH, Lee YC, Chen JC, Lee WJ. Long-term effect of bariatric surgery on resolution of nonalcoholic steatohepatitis (NASH): An external validation and application of a clinical NASH score. Surg Obes Relat Dis 2018;14(10):1600-1606 View Article PubMed/NCBI
  18. Li Y, Liu L, Wang B, Wang J, Chen D. Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomed Rep 2013;1(1):57-64 View Article PubMed/NCBI
  19. Zhang Y, Wang H, Xiao H. Metformin Actions on the Liver: Protection Mechanisms Emerging in Hepatocytes and Immune Cells against NASH-Related HCC. Int J Mol Sci 2021;22(9):5016 View Article PubMed/NCBI
  20. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67(1):328-357 View Article PubMed/NCBI
  21. Zhang Y, Cai T, Zhao J, Guo C, Yao J, Gao P, et al. Effects and Safety of Sitagliptin in Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Horm Metab Res 2020;52(7):517-526 View Article PubMed/NCBI
  22. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016;65(2):369-376 View Article PubMed/NCBI
  23. Komorizono Y, Hosoyamada K, Imamura N, Kajiya S, Hashiguchi Y, Ueyama N, et al. Metformin dose increase versus added linagliptin in non-alcoholic fatty liver disease and type 2 diabetes: An analysis of the J-LINK study. Diabetes Obes Metab 2021;23(3):832-837 View Article PubMed/NCBI
  24. Li JJ, Zhang P, Fan B, Guo XL, Zheng ZS. The efficacy of saxagliptin in T2DM patients with non-alcoholic fatty liver disease: preliminary data. Rev Assoc Med Bras (1992) 2019;65(1):33-37 View Article PubMed/NCBI
  25. Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, et al. Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Clin Gastroenterol Hepatol 2018;16(4):558-566.e2 View Article PubMed/NCBI
  26. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685 View Article PubMed/NCBI
  27. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med 2016;165(5):305-315 View Article PubMed/NCBI
  28. Shah P, Mudaliar S. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 2010;9(2):347-354 View Article PubMed/NCBI
  29. Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S, et al. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther 2021;54(7):880-889 View Article PubMed/NCBI
  30. Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med 2021;385(17):1547-1558 View Article PubMed/NCBI
  31. Joshi SR. Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin Pharmacother 2015;16(4):597-606 View Article PubMed/NCBI
  32. Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, et al. Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int 2018;38(6):1084-1094 View Article PubMed/NCBI
  33. Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology 2021;74(4):1809-1824 View Article PubMed/NCBI
  34. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87(4):1409-1439 View Article PubMed/NCBI
  35. Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016;387(10019):679-690 View Article PubMed/NCBI
  36. Yan J, Yao B, Kuang H, Yang X, Huang Q, Hong T, et al. Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Hepatology 2019;69(6):2414-2426 View Article PubMed/NCBI
  37. Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract 2017;3(1):3-14 View Article PubMed/NCBI
  38. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375(4):311-322 View Article PubMed/NCBI
  39. Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med 2017;377(9):839-848 View Article PubMed/NCBI
  40. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021;384(12):1113-1124 View Article PubMed/NCBI
  41. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021;384(11):989 View Article PubMed/NCBI
  42. Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397(10278):971-984 View Article PubMed/NCBI
  43. Pratley R, Amod A, Hoff ST, Kadowaki T, Lingvay I, Nauck M, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet 2019;394(10192):39-50 View Article PubMed/NCBI
  44. Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018;6(4):275-286 View Article PubMed/NCBI
  45. Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381(9):841-851 View Article PubMed/NCBI
  46. Zhou J, Cai X, Huang X, Dai Y, Sun L, Zhang B, et al. A novel glucagon-like peptide-1/glucagon receptor dual agonist exhibits weight-lowering and diabetes-protective effects. Eur J Med Chem 2017;138:1158-1169 View Article PubMed/NCBI
  47. Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009;58(10):2258-2266 View Article PubMed/NCBI
  48. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L, et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 2018;391(10140):2607-2618 View Article PubMed/NCBI
  49. Nahra R, Wang T, Gadde KM, Oscarsson J, Stumvoll M, Jermutus L, et al. Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study. Diabetes Care 2021;44(6):1433-1442 View Article PubMed/NCBI
  50. Asano M, Sekikawa A, Kim H, Gasser RA, Robertson D, Petrone M, et al. Pharmacokinetics, safety, tolerability and efficacy of cotadutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, in phase 1 and 2 trials in overweight or obese participants of Asian descent with or without type 2 diabetes. Diabetes Obes Metab 2021;23(8):1859-1867 View Article PubMed/NCBI
