6.2.1 Introduction
Between 6 to 11% of the adult population of the United Kingdom is thought to have CKD. These individuals are not just at risk of progressive decline of kidney function resulting in them suffering symptoms related to poor kidney function and requiring them to be considered for end-stage kidney disease treatment (dialysis or transplant) but they also have a greatly increased risk of cardiovascular disease (heart attacks, heart failure, strokes and narrowing of the arteries to the legs termed peripheral vascular disease). This represents a significant burden for both the health economy of the United Kingdom and, more importantly, for the individuals themselves.
Treatment for CKD aims to halt or slow down progression of declining kidney function and reduce cardiovascular risk. These treatments have up until now been centred on a group of medications known as the inhibitors of the renin angiotensin system, which is a system that has a controlling influence on blood pressure and fluid status. In addition, control of blood pressure, blood glucose and blood lipids (or fats) remain key to reducing progression of CKD and the associated poor cardiovascular outcome. However, these treatments are only partially effective and there has been a pressing need to identify new treatments to help the large number of people with CKD avoid the requirement for dialysis or transplant, or from suffering cardiovascular harm.
SGLT 2 inhibitors are medications that were initially developed as a treatment for diabetes because they effectively reduce blood glucose (sugar). New research has found that these medications provide significant benefit to people with CKD both in terms of reducing decline in kidney function and also reducing the poor cardiovascular outcomes people with CKD suffer.
The purpose of this guideline document is to produce practical advice for clinicians caring for people with kidney disease in relation to when and how to use SGLT 2 inhibitors.
It is the purpose of this section to provide lay individuals a greater understanding of the nature of SGLT 2 inhibitors, the benefits they offer, in which individuals they are most likely to be effective and to obtain a greater appreciation of the risks of these medications and how these risks can be reduced.
6.2.2 SGLT 2 inhibitors: what are they?
The kidneys function to clean the blood and control the concentration of many constituents of the blood. They do this by “filtering” the blood through individual filtering units (called glomeruli, of which there are approximately 1 million within each kidney in healthy adults) and thereafter the filtered fluid or “filtrate” passes into small pipes or “tubules” within the kidneys where its content is adjusted. The filtrate eventually becomes urine, which is passed from the kidneys to the bladder and removed when we pass urine.
Glucose is freely filtered from the blood but normally all of this filtered glucose is returned back into the blood within the early part of the tubule of the kidneys called the proximal tubule. This return is undertaken by particular transporter proteins called SGLT 2 which sit in the wall of the proximal tubule. Every person has a maximal amount of glucose that their kidney can reabsorb and in individuals who have high amounts of filtered glucose (typically in people with diabetes) the SGLT 2 co-transporters become flooded and residual glucose is lost in the urine (and in fact it is the resulting sweet urine which gives diabetes mellitus its name).
SGLT 2 inhibitors are medicines that block the activity of the SGLT 2 co-transporter and by blocking this protein’s actions, SGLT 2 inhibitors cause a loss of glucose into the urine and is the reason these medicines have been developed as a treatment to help reduce blood glucose in people with diabetes.
In addition to SGLT 2 co-transporters there are, within the body, a group of related proteins called SGLT-1 co-transporters. These proteins are found more predominantly in the gut where they are involved in the uptake of glucose from the food into the bloodstream. They are also found, albeit to a much lesser extent, in the kidney tubules where they make only a very minor contribution to total glucose reuptake in the kidneys.
6.2.3 Benefits of SGLT 2 inhibitors
All new medications being introduced to treat diabetes are required to demonstrate that not only do they improve blood glucose control but they do not have an adverse effect on cardiovascular outcomes in people with diabetes. This is because there has been an example of a previous medication which provided significant benefit in relation to reducing blood glucose but at the same time was associated with an increased risk of heart attacks. Therefore, all new medications being introduced to treat diabetes are required to undergo what are termed cardiovascular outcome trials.
All the major SGLT 2 inhibitor medications have reported on their cardiovascular outcomes and the findings from these studies has provided significant information in relation to additional benefits that these medications provide.
