Ketones: the double-edged sword of SGLT-2 inhibitors

The use of SGLT-2 inhibitors in diabetes for cardiorenal protection, as well as for glucose lowering, is now backed by clinical guidelines. However, the heart and kidney benefits may actually arise from circulating ketones, which can also lead to diabetic ketoacidosis (DKA). A new paper in Diabetologia explores the benefits and risks of ketones in SGLT-2 inhibitors. Dr Susan Aldridge reports.

Recent clinical trials have shown that the benefits of the SGLT-2 inhibitors extend far beyond their glucose-lowering properties – they also have significant cardiorenal benefits. For example, empagliflozin and canagliflozin both decrease the risk of major adverse cardiovascular events (MACE – a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke) in people with type 2 diabetes and either established cardiovascular disease (CVD) or at high CV risk.

Moreover, all the SGLT-2 inhibitors reduce the risk of hospitalisation for heart failure (HHF) in people with type 2 diabetes by 27-35%, even in those who did not have heart failure at baseline, suggesting a preventive effect. These benefits even extend to people without diabetes. As a result, SGLT-2 inhibitors are now recommended in type 2 diabetes guidelines for those with established CVD or at high CV risk.

Meanwhile, several trials have shown that SGLT-2 inhibitors can reduce the progression of chronic kidney disease (CKD). Some were designed to look at CV rather than renal outcomes. Then the CREDENCE trial, which had a composite renal endpoint as a primary outcome, showed that canagliflozin reduces serum creatinine, end-stage renal disease (ESRD) or death from renal causes by 34% in people with type 2 diabetes and CKD. Renal benefit was also seen for dapagliflozin in the DAPA-CKD trial, where the composite outcome of decline in estimated glomerular filtration rate (eGFR), end stage renal disease (ESRD) or death from renal or CV causes was reduced for those on the SGLT-2 inhibitor. Accordingly, SGLT-2 inhibitors are now recommended for people with CKD with and without type 2 diabetes.

Underlying mechanisms of cardiorenal benefits

The benefits of SGLT-2 inhibitors for the heart and kidneys are great news for people with and without type 2 diabetes. However, they were unexpected, so it’s not surprising that the underlying mechanisms are still a matter for debate and are likely to be multifactorial. One of the many proposals put forward is that the modest and transient elevation in ketones seen during SGLT-2 treatment may have therapeutic relevance to the benefits to the heart and kidney. 

Ketones – acetoacetate, β-hydroxybutyrate (β-OHB) and acetone – are byproducts of fat metabolism that can be used as a non-glucose fuel source during fasting and exercise. Put simply, chronic glycosuria from SGLT-2 inhibitor treatment favours ketogenesis. And this, in turn, may help the heart, which requires a large amount of ATP synthesis, some of which is obtained via the metabolism of ketones. In heart failure, the ‘energy-starved heart’ theory involves a lessening of glucose oxidation, but this energy deficit might be made up if there are ketones around. This idea is supported by a small study in which β-OHB was infused into patients with heart failure with reduced ejection fraction, producing a dose-dependent increase in stroke volume, cardiac output and left ventricular ejection fraction.

Ketones might also reduce oxidative stress by a number of pathways, which could help alleviate atherosclerosis. They may also play a role in lowering blood pressure by suppressing sympathetic nervous system activity and heart rate, via the action of β-OHB on G-protein coupled receptor 41.

As far as the kidney is concerned, ketones are also an energy-efficient fuel for renal tubular cells, so it may be that SGLT-2 inhibitors protect the kidney via the same mechanism that they protect the heart. Ketones may also inhibit rapamycin complex 1, known to be a mediator of kidney injury, at least in animal models.

So, in conclusion, there are several potential mechanisms by which the modest increase in ketones associated with SGLT-2 inhibitors could confer cardiorenal benefit. Further studies are now needed to clarify the relevance of these.

The downside of ketones – DKA

Most people on SGLT-2 inhibitors experience only a mild rise in circulating ketones. However, in some circumstances, there may be a greater increase. DKA is a well-known serious complication of type 1 diabetes occurring with the combination of hyperglycaemia, metabolic acidosis and elevated serum and/or urinary ketones. It can also occur in type 2 diabetes, typically when the person has a severe, acute illness.

Sometimes, however, DKA occurs when the blood glucose is high but not as high as typically seen in this condition. This has been termed euglycaemic DKA (eDKA). Before the widespread use of SGLT-2 inhibitors, eDKA accounted for 3% of all DKA cases. It is suspected that it occurs when there is impaired hepatic glucose production, as in chronic liver disease, or when there is excess glycosuria, as in pregnancy. eDKA has also been associated with SGLT-2 inhibitor treatment, as has traditional DKA. However, the underlying mechanisms of DKA with the use of SGLT-2 inhibitors are not completely understood, although a number of theories have been proposed and are still under investigation.

