Empagliflozin and dulaglutide: Your questions answered

45 minutes to Delve
Contributor
Dr Ryan Paul
23 April 2021
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The following list of Q&A reflects issues discussed in webinars held early in 2021. The content has been edited, and reviewed by Waikato DHB endocrinologist/diabetologist Dr Ryan Paul.

Scroll through to see the Q&A grouped in sections titled genitourinary/renal, general, cardiovascular, ketoacidosis, and Special Authority funding.

If you would like to contribute to the Q&A list with information that may be helpful to others, please contact us with the details.

Genitourinary/renal

Is there any guidance if a patient develops a UTI while taking empagliflozin?

Empagliflozin should be stopped temporarily, the UTI treated, and the empagliflozin restarted when the patient is well. If UTIs are recurrent, stopping the empagliflozin and switching to an alternative agent should be considered.

Would prophylactic antibiotics such as nitrofurantoin be indicated if someone has a history of recurrent UTIs in order for them to take an SGLT2 inhibitor?

Generally in such patients, long-term antibiotics are not recommended just to allow them to take an SGLT2 inhibitor. Nitrofurantoin should not be used as it can cause pulmonary fibrosis if taken for several months. If a patient is experiencing recurrent urinary problems with empagliflozin, it should generally be stopped. A GLP-1 receptor agonist eg, dulaglutide, could be considered instead as it will also provide significant benefit in terms of reducing cardiovascular and renal disease.

Are genital infections with empagliflozin dose related, and would you drop the dose from 25mg to 10mg daily?

Genital infections such as thrush around the vulva, foreskin or perineum are due to glucose on the skin. The patient is passing glucose in urine, which causes a lot of thrush issues; as the blood glucose level decreases, this tends to resolve. Perineal hygiene such as cleaning twice daily is an important preventive measure and antifungal cream such as clotrimazole can be used to treat active thrush infections. If these infections are going to occur, they are likely to do so with the 10mg dose but if the patient is already taking 25mg it could be reasonable to reduce to 10mg or even stop for a while for significant infections. The 10mg dose can be reintroduced once the infection has gone. It is inadvisable to increase a patient from 10mg to 25mg if there are ongoing problems with recurrent genitourinary infections.

Are there any risk factors for the perineal necrosis that may occur with empagliflozin?

It is not clear what the risk factors are for perineal necrosis but it is likely more common in men and those who are obese, have poorer glycaemic control or are immunocompromised. It is a rare adverse reaction and was included as one by the US Food and Drug Administration because of a few case reports. It is unlikely it will be seen in New Zealand, but the possibility exists; it is just a matter of awareness. Patients should be advised to seek advice if they get pain around the genital area. If there is pain out of keeping with expectations, then as in any necrotising infection assume the worst until it is excluded.

Would a patient with a history of renal calculi, in all other respects, benefit from empagliflozin? Is it safe to start or is it a contraindication?

It's only a precaution and probably related to dehydration and increased urinary excretion of urate. With patients who have a previous history of calculi empagliflozin can be used cautiously with ensuring good hydration, but in patients with recurrent calculi, extra care would be needed.

Do SGLT2 inhibitors reduce proteinuria in patients with diabetic nephropathy?

Yes, and there are several studies now that show this effect with empagliflozin, including the EMPA-REG OUTCOME trial published in 2017 in Lancet Diabetes Endocrinol (https://pubmed.ncbi.nlm.nih.gov/28666775/)

Would you consider withholding an SGLT2 inhibitor such as empagliflozin in acute kidney injury?

Definitely, and the general advice is to stop empagliflozin in the case of any acute illness. It should be made clear to patients that if they are unwell for any cause, they should stop the SGLT2 inhibitor temporarily.

How does renal function as measured by eGFR affect whether use of empagliflozin is appropriate?

Empagliflozin can be used if eGFR is 30mL/min/1.73m² or greater. It is not currently known whether empagliflozin is safe when the eGFR is below 30mL/min/1.73m², so present advice is to not to start or to stop empagliflozin if the eGFR is <30mL/min/1.73m².

Note: The US Food and Drug Administration sets the threshold at 45mL/min/1.73m², but a figure of 30mL/min/1.73m² was recommended by international kidney societies in mid-2020. It used to be 45mL/min/1.73m² in New Zealand but was changed to be consistent with international guidelines. Recent data revealed that dapaglifozin (another SGLT2 inhibitor) is safe with an eGFR down to 25mL/min/1.73m², so this is a rapidly evolving cut off.