It was already known that these medications have benefits over and above their glucose reducing effect, which included a reduction in weight of around 2 to 4 kg and a small reduction in blood pressure. These additional effects were believed to result from the loss of salt in the urine (called the diuretic effect) and the loss of calories in the form of glucose within the urine. In addition to these effects, the cardiovascular outcome studies identified significant benefits in relation to reducing cardiovascular harm, most particularly in relation to reducing admission to hospital with heart failure and in reducing the progression of CKD.
6.2.4 How this guideline was developed
This guideline has been developed by a writing group containing a broad range of healthcare clinicians with experience in kidney disease, diabetes and primary care who have worked together to review the evidence for the use of SGLT 2 inhibitors in people with kidney disease. In addition writing group has also included people with kidney disease to provide the patients’ perspective. As a group, they have followed good practice in relation to reviewing the evidence and using that evidence to provide recommendations for the use of SGLT 2 inhibitors in people with CKD.
In generating the recommendations, the guideline writing committee gave the greatest priority to the results of trials that were most effective at discriminating both beneficial and adverse effects of SGLT 2 inhibitors. These were trials comparing people who were allocated to take SGLT 2 inhibitors at random (like a toss of a coin) to those who were allocated to take a dummy pill (known as the placebo group) and containing large (greater than 1000) numbers of participants.
From this evidence base, the guideline writing committee has developed summaries of evidence and proposed draft recommendations which were discussed at a consensus meeting of all members before final recommendations were made.
When making recommendations, the evidence that supported each recommendation was graded according to the UK Kidney Association’s recommended grading system, which defines the level of evidence and the quality of evidence for each recommendation. Broadly, a grade 1 recommendation is a strong recommendation while a grade 2 recommendation is a weaker one. In addition, there is a letter designating the quality of the evidence that supports that recommendation.
Where the evidence to support a recommendation is strong (grade 1) we use the term “recommend” and where it is weaker (grade 2) we use the term “suggest”.
We have also subdivided our recommendations into the following categories:
a) Recommendations for Use which defines who should be offered SGLT 2 inhibitors
b) Recommendations for Implementation which defines how SGLT 2 inhibitors should be used
c) Recommendations for Clinical Research which defines where there is ongoing clinical uncertainty
d) Recommendations for Audit which defines how to demonstrate effective implementation of grade 1 Recommendations
6.2.5 Benefits of SGLT 2 inhibitors: cardiovascular benefits
The cardiovascular outcome trials identified the fact that SGLT 2 inhibitors had a small effect on reducing the incidence of heart attack which varied between the individual SGLT 2 inhibitors. However, all the trials demonstrated a significant reduction in heart failure hospitalizations that pointed to a significant benefit in people with heart failure. This benefit has now been confirmed in studies that have specifically looked at the use of SGLT 2 inhibitors in people with heart failure including people with and without diabetes.
6.2.6 Benefits of SGLT 2 inhibitors: kidney protection
An unexpected and consistent finding from the cardiovascular outcome trials was that individuals treated with SGLT 2 inhibitors as opposed to placebo or dummy medications had improved kidney outcome in terms of a reduction in decline of kidney function, the need to commence treatment for end-stage kidney failure and death due to kidney causes.
These findings have been tested in further studies called CREDENCE, DAPA-CKD and EMPA KIDNEY which have specifically looked at kidney outcomes in people with evidence of chronic kidney disease and for DAPA-CKD and EMPA KIDNEY this kidney beneficial effect was seen in both people with and without diabetes.
6.2.7 Separation of glucose from cardiac and kidney benefit
The benefits of SGLT 2 inhibitors in relation to the improvement in blood glucose control is known to be related to the glomerular filtration rate (GFR). This is a measure of global kidney filtering function and is the measure that progressively reduces as kidney function declines in CKD. A normal GFR should be approximately 90 mL/min/1.73m2, but there is a progressive normal decline with ageing. Excessive decline down to single figures (i.e. less than 10 mL/min/1.73m2) is usually an indicator of the need to commence kidney failure treatment.
