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Brodosi et al. Hepatoma Res 2020;6:82 I http://dx.doi.org/10.20517/2394-5079.2020.88 Page 7 of 11

Table 2. A decalogue for safe and effective NAFLD treatment in patients with T2DM
1. Implement a systematic, intensive, continuing lifestyle intervention (healthy diet and habitual physical activity) aimed at
maintaining or slowly achieving a near-normal body weight. Physical activity is particularly needed to prevent sarcopenia
2. Carefully assess NAFLD stage by surrogate biomarkers, as well as T2DM comorbidities (cardiovascular and renal involvement).
In patients with cirrhosis determine Child-Pugh class and MELD score
3. Define treatment targets on the basis of patients’ frailty and disease severity. Although HbA1c below 6.5% (48 mmol/mol) may
be the desired target in subjects without comorbidities, in individual cases values up to 8% (64 mmol/mol) may be acceptable.
Consider that HbA1c may be unreliable in the presence of recent hemorrhage, and random glucose monitoring may be advisable
4. Background metformin (2 g/day) treatment should always be used and maintained also in compensated cirrhosis, although at
reduced doses (1-1.5 g/day), as long as compatible with gastrointestinal symptoms and renal function
5. Sulfonylureas and glinides should not be used, except as third-line therapy; they both increase the risk of hypoglycemia, and
sulfonylureas are also associated with increased cardiovascular risk
6. Add pioglitazone (30-45 mg/day) in patients not at risk of heart failure or ascites. Further intensify lifestyle intervention to
prevent weight gain
7. Add DPP4-Is to improve glucose control to near-normal glucose targets in patients without comorbidities
8. Add GLP-1RAs in patients at high risk of cardiovascular disease, including patients with previous cardiovascular events. Caution
should be used in subjects with cirrhosis at risk of bleeding
9. SGLT2-Is should be preferred in patients at risk of heart failure, as well as in patients with progressive decline of glomerular
filtration rate. Consider the risk of genitourinary infection, particularly in women and in elderly men with prostate problems
10. Avoid insulin use as long as possible, to reduce the risk of hypoglycemia and the impact on quality of life. Late insulin use may be
needed in most advanced stages; whenever possible use basal or basal-bolus regimens. Combination of basal insulin with GLP-
1RAs may be a likely option in selected cases

to lose weight for subjects with obesity - suggests that efforts should be aimed at limiting insulin use. The
use of oral DPP-4Is and, later, of weekly-injectable GLP-1RAs or SGLT-2Is in comparison to basal insulin
is under investigation [87,88] . There is evidence that early initiation of GLP-1RAs may achieve similar or even
better results than treatment with basal insulin [89,90] and the improved ease of treatment is associated with
better quality of life in advanced disease states. Fewer data are available for SGLT-2Is, but also this drug
class appears to be non-inferior to add-on basal insulin as to effectiveness and safety [91,92] .

In conclusion, we are living a totally new era in the pharmacologic treatment of type 2 diabetes and patients
with NAFLD are likely to take the greatest advantage from novel agents. The beneficial effects of GLP-1RAs
and SGLT-2Is on metabolic outcomes extend well beyond the area of diabetes, namely to obesity,
cardiovascular risk, heart failure and renal disease [93,94] , and might soon be available for NAFLD patients
outside of T2DM [95,96] .

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and interpretation: Brodosi L, Musio
A, Marchesini G, Petroni ML
Performed data acquisition, as well as provided technical, and material support: Barbanti FA, Mita D
Drafted the manuscript: Brodosi L, Marchesini G

Availability of data and materials
Not applicable.

Financial support and sponsorship
Barbanti FA is supported by a contract financed by Italian Ministry of Health and Italian Regions (NET-
2016-02364191).

Conflicts of interest
All authors declared that there are no conflicts of interest in relation to the material presented here.