  51. Visentin R, Schiavon M, Göbel B, Riz M, Cobelli C, Klabunde T, et al. Dual glucagon-like peptide-1 receptor/glucagon receptor agonist SAR425899 improves beta-cell function in type 2 diabetes. Diabetes Obes Metab 2020;22(4):640-647 View Article PubMed/NCBI
  52. Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, et al. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab 2019;21(1):120-128 View Article PubMed/NCBI
  53. Jepsen MM, Christensen MB. Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs 2021;26(3):231-243 View Article PubMed/NCBI
  54. Min T, Bain SC. The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Diabetes Ther 2021;12(1):143-157 View Article PubMed/NCBI
  55. Hartman ML, Sanyal AJ, Loomba R, Wilson JM, Nikooienejad A, Bray R, et al. Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes. Diabetes Care 2020;43(6):1352-1355 View Article PubMed/NCBI
  56. Simes BC, MacGregor GG. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician’s Guide. Diabetes Metab Syndr Obes 2019;12:2125-2136 View Article PubMed/NCBI
  57. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377(7):644-657 View Article PubMed/NCBI
  58. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373(22):2117-2128 View Article PubMed/NCBI
  59. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380(4):347-357 View Article PubMed/NCBI
  60. Raj H, Durgia H, Palui R, Kamalanathan S, Selvarajan S, Kar SS, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: A systematic review. World J Diabetes 2019;10(2):114-132 View Article PubMed/NCBI
  61. Kuchay MS, Krishan S, Mishra SK, Farooqui KJ, Singh MK, Wasir JS, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care 2018;41(8):1801-1808 View Article PubMed/NCBI
  62. Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: A common comorbidity associated with severe complications. Diabetes Metab 2019;45(3):213-223 View Article PubMed/NCBI
  63. Taheri H, Malek M, Ismail-Beigi F, Zamani F, Sohrabi M, Reza Babaei M, et al. Effect of Empagliflozin on Liver Steatosis and Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease Without Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial. Adv Ther 2020;37(11):4697-4708 View Article PubMed/NCBI
  64. Rabizadeh S, Nakhjavani M, Esteghamati A. Cardiovascular and Renal Benefits of SGLT2 Inhibitors: A Narrative Review. Int J Endocrinol Metab 2019;17(2):e84353 View Article PubMed/NCBI
  65. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med 2021;385(16):1451-1461 View Article PubMed/NCBI
  66. Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, et al. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation 2021;143(4):326-336 View Article PubMed/NCBI
  67. Kosiborod MN, Jhund PS, Docherty KF, Diez M, Petrie MC, Verma S, et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation 2020;141(2):90-99 View Article PubMed/NCBI
  68. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393(10166):31-39 View Article PubMed/NCBI
  69. Li N, Lv D, Zhu X, Wei P, Gui Y, Liu S, et al. Effects of SGLT2 Inhibitors on Renal Outcomes in Patients With Chronic Kidney Disease: A Meta-Analysis. Front Med (Lausanne) 2021;8:728089 View Article PubMed/NCBI
  70. Chehrehgosha H, Sohrabi MR, Ismail-Beigi F, Malek M, Reza Babaei M, Zamani F, et al. Empagliflozin Improves Liver Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Diabetes Ther 2021;12(3):843-861 View Article PubMed/NCBI
  71. Shimizu M, Suzuki K, Kato K, Jojima T, Iijima T, Murohisa T, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab 2019;21(2):285-292 View Article PubMed/NCBI
  72. Eriksson JW, Lundkvist P, Jansson PA, Johansson L, Kvarnström M, Moris L, et al. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study. Diabetologia 2018;61(9):1923-1934 View Article PubMed/NCBI
  73. Yoneda M, Honda Y, Ogawa Y, Kessoku T, Kobayashi T, Imajo K, et al. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial. BMJ Open Diabetes Res Care 2021;9(1):e001990 View Article PubMed/NCBI
  74. Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, et al. Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Diabetes Ther 2020;11(2):549-560 View Article PubMed/NCBI
  75. Wang XC, Gusdon AM, Liu H, Qu S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J Gastroenterol 2014;20(40):14821-14830 View Article PubMed/NCBI
  76. Kontana A, Tziomalos K. Role of sodium-glucose co-transporter-2 inhibitors in the management of nonalcoholic fatty liver disease. World J Gastroenterol 2019;25(28):3664-3668 View Article PubMed/NCBI
  77. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, et al. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne) 2021;12:721135 View Article PubMed/NCBI
  78. Czaja MJ. Pioglitazone: more than just an insulin sensitizer. Hepatology 2009;49(5):1427-1430 View Article PubMed/NCBI
  79. Palmer SC, Tendal B, Mustafa RA, Vandvik PO, Li S, Hao Q, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. BMJ 2021;372:m4573 View Article PubMed/NCBI
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  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

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Pharmacotherapy for Non-alcoholic Fatty Liver Disease Associated with Diabetes Mellitus Type 2

Emmanouil S. Koullias, John Koskinas
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