As the GFR declines so also does the ability of SGLT 2 inhibitors to improve glucose control in diabetes, such that by the time the GFR has reduced to 45 mL/min/1.73m2, the glucose-reducing effect of SGLT 2 inhibitors virtually disappears in people with diabetes treated with these agents. It is for this reason that these medications have not been recommended for use as a treatment for diabetes in people whose kidney function is already deranged because they have CKD.
In the kidney-specific outcome studies and studies looking at SGLT 2 inhibitors in people with heart failure, people with kidney function down to 20 mL/min/1.73m2 have now been enrolled. Indeed there is evidence from analysis of all these studies to suggest that the heart and kidney protection continues even at the lowest levels of kidney function perhaps down to the level at which dialysis or transplantation is required.
This separation of the glucose and cardiac and kidney protective effect was exemplified further by the fact that, in the DAPA-CKD, EMPA KIDNEY and the heart failure-specific studies, SGLT 2 inhibitors were beneficial even in people without diabetes.
6.2.8 Identifying individuals where there is benefit in prescribing SGLT 2 inhibitors
SGLT 2 inhibitors can only be recommended as a treatment if there is sufficient evidence to support that use and this is usually obtained from randomized controlled trials where participants in the trials are split randomly into those given the treatment and those given a dummy treatment. There are now a significant number of trials with SGLT 2 inhibitors that were designed first of all to assess the cardiovascular safety of these medications (cardiovascular outcome trials) as well as trials looking at these medications in people with heart failure and in people with kidney disease.
As these results have emerged, the licences (which determines how the treatment can be prescribed in the UK) for a number of SGLT 2 inhibitors have been broadened to allow the use of that specific SGLT 2 inhibitor for the purpose not just of glucose control, but also as protection against cardiovascular or kidney disease.
In assessing the evidence for benefit, one also needs to be clear about the outcomes that are being measured. For kidney disease there are many different potential outcomes that have been used in previous studies; however, not all of these clearly define outcomes that truly benefit people with CKD. Therefore, determination of benefit of SGLT 2 inhibitors for the purpose of generating recommendations in this guideline is based on real evidence for the reduction in progression of kidney disease which has been measured by the need to commence any form of kidney replacement therapy, death caused by kidney disease and significant reduction in decline in kidney function.
In the major cardiovascular outcome trials of all four of the SGLT 2 inhibitors, kidney effects were monitored and in all of these studies there was a decline in progression of kidney disease, need to commence kidney replacement therapy or death due to kidney disease. However, these effects were not the primary purpose of the studies and therefore there is a risk that the findings could have been identified by chance. Therefore, further studies have been undertaken that have looked primarily at the effect of SGLT 2 inhibitors in people with kidney disease. These studies include:
1) CREDENCE which tested the SGLT 2 inhibitor canagliflozin in people with type 2 diabetes and evidence of diabetic kidney disease in the form of some reduction in GFR and the presence of protein in the urine
2) DAPA-CKD which tested the SGLT 2 inhibitor dapagliflozin in people with evidence of kidney disease in the form of a reduction in GFR and presence of protein in the urine but, importantly, not just in people with diabetes as a cause for their kidney disease.
3) EMPA KIDNEY which tested the SGLT 2 inhibitor empagliflozin in a wide range of people with evidence of kidney disease at risk of progression, in the form of reduction in GFR both with and without the presence of protein in the urine and in both people with and without diabetes.
CREDENCE, DAPA-CKD and EMPA KIDNEY have confirmed the safety findings from the cardiovascular outcome trials and demonstrated significant kidney benefits of SGLT 2 inhibitors in people with CKD. These benefits included clear reduction in progression of diabetic kidney disease by approximately 30 to 50%. Overall, they also reduced occurrences of heart attacks and deteriorations of heart failure in people with CKD.