Fear of hypoglycaemia and weight gain can be barriers to the optimal use of insulin by people with type 1 diabetes. In such cases, SGLT-2 inhibitors can be a useful way of reducing HbA1c, body weight and insulin requirements without increasing the risk of hypoglycaemia. And there is no reason to think that people with type 1 diabetes would not also get cardiorenal benefit from the SGLT-2 inhibitors. Indeed, these drugs are increasingly being used off-label in type 1 diabetes. However, there is concern about the increased risk of DKA with their use.

These fears are not unfounded – a meta-analysis of randomised controlled trials showed that SGLT-2 inhibitors do indeed increase the risk of DKA in a dose-dependent fashion. At higher doses, there are 34 events per 1000 person-years and, at lower doses, seven events per 1000 person-years. In a study of people with type 1 diabetes treated with canagliflozin as an add-on to insulin, the incidence of DKA was 5.1% with the 100 mg dose and 9.4% with the 300 mg dose. All serious DKA episodes were associated with precipitating factors such as flu, pneumonia, pump failure or incorrect insulin dosing.

This means that, although SGLT-2 inhibitors are a potentially valuable adjunct therapy to insulin in type 1 diabetes, they should only be used in people who are well educated about the risks of DKA as well as prevention and treatment strategies. They should be willing and able to monitor ketones and seek urgent medical help if they are elevated.

SGLT-2 inhibitors and type 2 diabetes

SGLT-2 inhibitors are now used extensively in type 2 diabetes because, although their blood glucose-lowering effect is relatively modest, they induce weight loss, blood pressure-lowering and, of course, the cardiorenal benefits described above. Do these benefits outweigh the risks of DKA in type 2 diabetes?

In randomised controlled studies, the rate of DKA is much lower in type 2 diabetes than in type 1, being just 2.5 times higher than controls on either placebo or a comparator medication. Risk factors include autoimmune diabetes (misdiagnosed as type 2 diabetes), pregnancy, previous DKA and restricting carbohydrate intake. DKA can be precipitated by an acute event like surgery, trauma, infection, heart attack or, as in type 1 diabetes, inappropriate insulin dosing.

Presentation, prevention and treatment

People with SGLT-2 inhibitor-related DKA present with nausea, vomiting, abdominal pain and malaise. There will be acidosis and ketones but glucose concentrations may be below 13.9 mmol/l (eDKA). It is this absence of very elevated glucose levels that may delay recognition of the problem by patients and clinicians, particularly in a very busy A&E setting.

People with type 1 and type 2 diabetes should know that they need to monitor ketones if they are unwell. If they are positive, they need to follow the instructions they have been given by their diabetes team, seeking immediate medical help if necessary.  

Inpatient treatment involves administration of intravenous insulin and fluids to resolve acidosis. The insulin will suppress lipolysis and the formation of ketones.

To minimise the risk of DKA, SGLT-2 inhibitors should be stopped during acute illness and for at least three days before surgery. DKA has been shown to occur in people undergoing colonoscopy and should be stopped at least two days before the procedure. Finally, if someone does develop DKA in the setting of SGLT-2 inhibitor treatment, the drug should not be restarted immediately. There have been cases of recurrences of DKA with continuous SGLT-2 therapy. They should, therefore, only be restarted after careful consideration of the risk/benefit ratio – if the patient has established CKD or heart failure, for instance, and if they are well-educated in the use of the drugs.

In conclusion, SGLT-2 inhibitors, originally developed as glucose-lowering agents in type 2 diabetes, have recently been shown to have significant cardiorenal benefit. So they are now recommended to reduce heart and kidney complications in people with and even without type 2 diabetes. However, the mechanisms underlying these benefits are not completely understood. One proposed theory is that they arise from a modest increase in the level of circulating ketones but ketones are also linked with the significant side-effect of DKA, which may be under-recognised if it is euglycaemic. Thus, ketones are a ‘double-edged sword’ in the use of these increasingly popular medications and a careful analysis of their benefit/risk ratio is always needed.

To read this paper, go to: Lupsa B, Kibbey R, Inzucchi R. Ketones: the double-edge sword of SGLT-2 inhibitors. Diabetologia online 18 October 2022. https://link.springer.com/article/10.1007/s00125-022-05815-1

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.