Sodium glucose cotransporter 2 inhibitors prevent heart failure in diabetes by promoting ketone bodies as fuel

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Sodium glucose cotransporter 2 (SGLT2) inhibitors are medications recently developed for the treatment of type 2 diabetes, which help treat insulin resistance by reducing blood sugar levels. SGL2 inhibitors additionally protect the heart from failure, an action that scientists and doctors have so far been unable to explain. Dr Yoshiyuki Hattori, at Hattori Diabetology Clinic in Japan, investigates the impact of SGLT2 inhibitors on heart failure. Hattori thinks the answer may lie in how the medication affects fuel regulation and the use of ketone bodies by the heart muscle.
Diabetes mellitus, or diabetes for short, is a lifelong metabolic disorder characterised by elevated levels of blood sugar. In the long run, diabetes leads to a number of serious complications, including damage to the nerves and blood vessels that can then cause heart disease, loss of eyesight, and kidney failure. Type 2 diabetes is primarily caused by lifestyle factors: diets high in fat and calories, obesity, and lack of exercise. However, genetic factors are also responsible for someone’s chance of developing the disease. The main characteristic of type 2 diabetes is insulin resistance, which means the body’s cells don’t respond normally to the hormone insulin and thus fail to regulate the level of sugar in the blood.

These metabolic changes and biochemical processes, along with the damage caused by diabetes to the blood supply of the heart, can often lead to heart failure. Dr Yoshiyuki Hattori at Hattori Diabetology Clinic in Tochigi, Japan, has been studying the mechanisms of heart failure in diabetic patients. Hattori recently published a review paper specifically on the protective effects of sodium glucose cotransporter 2 (SGLT2) inhibitors on the heart, while trying to solve the puzzle of how they work.

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Ketone bodies: alternative fuel

The heart is a muscular organ that continuously pumps blood towards every part of the body, a function that requires large amounts of fuel and oxygen. Factors that increase the risk for cardiovascular diseases such as heart attack and heart failure include obesity and resistance to insulin – which are present in patients with type 2 diabetes. To overcome the problem of insulin resistance, the heart uses less glucose as fuel and more fatty acids.

“SGLT2 inhibitors might actually be improving heart function by regulating energy production through inducing increased production of ketone bodies.”

Hattori evaluates recent evidence suggesting that heart failure in diabetic patients could be explained by the fact that the heart of these patients is energy deprived, something that is also supported by recent evidence on the heart’s inability to properly use fatty acids as fuel. Although the heart preferentially uses fatty acids as a source of energy, when energy deprived it can effectively use ketone bodies as well. Ketone bodies are molecules derived from fatty acids that are produced in the liver by ketogenesis during periods of caloric restriction caused by fasting or insulin resistance. Ketone bodies are then sent to body tissues where they are converted into acetyl-CoA (acetyl-Coenzyme A), which is oxidised to provide energy. For this reaction to happen, the presence of an enzyme called succinyl-CoA:3-ketoacid CoA transferase (SCOT) is required. Hattori says SCOT is present at higher levels in the heart muscle compared to the brain, kidney, and skeletal muscle. In diabetic patients with heart failure, the observed elevation of SCOT levels in the heart is potentially explained by the increased use of ketone bodies as fuel: the failing heart is adapting to the use of ketone bodies as an alternative source of energy.

Insulin resistance and heart failure

Insulin is a hormone produced by the pancreas. Insulin regulates blood sugar levels by facilitating the entrance of circulating glucose molecules into cells, leading to a reduction of sugar concentration in the blood. For diabetes-related insulin resistance, cells don’t respond normally to insulin. The same amount of the hormone has much less effect – resulting in less circulating glucose being absorbed by the cells, which causes higher blood sugar concentrations. Besides type 2 diabetes, other risk factors for insulin resistance include obesity, metabolic syndrome, sedentary lifestyle, and hereditary factors.

Insulin resistance can increase the risk of heart failure. Instead of glucose, the body produces more ketone bodies, which can lead to diabetic ketoacidosis (DKA). joshya/Shutterstock.com

Hattori identifies that ‘heart failure is associated with generalised insulin resistance’. For those affected, the body’s general resistance to insulin extends to an inability of the heart to respond to the hormone. Insulin resistance affects the heart’s metabolism and can subsequently have a vast impact on the organ’s function, which may eventually culminate in heart failure.

Role of SGLT2 inhibitors

SGLT2 inhibitors, also known as gliflozins, are medications used to regulate the levels of sugar (glucose) in the blood of patients with type 2 diabetes. SGLT2 inhibitors act by altering kidney function to decrease sugar concentration in the blood; sugar is expelled via urine rather than reabsorbed by the kidneys. Hattori reveals that, as well as being effective for treating insulin resistance, SGLT2 inhibitors are also shown to protect heart function in type 2 diabetes patients and prevent heart failure.

However, there is still a lot of debate about how SGLT2 inhibitors improve heart function in diabetic patients. It’s been suggested that SGLT2 inhibitors have beneficial haemodynamic (related to the volume and pressure of the circulating blood) and metabolic effects on the function of the left ventricle (the heart chamber that pumps the oxygenated blood towards the body tissues). Studies have shown that left ventricular function improves with SGLT2 inhibitor treatment (Lan et al, 2019), potentially secondary to osmotic diuresis (increased urination used by the body as a mechanism to get rid of the excess glucose and sodium) which is a beneficial side effect of the treatment. However, there is not enough evidence yet to support this hypothesis.