Because of the findings from review of the studies this guideline recommends the initiation of SGLT 2 inhibitors in people both with and without diabetes who have evidence of increased albumin in the urine (at a level of greater than 25 mg/mmol) down to an eGFR of 20 or if they have an eGFR between 20 and 45 mL/min/1.73m2 even in the absence of albuminuria. In addition, the guideline recommends initiation of SGLT 2 inhibitors in people with CKD and a history of heart failure.
Once initiated, this guideline recommends that the SGLT 2 inhibitor can be continued until the individual reaches end-stage kidney disease.
Practically, the SGLT 2 inhibitor that would be utilised would be dependent on the current licence for that individual SGLT 2 inhibitor and whether primary care (general practitioners) are able to prescribe that specific medicine.
6.2.9 Groups where there is uncertainty
As described, it is only possible to recommend SGLT 2 inhibitor treatment for cardiac and kidney benefit in people who were represented in the studies of these medications, and in whom there is clear evidence of benefit.
There are a number of groups of people in whom it is not yet possible to be specific about the cardiac and kidney benefits of SGLT 2 inhibitors.
Currently, this includes people who have CKD caused by the genetically inherited condition called adult polycystic kidney disease. Clinical trials to date that have studied SGLT 2 inhibitors have not included people with adult polycystic kidney disease, meaning that there is not enough evidence to recommend this medication class.
Type 1 Diabetes Mellitus
There are two main types of diabetes which include type 1 diabetes (which occurs more usually at a younger age and in which there is loss of the ability to produce insulin) and the much more common type 2 diabetes. Type 2 diabetes usually occurs in the older age group and is related to the ability of insulin to be effective, with the most common reason for this being association with obesity.
Whilst there have been some studies of SGLT 2 inhibitors in type 1 diabetes, these have not been sufficient to make a clear recommendation on the use of SGLT 2 inhibitors in people with type 1 diabetes. There may be benefits in people with type 1 diabetes, but there is a risk of a condition called diabetic ketoacidosis which is particularly high in people with type 1 diabetes. This means any potential benefits of SGLT 2 inhibitors may be finely balanced with potential risk of harm (more details below).
People with functioning kidney transplants
Whilst it would be appealing to assume that the benefits that SGLT 2 inhibitors provide in relation to reduction in progression of CKD and protection against cardiovascular disease is present in all people with abnormal kidney function, kidney transplant recipients were not included in any of the trials. There is currently insufficient evidence at this time to recommend that people with a kidney transplant should be included in those initiated on SGLT 2 inhibitors. Whilst there are ongoing studies in this area, SGLT 2 inhibitors should only be offered to people with a kidney transplant after careful consideration and discussion between the kidney transplant team and the diabetes teams and with clear discussion undertaken with the individual with the kidney transplant.
6.2.10 Side effects of SGLT 2 inhibitors and how to avoid them
Every medication has potential to result in adverse events and it is important that these are appropriately understood in order for people to be advised appropriately about the risks of the medication and how it is possible for them to take steps to reduce any harm that could occur from taking a medication.
All people who are being prescribed new medications need information given to them that allows them to make an informed choice as to whether they wish to commence the treatment. This information needs to include a balance between both the risks of the medication and the potential benefit to them as an individual. Furthermore, the information needs to include advice on actions that would reduce the chance of harm coming to them by taking a particular medication.
SGLT 2 inhibitors have been found to have a number of adverse effects that people need to be informed about prior to initiation of this therapy. It is important to also appreciate that the likelihood of suffering an adverse effect may depend on the individual as well as the medication, and this would include factors such as whether they have diabetes, their age and their frailty.
6.2.11 Diabetes specific: diabetic ketoacidosis
SGLT 2 inhibition has an effect on the breakdown of carbohydrates and fats, which results in an excess of a group of substances known as ketones. These molecules are not dangerous of themselves, however, if the level of these ketones increases this can result in a dangerous situation in which the blood becomes very acidic which is termed ketoacidosis.
