Two diseases, one drug: SGLT-2 inhibitors in patients with diabetes and liver disease

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Type 2 diabetes (T2D) is a chronic health condition that is increasing at a global level. There are many health complications associated with poorly managed blood glucose levels, some of which have the same risk factors as T2D. Dr Binayak Sinha, AMRI Hospitals, Dr Debasis Datta, Fortis Hospital and Dr Samit Ghosal, Nightingale Hospital, India have explored the concurrent benefits of sodium glucose co-transporter-2 inhibitors for patients with T2D and non-alcoholic fatty liver disease. Their research shows that the drug has a positive effect, both on blood glucose levels and markers of liver health, suggesting that current guidelines may need to be updated.

Diabetes is a chronic condition that occurs when the pancreas does not produce insulin or is unable to effectively use the insulin it does produce. Insulin is the hormone needed to unlock gateways on the surface of cells, which then allow glucose (sugar) to enter the cell and be utilised for energy. If glucose is unable to enter the cells of the body, it accumulates in the blood. Long term high blood sugar levels can lead to health complications, such as damage to the nervous system, kidneys and eyes.

Type 1 diabetes is a genetic condition, where the cells of the pancreas are unable to produce any insulin. However, most people with diabetes have type 2 diabetes (T2D), which results from the body’s inability to use insulin efficiently. An estimated 462 million people were living with type 2 diabetes in 2017. This corresponds to around 6.3% of the global population and is predicted to continue to increase.

The hormone insulin allows glucose (sugar) to enter cells and be utilised for energy.

A holistic approach

T2D is commonly associated with a suite of other health conditions, such as high blood pressure, obesity and high cholesterol. The presence of three or more of these health conditions is often referred to as ‘metabolic syndrome’. Metabolic syndrome causes an increased risk in cardiovascular disease, including stroke and coronary heart disease. It can also lead to non-alcoholic fatty liver disease, or NAFLD. The global prevalence of non-alcoholic fatty liver disease in the T2D population is estimated to be 55.5%.

“The global prevalence of non-alcoholic fatty liver disease in the T2D population is estimated to be 55.5%.”

Normally, the liver contains little or no fat. However, around one in three people in the UK have a small amount of fat in their liver which has the potential to progress to more serious liver damage if left untreated. NAFLD is also known to increase the risk of cardiovascular disease in people with T2D and is an independent cause of death.

T2D occurs alongside other health conditions and may cause potential complications in other organs of the body. Therefore, Dr Binayak Sinha, an endocrinologist at AMRI Hospitals, Dr Debasis Datta, a hepatologist at Fortis Hospitals, and Dr Samit Ghosal, an endocrinologist at the Nightingale Hospital suggest that a holistic approach to treatment is required.

Which medication is best?

There are a number of medications that can be used in the management of T2D. These work in a variety of different ways, for example by increasing the body’s sensitivity to insulin, or by mimicking other hormones in the body. However, Dr Sinha, Dr Datta, and Dr Ghosal point out that only a handful of these also have the potential to prevent problems with the liver, or to slow progression of disease. One such medicine is pioglitazone, which is effective at treating both T2D and NAFLD, but has side effects including weight gain, altered bone health, and heart failure, to mention a few. Another medication is GLP1-RA, which needs to be injected, rather than swallowed as a tablet, so it is not often the first choice for treatment. Finally, SGLT-2 (sodium-glucose co-transporter-2) inhibitors should also be considered. These drugs work by preventing the kidneys reabsorbing glucose back into the blood, meaning that excess glucose is excreted in urine. The use of SGLT-2 inhibitors has already been shown to reduce weight and fat accumulation.

Type 1 diabetes is a genetic condition where the cells of the pancreas are unable to produce any insulin. Type 2 diabetes (T2D) results from the body’s inability to use insulin efficiently.

However, there are only a small number of studies looking at the impact of SGLT-2 inhibitors for T2D and NAFLD. Therefore, in order to investigate whether SGLT-2 inhibitors were beneficial for NAFLD, as well as T2D, Dr Sinha, Dr Datta and Dr Ghosal undertook a meta-analysis of the existing literature. A meta-analysis combines the results of multiple, high quality research studies to collate the information and arrive at an overall conclusion based on their findings. It allows more confidence in the study findings, as whilst individual studies may not carry much weight by themselves, combining multiple small studies which report the same findings can add strength to a hypothesis.

Meta-analysis methods

Dr Sinha, Dr Datta, and Dr Ghosal searched for scientific publications containing a number of key words on online databases. On further evaluation of the publications, duplicates were excluded as well as any studies not available as full text versions. There was also an inclusion criterion that the studies had to meet. These included a minimum of 12 weeks follow up, measurements of metabolic outcomes and outcomes relating to liver conditions, and the need for the study to be a randomised controlled trial. Furthermore, one of the first things that the researchers needed to consider was how a diagnosis of NAFLD was made. In most of the studies, this was done through clinical suspicion and other investigations such as scans or blood tests.

Normally, the liver contains little or no fat. However, around one in three people in the UK have a small amount of fat in their liver which has the potential to progress to more serious liver damage if left untreated. NAFLD is also known to increase the risk of cardiovascular disease in people with T2D and is an independent cause of death.