Molecular structure of SGLT2 inhibitor dapagliflozin. StudioMolekuul/Shutterstock.com
Molecular structure of β-hydroxybutyrate.

Hattori points to a different explanation of why SGLT2 inhibitors are beneficial for the hearts of type 2 diabetic patients. SGLT2 inhibitors might be improving heart function by regulating energy production by inducing increased production of ketone bodies. This in turn increases the circulating β-hydroxybutyrate (βOHB) levels, an intermediate product of the process of ketogenesis. βOHB is a carrier of energy from the liver to peripheral tissues when the supply of glucose is low, and therefore participates in the increased production of ketone bodies. βOHB also has anti-oxidative and anti-inflammatory effects, which suggests it may combat oxidative stress in failing hearts and increase energy production rates. As well as potentially regulating the heart’s fuel supply and consumption, SGLT2 inhibitors also seem to improve insulin resistance.

“SGLT2 inhibitors might actually be improving heart function by regulating energy production through inducing increased production of ketone bodies.”

Recent studies (Merovci et al, 2014) have shown that insulin sensitivity in body muscles significantly increases after a few weeks of treatment with an SGLT2 inhibitor. This could be due to the high concentrations of βOHB caused by SGLT2 inhibitors as mentioned earlier. βOHB antioxidant effects could potentially include the amelioration of insulin resistance, especially since the last one is strongly associated with oxidative stress (an imbalance between the by-products of reactive oxygen species and the body’s ability to detoxify or repair the damage caused by them).

The latest research on SGLT2 inhibitors can ultimately lead to improved treatment for type 2 diabetes and heart failure. StanislauV/Shutterstock.com

Solving the puzzle

SGLT2 inhibitors have been shown to improve heart function and decrease hospitalisation rates for heart failure in patients with type 2 diabetes. They also reduce death rates caused by cardiovascular events in these patients. However, the underlying mechanisms of how they do this remain elusive. Previous efforts to explain these beneficial effects, including the hypothesis that increased urination caused by SGLT2 inhibitors to help the body get rid of excessive blood sugar can lessen the strain on the heart, haven’t so far been confirmed. Hattori thinks that the SGLT2 inhibitors’ positive impact and favourable outcome on heart failure may be associated with its beneficial effect on the heart’s energy regulation and insulin resistance in general – but also specifically in the heart muscle. βOHB’s anti-oxidative and anti-inflammatory properties could also combat oxidative stress and insulin resistance in failing hearts, therefore improving energy production rates. The benefit of SGLT2 inhibitors for treating heart failure could be due to improving fuel regulation by utilising ketone bodies and ameliorating insulin resistance.

Hattori’s review brings together the latest research to finally piece together the puzzle for how SGLT2 inhibitors potentially work, providing future researchers with the foundations for improving treatments for type 2 diabetes treatment and heart failure.

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How could your findings on the value of SGLT2 inhibitors affect the future treatment of type 2 diabetes and heart failure?
Organ distribution of SGLT2 is kidney specific. Thus, the pleiotropic effects of SGLT2 inhibitors may be attributed to glucose deprivation caused by its glucose-losing effect. Glucose deprivation leads to glycogenesis, which in turn leads to the production of ketone bodies from fatty acids to spare glucose consumption. Marked ketosis has been considered a condition that should be avoided at all costs. In recent years, however, the ketone bodies are not only efficient energy substrates, but also function as a transcription regulation molecule through inhibition of histone deacetylase activity. It has become clear that it is a functional molecule with pleiotropic effects.

 

References

  • Hattori, Y, (2020) Insulin resistance and heart failure during treatment with sodium glucose cotransporter 2 inhibitors: proposed role of ketone utilization. Heart Failure Reviews, 25(3), 403–408. doi.org/10.1007/s10741-020-09921-3
  • Lan, NSR, Fegan, GP, Yeap, BB, Dwivedi, G, (2019) The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions. ESC Heart Failure, 6(5), 927–935. doi.org/10.1002/ehf2.12505
  • Ferrannini, E, Mark, M, Mayoux, E, (2016) CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” Hypothesis. Diabetes Care, 39 (7), 1108–1114. doi.org/10.2337/dc16-0330
  • Merovci, A, Solis-Herrera, C, Daniele, G, et al, (2014) Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. Journal of Clinical Investigation, 124, 509–514. doi.org/10.1172/JCI70704
DOI
10.26904/RF-141-2544196334

Research Objectives

Dr Hattori studies heart failure mechanisms in individuals with type 2 diabetes.

Bio

Dr Yoshiyuki Hattori MD PhD is based at the Hattori Diabetology Clinic in Tochigi, Japan.

Dr Yoshiyuki Hattori

Contact
Hattori Diabetology Clinic,
Okura-cho, Sano-shi,
Tochigi, 327-0012,
Japan

E: yh05122001@zpost.plala.or.jp
T: +81 283 22 7450

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