Ketoacidosis is a dangerous complication, seen most particularly in people with type 1 diabetes, but can occur (although rarely) in people with type 2 diabetes and there is evidence that SGLT 2 inhibitors increase the risk of this happening. Diabetic ketoacidosis usually occurs in conjunction with high levels of glucose, however, when it occurs in a person taking an SGLT- 2 inhibitor, the excess glucose can be lost in the urine and this dangerous complication can occur in conjunction with normal levels of glucose which has the potential to confuse both the person with diabetes and the healthcare worker assessing the person.
The risk of diabetic ketoacidosis increases in the presence of infection or if the individual becomes dehydrated because of diarrhoea, vomiting or fasting. It also occurs in situations where there is not enough insulin, such as in people with type 2 diabetes who have low levels of their own insulin production and in situations when people who are treated with insulin have their insulin reduced, or even stopped.
A further factor that can be associated with an increased risk of diabetic ketoacidosis in people prescribed SGLT 2 inhibitors is the use of specific diets which are termed “very low carbohydrate” or ”ketogenic” diets and which increase the blood levels of ketones (such as the Atkins diet).
Because of their greater risk of suffering diabetic ketoacidosis, people with type 1 diabetes should only be commenced on SGLT 2 inhibitors under strict direction of the diabetes team, and may be offered lower doses.
It is also recognised that there are a group of people with type 2 diabetes who are at greater risk of diabetic ketoacidosis because they have lower levels of insulin. One can identify this group of individuals by features associated with low insulin levels, of which the most important are the rapid requirement for insulin treatment following diagnosis (within one year) and the presence of type 2 diabetes and low body weight. It is recommended that for these people with type 2 diabetes who are at greater risk of diabetic ketoacidosis, SGLT 2 inhibitors should only be initiated after discussion with the diabetes team.
If an individual prescribed SGLT 2 inhibitors develops diabetic ketoacidosis, it is recommended that the SGLT 2 inhibitor should be stopped and that individual should be reviewed by a member of their clinical team to determine whether treatment could be re-initiated in the future. That decision will be dependent on the analysis of the reasons why the diabetic ketoacidosis occurred, and whether with changes to treatment, or better advice on management, the risk of future diabetic ketoacidosis can be significantly reduced. That decision should be discussed between the clinical team and that individual themselves.
Because of the risk of diabetic ketoacidosis, people started on SGLT 2 inhibitors need to be told about diabetic ketoacidosis and in particular the signs and symptoms of this disorder and the importance of seeking immediate medical advice if those symptoms develop.
Perhaps one of the most effective ways of preventing the occurrence of diabetic ketoacidosis is to use what is termed “sick day guidance”. This is where a medication, which ordinarily has a significant benefit to the individual, can cause an adverse effect if it is continued when they become unwell with features of a fever or inability to maintain their fluid status (such as vomiting or diarrhoea). In this instance, it is important to miss out the specific medication (such as the SGLT 2 inhibitors) if they become unwell or if they are hospitalized. The medication should be resumed once the illness has passed or the person has been discharged from hospital. If a person stops their SGLT 2 inhibitor because of ill health and there is no improvement beyond a period of 48 hours they should seek medical attention. It is for this reason that all people prescribed SGLT 2 inhibitors should be taught about sick day guidance to be used if they become unwell and that this advice should be reiterated at every medication review.
Because of the relationship of diabetic ketoacidosis to specific diets and to situations where the individual is taking a reduced fluid intake such as when fasting, the individual should be advised not to follow these particular diets when on an SGLT 2 inhibitor and be given specific advice if they do choose to fast. This might include missing out the SGLT 2 inhibitors on fast days or testing for the presence of ketones if they become unwell.
6.2.12 Diabetes specific: Low blood glucose or hypoglycaemia
SGLT 2 inhibitors have beneficial effects in improving blood glucose control, which is dependent on good kidney function. Hypoglycaemia is a situation where the person’s blood glucose drops to a low level causing harm that varies from mild symptoms to profoundly significant symptoms including coma. Furthermore, severe hypoglycaemia can be associated with long-term damage affecting both the cardiovascular system and the brain. People who have suffered episodes of hypoglycaemia may have limitations on their ability to drive or to undertake certain occupational activities. Therefore, hypoglycaemia is a complication of diabetes that needs to be avoided and certainly minimised.