Regarding the monitoring of serum creatinine for renal function, is that every two weeks after starting empagliflozin?

It is important to monitor renal function from a baseline before starting empagliflozin. The frequency of subsequent monitoring depends on assessment of risk. In someone who is at lower risk, wait until the next review. But in someone at high risk – for example, they're elderly or taking an ACE inhibitor/angiotensin receptor blocker and diuretics – it may be prudent to monitor renal function earlier. Once a high-risk patient’s renal function is stable, perhaps after a couple of checks after starting empagliflozin, it would be unlikely to have to check creatinine outside of normal monitoring unless clinically indicated.

What diabetes medicines can be used when eGFR is <30mL/min/1.73m²?

This is a common situation and the only options are low-dose metformin (up to 500mg daily) if eGFR is between 15 - 30mL/min/1.73m² or vildagliptin 50mg once a day. Dulaglutide (the GLP-1 receptor agonist that will be available soon) may be able to be used with an eGFR > 15mL/min/1.73m² (as internationally), but Medsafe are yet to decide on the eGFR cut off in New Zealand.

The only other option is insulin.

If a patient’s eGFR was 29mL/min/1.73m² but a calculation using the Cockcroft–Gault formula gave a creatinine clearance of, say, 35mL/min, would you use creatinine clearance and prescribe empagliflozin?

Yes, generally this would be fine. Creatinine clearance is a better measure in these situations and in most cases the results will be similar. SGLT2 inhibitors are probably safe (but less effective) in patients with a low eGFR (less than 30mL/min/1.73m2), but until this safety is confirmed the advice is to avoid them. Even if SGLT2 inhibitors are less effective at lowering blood glucose in patients with low eGFR, they likely still have renal and cardiovascular benefits – research is ongoing.

Note: In some cases a low eGFR may move above the threshold if a dehydrated patient increases their fluid intake. Repeat testing is beneficial if low fluid intake is suspected.

A transient reduction in eGFR may occur when starting an SGLT2 inhibitor; what percentage reduction is acceptable?

Up to 25 per cent is reasonable, but the main issue is monitoring renal function to ensure it is not progressive or permanent.

Are the renal and cardiovascular benefits of empagliflozin dose-related? For example, if the HbA1c level indicates good glycaemic control on 10mg of empagliflozin, would you increase the dose further?

Base the empagliflozin dose primarily on glycaemic control and leave it at 10mg daily if glycaemia is well controlled. The only caveat would be if the intent is to get someone off insulin or sulfonylureas, because the aim is to limit the use of these if possible. There may be benefits in increasing the empagliflozin dose in this scenario.

Would it be reasonable to consider continuing Jardiance in a patient whose eGFR fell below the <30 mL/min threshold, to continue cardiac benefits while knowing that the glycaemic benefits are not there?

Although Jardiance is likely safe in this situation, there are no safety data to confirm this. Therefore, the current Medsafe recommendations are for Jardiance to be stopped at any time the eGFR is < 30 mL/min. However, studies are ongoing to determine the safety of Jardiance in those with poorer renal function. For example, dapagliflozin (another SGLT2 inhibitor) has been shown to be safe down to an eGFR of 25 mL/min/1.73m².

General

What diabetes inequity issues exist for Māori and Pacific peoples?

It is well documented that Māori and Pacific peoples have a higher incidence of type 2 diabetes and have worse health outcomes associated with it, than Europeans. There is a significant shift to younger onset of diabetes in Māori and Pacific peoples; the so-called left-shift. The risk of progression to diabetic kidney disease in Māori and Pacific peoples is significantly higher than other groups and their outcomes are also much worse. The reasons for the disparities are multifactorial and a combination of inequity of care and access to care, poorer control, lifestyle, poverty, genetics and perhaps other factors.

You can read more about inequities in diabetes in the He Ako Hiringa bulletin.

Would Indian people who have type 2 diabetes benefit from empagliflozin?

There are many patients of Indian sub-continent descent who have type 2 diabetes that is hard to manage. Indian men have the highest rate of cardiovascular disease in New Zealand, and in a study of gout patients, Indian men with diabetes had the poorest control. This is a group that will benefit from SGLT2 inhibitors such as empagliflozin.

How will a GLP-1 receptor agonist (eg, dulaglutide) fit into the T2D management pathway?

The GLP-1 receptor agonist that will be funded is dulaglutide, which is given as a once-weekly subcutaneous injection via a device very similar to an insulin pen. GLP-1 receptor agonists also reduce cardiovascular and likely renal disease over and above their effect on glycaemic control. They probably lead to greater weight loss and glycaemic control than SGLT2 inhibitors but they have no benefit for heart failure, and hard renal outcomes (eg, reduction in renal replacement therapy) are awaited.

