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Kalloo et al. Metab Target Organ Damage 2023;3:7 https://dx.doi.org/10.20517/mtod.2022.26 Page 7 of 19

reductions than sitagliptin and was similarly tolerated by participants [11,12] . Other trials such as PRoACTIVE
suggest there may be some benefit in CV disease - in this trial, pioglitazone compared to placebo resulted in
a reduced composite endpoint of all-cause mortality, nonfatal myocardial infarction and stroke in patients
[13]
with type 2 diabetes at high risk of macrovascular events . Additionally, the Insulin Resistance
Intervention after Stroke (IRIS) trial, which assessed patients with insulin resistance (based on HOMA-IR
[14]
index), found those on pioglitazone had a lower risk of stroke or myocardial infarction . However, given
the stronger data for SGLT2s and GLP-1s in these areas, specifically with cardiac outcomes but less so with
cerebrovascular (given the lack of clear benefit with SGLT-2 inhibitors on stroke outcomes and the
secondary analyses of GLP-1 outcome trials), pioglitazone remains overlooked to some extent in recent
guidelines.

One area where they remain an attractive option and perhaps have stronger data is in those with fatty liver
disease. Data suggest that pioglitazone improves liver function tests, steatosis, inflammation and ballooning
grade in those with pre-diabetes or diabetes and NAFLD . Reversal of lipotoxicity with pioglitazone
[15]
leading to significant histological improvement has the potential to modify the natural history of the disease
and data also suggest potential benefit in non-diabetic patients - though that is beyond the scope of this
article .With the recent increased awareness about the prevalence and impact of NAFLD in those with
[16]
type 2 diabetes and suggestions for screening, it may be that in the near future the use of pioglitazone may
increase. Though, with upcoming trials with incretin molecules in NAFLD (discussed below), there may be
competition for pioglitazone in this area.

DPP4 inhibitors, the first oral medication after metformin that did not cause weight gain or increase
hypoglycaemia risk, were accepted fairly well into clinical practice; however, they were also limited by their
limitation beyond glucocentric efficacy and acquisitional cost. However, with patents due to expire for some
DPP4 inhibitor molecules and together with data from the VERIFY trial highlighting benefits of dual
initiation with metformin (higher percentage of participants achieving target Hba1c compared to
monotherapy), the use of DPP4 inihibitors may start to rise. This may result in increased use of
combination metformin/DPP4 as the first line for glucose lowering in order to rapidly achieve glycaemic
targets, especially in countries where SGLT2s or the higher cost of GLP-1s limit their utilization. Currently,
their role has been highlighted in those where hypoglyacemia is a concern, such as in the ADA-EASD
consensus or, more specifically, in frail older adults where their reasonable efficacy balanced with the
favourable side effect and tolerability profile make them an ideal consideration . Although promising
[18]
benefits, it must be noted that the US Food and Drug Administration has issued a warning about an
increased risk of serious heart failure events for both saxagliptin and alogliptin; therefore, in the older
[19]
individual, assessing such risks together with the choice of medication used should be considered .
SGLT2 INHIBITORS
SGLT2 inhibitors have changed the way type 2 diabetes has been managed, not just from a glycaemic
perspective, but since the cardiovascular outcome trials showed benefits not just from composite
cardiovascular outcomes but also secondary outcome findings of reductions in hospitalization for heart
failure and prevention of deterioration in Egfr [20-22] . Recent trials such as DAPA-HF and EMPEROR-
Reduced have moved SGLT2s from solely glucose-lowering medications to heart failure medications
(specifically reduced ejection fraction) with reductions in hospitalization for heart failure, improved quality
of life and CV mortality [23,24] . Similar trials such as CREDENCE and DAPA-CKD have highlighted the
benefits in chronic kidney disease (in those with and without type 2 diabetes) with prevention of eGFR
deterioration and composite renal outcomes [25,26] . There is clear evidence for the class in heart failure and/or
CKD; however, there remain a few considerations for SGLT2 inhibitors that may further develop.