Whilst SGLT 2 inhibitors on their own do not produce hypoglycaemia, this can occur if they are used with a diabetes agent that has such a risk, such as insulin or the group of diabetes medications that work by directly stimulating insulin release (these are termed insulin secretagogues and include gliclazide, glimeprimide, glipizide, repaglinide etc.).
In people treated for their diabetes with insulin or insulin secretagogues, consideration needs to be given as to whether to reduce the current diabetes treatment when commencing an SGLT 2 inhibitor. The decision on whether to make this change should be discussed by the clinician prescribing the SGLT 2 inhibitor and the individual who is receiving it. This decision should be based on a number of factors and should include an assessment of the underlying blood glucose control of that individual. For example, someone who has poor blood glucose control as assessed by their HbA1c (this is the blood test that is used to assess average blood glucose control over the preceding 8 to 12 weeks), may benefit from the addition of the SGLT 2 inhibitor without the need for any reduction in their insulin or insulin secretagogues dose. Conversely, an individual with better controlled HbA1c may need a reduction in their insulin or insulin secretagogue dose. As has been described, if the kidney function is poor (GFR <45 mL/min/1.73m2), then the blood glucose-reducing effect of the SGLT 2 inhibitor will be significantly reduced and there may therefore be no reason to make that reduction in insulin or insulin secretagogue.
It is therefore recommended that where the person being prescribed the SGLT 2 inhibitor has diabetes and is on insulin or an insulin secretagogue, the dose of these medications should be reviewed together with their prescribing clinician. If they are on an insulin secretagogue and their HbA1c is <58 mmol/mol and their eGFR >45 mL/min/1.73m2, the insulin secretagogue dose should be reduced by approximately 50% and the insulin by approximately 20% in order to avoid the risk of hypoglycaemia.
Where the person with type 2 diabetes is being prescribed an SGLT 2 inhibitor and they are not on an insulin secretagogue or insulin then there is no need to adjust any other diabetes medications.
There is no evidence to suggest that there is a risk of low blood glucose in people prescribed SGLT 2 inhibitors who do not have type 2 diabetes.
6.2.13 Acute kidney injury
Because of their mechanism of action, there can be an initial small, reversible reduction in kidney function over the first few weeks after commencing an SGLT 2 inhibitor. This results from changes to the blood flow in the kidneys with a small reduction in the blood flow going through the filtering units (glomeruli). This effect is believed to be protective rather than an indicator of harm. In all the major cardiovascular outcome trials, there was an initial small fall in GFR (of the order of 2 to 5% but with wide variation within the individual studies) and thereafter stabilisation of the GFR in participants given an SGLT 2 inhibitor. In the placebo group, there was a slow progressive decline in GFR such that the kidney function of the placebo-treated participants was significantly lower than the SGLT 2 inhibitor-treated participants at the end of the study.
Further reassurance of the lack of harm and indeed possible beneficial effect of SGLT 2 inhibitors in relation to acute kidney injury is the fact that in all the major cardiovascular outcome trials, kidney studies and heart failure studies, the incidence of acute kidney injury (this is where there is a significant drop in kidney function which is usually reversible) was always greater in the placebo-treated groups compared to the SGLT 2 inhibitor-treated groups. It may even be that SGLT 2 inhibitors protect against acute kidney injury.
It is important that this effect is properly understood so that people who are prescribed SGLT- 2 inhibitors and who may gain significant benefit from these medications do not have them stopped because of changes in GFR if measured in the period following prescription of these agents.
It is therefore recommended that when a person is commenced on an SGLT 2 inhibitor, there is no need to routinely check the kidney function in the early period following initiation of treatment, but this should be undertaken at the next usual review appointment for that individual. Furthermore, it is also recommended that if kidney function is assessed for another reason within the first few weeks following initiation of an SGLT 2 inhibitor, the result needs to be interpreted carefully and unwarranted discontinuation of treatment should not occur.
