‘SGLT2i+TZD promising for diabetics with fatty liver risk’

Cheol-Young Park, Professor of Endocrinology at Kangbuk Samsung Hospital

”Followed 500,000 diabetes patients in Korea... Mortality risk increases by 1.2 times when accompanied by liver disease“

”Fatty liver causes metabolic dysfunction in the body... Exacerbates diabetes and increases the risk of cardiovascular disease”

“SGLT2i+TZD combination is a promising treatment option for diabetes patients with metabolic dysfunction–associated steatotic liver disease"

A large-scale epidemiological study conducted on a Korean population has found that metabolic dysfunction-associated steatotic liver disease (MASLD), which commonly accompanies diabetes, increases the risk of cardiovascular disease and mortality.

 

MASLD is not merely a liver disease but a cause that exacerbates overall metabolic disorders, making it a focus of recent attention.

 

As a result, proactive treatment strategies to address it early are gaining prominence.

 

Professor Cheol-Young Park of the Endocrinology Department at Gangnam Samsung Hospital said, “Combining SGLT-2 inhibitors and TZD-class diabetes medications early on could be a promising treatment option for diabetes patients with MASLD.

 

This combination therapy not only improves blood sugar control but also regulates lipid metabolism and insulin resistance, while also mitigating the side effects of each medication.” A follow-up study on 500,000 diabetes patients revealed that those with MASLD had a 1.2-fold increased risk of death.

 

Professor Cheol-Young Park, along with Professor Kyung Soo Kim from Bundang Cha Hospital, Professor Sangmo Hong of Hanyang University Guri Hospital, and Professor Kyung-do Han of Soongsil University, conducted a large-scale epidemiological study to examine the correlation between MASLD, cardiovascular disease, and mortality in patients with Type 2 diabetes.

 

MASLD is a condition previously known as non-alcoholic fatty liver disease (NAFLD).

 

It refers to the accumulation of fat in the liver in the presence of metabolic abnormalities (such as diabetes, hyperlipidemia, and obesity), regardless of alcohol consumption.

 

It is not merely a liver disease but is considered a manifestation of systemic metabolic issues and is associated with cardiovascular disease, kidney disease, and certain cancers.

 

Professor Cheol-Young Park’s team conducted a follow-up study on 500,000 patients with type 2 diabetes among 7.7 million participants in the National Health Insurance Service's health screening program in 2009.

 

The results showed that patients with diabetes and MASLD had a 1.37 times higher risk of developing major cardiovascular diseases such as myocardial infarction and ischemic stroke.

 

The risk of death from all causes also increased significantly by 1.21 times.

 

This trend was consistently observed even in those with mild NAFLD (grade 1).

 

In patients with NAFLD but without diabetes, the absolute risk of developing cardiovascular disease within 5 years was 1.23% to 1.42%.

 

In contrast, patients with NAFLD and diabetes had a significantly higher absolute risk of developing cardiovascular disease within five years, ranging from 3.34% to 4.66%.

 

The risk of death also showed a similar trend.

 

Professor Cheol-Young Park explained, “This study shows that MASLD does not simply affect liver health, but also has a significant impact on overall cardiovascular outcomes.

 

In particular, the results showing that patients with diabetes and NAFLD have a higher risk of cardiovascular disease and death highlight the importance of treating both conditions together.” “SGLT2i+TZD combination, a promising option for treating MASLD in patients with diabetes” Regarding these complex metabolic disorders, Professor Park proposed the SGLT-2 inhibitors and TZD drug combination as a promising treatment strategy.

 

The two drugs have complementary effects in alleviating insulin resistance and reducing fat accumulation in the liver through different mechanisms.

 

TZD class drugs promote the differentiation of subcutaneous adipocytes, redistribute fat from visceral depots, suppress hepatic glucose production, and enhance glucose uptake in muscle and adipose tissue, thereby improving insulin sensitivity.

 

SGLT-2 inhibitors induce energy loss by excreting glucose through the kidneys, thereby indirectly promoting fat oxidation and reducing liver fat.

 

Professor Park explained, “TZDs redistribute fat outside the liver to reduce fat accumulation within the liver, while SGLT-2 inhibitors reduce blood glucose levels and encourage the use of fat as an energy source.

 

When used in combination, they regulate the metabolic environment through different pathways, producing a synergistic effect in improving MASLD.” Furthermore, Professor Park emphasized that the combination of the two drugs has the potential to offset each drug’s side effects.

 

TZD-class drugs are associated with side effects such as weight gain and edema.

 

In this context, the weight-reducing and diuretic effects of SGLT-2 inhibitors can partially offset these side effects.

 

Additionally, by fundamentally improving insulin resistance, they reduce the burden on insulin-secreting cells (β-cells), thereby alleviating hyperinsulinemia and potentially contributing to reduced insulin dependence in the long term.

 

Professor Park added, “Combination therapy is an integrated strategy that can regulate not only blood sugar levels but also lipid metabolism, insulin resistance, weight, and lipid status.

 

It is necessary to consider this treatment approach early on for patients with both diabetes and MASLD.

 

“MASLD, a key risk factor for cardiovascular disease… Early use of combination therapy required to improve prognosis” Professor Park explained that considering the high prevalence of MASLD in Korea, early combination therapy is important for patients with both diabetes and MASLD.

 

He emphasized that since MASLD is not merely an indicator of liver health but also increases the risk of metabolic disorders and cardiovascular disease, an integrated management approach is required from early on.

 

MASLD is deeply associated with various metabolic abnormalities such as insulin resistance, dyslipidemia, visceral obesity, and hypertension.

 

These metabolic abnormalities interact synergistically to negatively impact the cardiovascular system.

 

For example, insulin resistance accelerates fat accumulation in the liver while also causing dyslipidemia through increased triglycerides, reduced HDL cholesterol, and changes in LDL cholesterol particle size.

 

Visceral obesity increases systemic inflammation by secreting inflammatory cytokines from fat cells, while hypertension increases atherosclerosis and cardiac burden, making it a direct risk factor for cardiovascular disease.

 

Professor Park stressed, “The factors do not exist independently.

 

When one worsens, it has a cascading effect on the others.

 

MASLD originates at the core of this metabolic imbalance and should be recognized not just as a simple liver disease but as the starting point of a systemic disease.” Professor Park noted, “For patients with MASLD accompanying diabetes, strategies that not only control blood sugar but also reduce liver fat accumulation and improve the overall metabolic environment should be used.

 

The combination of SGLT-2 inhibitors and TZDs could be an effective approach that can simultaneously target these complex goals.”