Over 10,000 studies were highlighted in the initial screening phase. However, as is normal in meta-analyses, most of these were rejected early in the study selection process. The researchers were left with nine high quality, relevant studies for further analysis. This corresponded to a pooled patient population of 11,369. Of these, 7,281 individuals were on SGLT-2 inhibitors and 4,088 individuals were on standard treatment pathways without SGLT-2 inhibitors.

Dr Sinha, Dr Datta, and Dr Ghosal then extracted the relevant data from the studies. They wanted to explore outcomes linked to liver function, such as liver enzymes called ALT, AST GGT, and liver fat as well as weight, blood sugar levels and visceral fat levels. Statistical analysis was used to look at the findings for each study separately and combined, hence why the outcome measures in the studies needed to be the same. Some studies were also given more weighting than others in the analysis, depending on their sample size and the level of heterogeneity (variation).

There are some limitations of the meta-analysis due to the heterogeneity in the ways that outcome measures were reported by the studies, the potential loss of individual patient level data and the absence of consistent liver biopsy in diagnosing NAFLD.

The impact of SGLT-2 inhibitors

A previous meta-analysis found that SGLT-2 inhibitors decreased liver markers and liver fat content, independently from their ability to lower blood glucose levels. However, this analysis was limited by the inclusion of only a small number of studies. The main strength of Dr Sinha’s, Dr Datta’s, and Dr Ghosal’s study was the large number of patients included, and the uniform reporting of outcome measures.
Their statistical analysis showed that use of SGLT-2 inhibitors was significantly associated with lower levels of liver enzyme ALT, AST and GGT. The drug also lowered levels of liver fat and abdominal fat, something that can indirectly improve both T2D and NAFLD management.

Phlorizin was first isolated in 1835 and subsequently found to be a potent but rather non-selective inhibitor of both SGLT-1 and SGLT-2 proteins. https://en.wikipedia.org/wiki/Discovery_and_development_of_gliflozins

Dr Sinha, Dr Datta, and Dr Ghosal explain that this is probably due to reducing accumulation of liver fat and improving inflammation markers, which shows subsequent improvements in liver inflammation and a likely slowing of the disease process. This improvement is likely to be partly due to improvements in weight and glycaemic control but may also be linked to potential antioxidant properties of SGLT-2 inhibitors.

Overall, the results showed that SGLT-2 inhibitors did improve markers of liver inflammation, as well as fat accumulation in the liver. The drugs also had a positive effect on blood sugar levels and weight reduction.

“Overall, the results showed that SGLT-2 inhibitors did improve markers of liver inflammation, as well as fat accumulation in the liver.”

Looking ahead

Whilst diet and lifestyle changes are usually the first line treatments for both T2D and NAFLD, this meta-analysis shows that the use of SGLT-2 inhibitors alongside these interventions may play an important role improving long-term liver health in patients with diabetes. Additional long-term studies are still needed to confirm the benefits of SGLT-2 inhibitors in NAFLD patients with T2D.

Dr Sinha’s, Dr Datta’s, and Dr Ghosal’s findings highlight a need to expand the guidance around T2D management to include liver disease in treatment plans, and to also recommend SGLT-2 inhibitors if appropriate for these patients.


Where do you think SGLT-2 inhibitors should fit into the treatment algorithm for type 2 diabetes, and do they have a role to play in the management of type 1 diabetes too?

SGLT-2 inhibitors should be considered in all T2D patients with the aim of controlling metabolic derangements and compulsorily indicated in those established cardiovascular disease, high cardiovascular risk, chronic kidney disease, and NAFLD.

SGLT-2 inhibitors have shown modest metabolic benefits in T1D at the cost of increased risk of diabetic ketoacidosis (DKA) in a subset of patients. As a result we do not have any definite recommendations from the guidelines committees on this issue.

 

References

  • Sinha, B., Datta, D., & Ghosal, S. (2020). Meta-analysis of the effects of sodium glucose cotransporter 2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes. JGH open : an open access journal of gastroenterology and hepatology, 5(2), 219–227. https://doi.org/10.1002/jgh3.12473
DOI
10.26904/RF-135-1207369403

Research Objectives

The research of Dr Binayak Sinha, Dr Debasis Datta and Dr Samit Ghosal centres on type 2 diabetes and metabolic syndrome.

Bio

Dr Binayak Sinha FRCP, CSST, Consultant Endocrinologist, AMRI Hospitals, India
Dr Debasis Datta MD, DNB, FRCP, Consultant Hepatologist, Fortis Hospitals, Kolkata, India
Dr Samit Ghosal MD, FRCP, Consultant Endocrinologist, Nightingale Hospital, Kolkata, India


Dr Binayak Sinha


Dr Debasis Datta


Dr Samit Ghosal

Contact
Address
East Kolkata Doctors Group
HB-158, Salt Lake City
Kolkata, 700106
India

E: eastkolkatadoctorsgroup@gmail.com
T: +91-9674328281
twitter: @SAMIT GHOSAL
twitter: @BinayakSinha1
Blog: https://thenewliberalscoin.in/

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