6.2.14 Dehydration issues
SGLT 2 inhibitors do cause an increase in urine output (diuretic effect), both because of the fact they result in loss of sodium (salt) in the urine but also because the extra glucose in the urine pulls in water to the urine. As a result, people started on these agents can experience an increased frequency of passing urine which is most prominent in the first few weeks after commencing the medication.
For the vast majority of people this is nothing more than a minor issue which reduces over time but there are occasional individuals who are at risk of dehydration when starting an SGLT 2 inhibitor. It is difficult to be certain how often this occurs because in all the trials that have been undertaken with SGLT 2 inhibitors there is variation in how this side effect is reported. In studies where there has been an increased frequency of dehydration issues reported, the increase has been small, affecting an extra 1-2 people out of 100. It is, however, most probable that it is only really relevant to individuals who are already taking “water-tablets” (diuretics) and particularly if they are taking these at high doses.
It is therefore recommended that if a person who is prescribed an SGLT 2 inhibitor is already on either diuretic or blood pressure medication, the prescriber should consider whether an early review to assess for dehydration or low blood pressure is undertaken and if either of these are identified, a reduction in the dose of either of these additional diuretic or blood pressure medications is required. Furthermore, if a person being commenced on an SGLT 2 inhibitor is already on a diuretic, they should be counselled on symptoms of dehydration or low blood pressure so they can seek medical attention if they develop such symptoms.
In addition, it is important again to remind people being treated with SGLT 2 inhibitors to use good sick day guidance and omit SGLT 2 inhibitors if they are unwell.
6.2.15 Peripheral vascular disease
People with CKD, and especially those with diabetes, are at an increased risk of suffering disorders of their cardiovascular system which includes disorders that affect the blood supply to their legs, termed “peripheral vascular disease”.
In all the cardiovascular outcome trials for SGLT 2 inhibitors, issues relating to peripheral vascular disease were monitored and recorded. In one of the larger trials in people with type 2 diabetes (called CANVAS), the medication canagliflozin significantly increased the number of amputations undertaken in the group allocated to an SGLT 2 inhibitor compared to those allocated to placebo. This increased incidence of amputation (mainly of toes) was not identified in any of the other cardiovascular outcome trials which included large numbers of participants who were broadly similar to those recruited to CANVAS. Furthermore, in a study that looked at people with kidney disease and diabetes known as CREDENCE, and which also used canagliflozin, there was no increased risk of amputation despite the fact that this group of participants were at high risk of vascular disease. Because of these findings a warning has been placed by the regulators in relation to using canagliflozin in people at high risk of amputation.
It is important to appreciate that any increased risk of amputation, if it exists, is significantly less than the benefits canagliflozin treatment would have in those individuals. It is for this reason that we recommend that when a person has evidence of active foot disease caused by problems with the blood supply, no SGLT 2 inhibitor should be started and if they have already been commenced on one of these agents then this should be withheld. However, because of the benefits that are likely to occur in these individuals it is also a recommendation that once the active foot disease has been effectively treated, discussion should occur with the individual in relation to the risks and benefits so that a decision can be made whether the resumption of an SGLT 2 inhibitor is in the person’s interests and in accordance with their wishes. Similarly, a discussion of this nature should be held prior to commencing an SGLT 2 inhibitor in a person with high risk of vascular disease.
We define active peripheral vascular disease as the presence of foot ulcers, what is termed intermittent claudication (which is when there is pain over the back of the calves associated with walking) or where there is other evidence of reduced blood supply to the legs and feet.
In order to reduce the chance of any harm occurring to a person prescribed SGLT 2 inhibitors, we recommend that all such individuals (and most particularly individuals with diabetes) should be given advice on good foot care and the importance of seeking early attention should any problems develop.
6.2.16 Bone Health
Within the CANVAS trial there was a small increase in fractures in the group allocated to canagliflozin. However, this has not been identified in any other cardiovascular outcome trial using an SGLT 2 inhibitor, nor in other studies using canagliflozin, such as CREDENCE. Therefore it is uncertain as to whether this is a real effect or just a result of the play of chance in that trial. People with CKD are at a greater risk of suffering from bone disorders and good practice already recommends that all these individuals should have measurements of good bone health monitored on a regular basis. It is our recommendation that any person with kidney disease who is commenced on an SGLT 2 inhibitor should receive the good care in relation to their bone health as recommended by national guidelines.
6.2.17 Fungal genital infections (i.e. thrush)
Because the use of SGLT 2 inhibitors results in an increase in sugar in the urine, this can provide an environment in which certain fungal infections thrive and therefore an increase in these infections locally. These infections are termed genital infections and are typified by thrush, which is not an uncommon infection, particularly in women and particularly in people with diabetes.
All SGLT 2 inhibitors increase the risk of thrush. This is not a dangerous complication, but can cause irritation and needs to be managed appropriately. Symptoms involve irritation or itchiness and redness or inflammation in the genital area (vulva-vagina for women and tip of the penis in men (inflammation of which is known as balanitis)). It is most likely that the risk is greater if the person being treated has type 2 diabetes.
Before anyone starts an SGLT 2 inhibitor they need to be counselled on the risk of fungal genital infections such as thrush and on simple measures that they can implement to maintain good genital hygiene and thereby reduce the risk of thrush. They also need to be counselled on the symptoms of genital infections and how to seek help which can often be attained simply by attending a local pharmacist to obtain an antifungal cream.
This advice is most particularly important for men as they may not have as much knowledge of thrush as women.
If genital infections such as thrush occur while a person is using an SGLT 2 inhibitor they should be treated, but they do not necessarily need to stop the SGLT 2 inhibitor. Usually once treated the genital infection does not recur but if the individual suffers recurrent infections their GP can give them treatment to prevent infections which is either a cream or a tablet they take intermittently.
6.2.18 Fournier’s gangrene
Fournier’s gangrene is a serious infection caused by bacteria infecting the skin in the genital area. It is exceedingly rare but theoretically it could be increased if the individual has an increased glucose concentration in the urine and it is recognised to occur, albeit very rarely, in people with diabetes. Occasional reports have been made of people suffering this complication while being treated with an SGLT 2 inhibitor and because of this the regulators have placed a warning of this complication for people using SGLT 2 inhibitors. It should be pointed out that no increased cases of Fournier’s gangrene were identified in any of the trials undertaken, which included large numbers of participants. However, even though we do not know whether SGLT 2 inhibitors truly increase the risk of this disorder, we recommend that all people started on an SGLT 2 inhibitor are counselled on the symptoms of Fournier’s gangrene and advised to stop their SGLT 2 inhibitor and seek urgent medical attention if they develop such symptoms. The main symptom to be aware of is severe pain on pressing the skin over the groin area.
6.2.19 Urinary infections
SGLT 2 inhibitors produce an increased amount of glucose in the urine, but despite this there is only a very small increased risk of urine infections. This may be because bacteria do not thrive in environments with high glucose or because there is an increase in urine output which works to help “flush away” bacteria in the urinary tract. There is a need to be alert to this, but it is unlikely that a person with a normal bladder and bladder function will have an increased risk of urine infection when using SGLT 2 inhibitors.
6.2.20 Special populations: Children, pregnancy and breastfeeding
There is little experience in using SGLT 2 inhibitors in children and therefore it is not recommended that these medications are used in people under the age of 18.
There is some theoretical evidence that SGLT 2 inhibitors, at much higher doses and in animal models, can potentially result in malformations and therefore the use of these medications in pregnancy should be avoided. If a person who is being treated with SGLT 2 inhibitors wishes to consider pregnancy they should discuss this with their doctor and plan the pregnancy in advance with a plan to stop the SGLT 2 inhibitor prior to becoming pregnant, or if an unplanned pregnancy occurs.
Whilst there is no real evidence to suggest that SGLT 2 inhibitors is passed in the breastmilk in important quantities, it is not recommended that these agents should be used when breastfeeding.