If patients have heart failure, an SGLT2 inhibitor will be the preferred agent. For other patients, there is no clear-cut decision. The renal benefits for SGLT2 inhibitors are probably greater than with GLP-1 agonists; so, for a patient with renal disease or heart failure, a SGLT2 inhibitor is a good option. If a patient is very overweight or obese, or has cerebrovascular disease, the tendency may be more toward prescribing a GLP-1 receptor agonist.

PHARMAC will have one Special Authority for both new agents, so it will be straightforward to switch from empagliflozin to dulaglutide when it is available. It will be beneficial to start patients on empagliflozin if there are no contraindications, rather than just waiting a few months and not doing anything. They can be switched to dulaglutide later if indicated. GLP-1 receptor agonists are often a good alternative to basal insulin, and more educational material will be available later in the year when it is expected their place in treatment will be discussed in more detail.

PHARMAC has funded empagliflozin in preference to dapagliflozin. How do they compare?

The medicines are in the same class and have similar adverse effect profiles, so PHARMAC has funded one preferred agent. While further head-to-head studies are required, the indications are that empagliflozin is associated with a better reduction in some clinical outcomes than dapagliflozin, including cardiovascular events.

Are there any clinical concerns about using dulaglutide in combination with empagliflozin, or is it purely a funding decision?

It's a funding decision – only one of these agents may be funded on Special Authority for a patient at any time. There are likely 250,000 New Zealanders with diabetes who may benefit from these agents but as a small country New Zealand has finite resources. In an ideal world, clinicians would probably prescribe metformin, empagliflozin and dulaglutide to many patients with type 2 diabetes.

What is the equivalent dose when switching from dapagliflozin to empagliflozin?

When switching from dapagliflozin to empagliflozin, start with 10mg daily, and increase to 25mg daily if necessary and tolerated.

Can patients be on glipizide, vildagliptin and empagliflozin?

Yes, but there may be an opportunity to get patients off some of their medicines. The ideal scenario would be to start empagliflozin in patients taking a sulfonylurea and vildagliptin and, if possible, stop the sulfonylurea as it causes weight gain and can cause hypoglycaemic episodes. When dulaglutide becomes available, it may be more possible to stop insulin in some patients, particularly if they are on relatively low doses of insulin.

There seems to be a drive in some general practices towards promoting low-carbohydrate diets for people with type 2 diabetes; where does this fit in with current thinking in terms of pharmacological agents?

This is about the only patient group for which the SGLT2 inhibitors will have the potential for risk (as a low-carbohydrate diet may increase the risk of diabetic ketoacidosis). This is a group where, if choosing between an SGLT2 inhibitor and GLP-1 receptor agonist, you may choose a GLP-1 receptor agonist (dulaglutide) – once it's available. There is an obvious potential for hypoglycaemic episodes with a low-carb diet if on insulin or sulfonylureas, but the SGLT2 inhibitors are the only other medications where extra consideration of this is needed (because of the added risk of DKA). Metformin, vildagliptin, pioglitazone and GLP-1 receptor agonists are absolutely fine in people on low-carb diets.

Should we be more cautious about starting an SGLT2 inhibitor if the patient has had uncontrolled type 2 diabetes for a long period (ie, pancreatic beta cells are likely to have died and there is a risk of diabetic ketoacidosis)?

Yes, more caution is needed, particularly due to the significant glycosuria patients will develop. However, in this scenario, particularly if they have poor blood glucose control (eg, HbA1c >100mmol/mol), it is probably necessary to start insulin first or at least concomitantly to achieve better glycaemic control. But these patients will still greatly benefit from empagliflozin.

If Galvumet (metformin and vildagliptin) preserves insulin cells in the same way metformin does, why aren't we encouraged to first maximise Galvumet before other medicines?

It is not yet known whether SGLT2 inhibitors and GLP1 receptor agonists delay the need for insulin therapy (they probably do, but this has not been confirmed). The main issue to consider about vildagliptin is that it doesn't offer any other benefits beyond glycaemic control. In order to reduce cardiovascular or renal risk, it will be beneficial to add in an SGLT2 inhibitor, or GLP-1 receptor agonist when it comes becomes available. For patients who don't have renal or cardiovascular disease, vildagliptin is an ideal second-line agent. Many patients with type 2 diabetes could be started on Galvumet; it depends on glycaemic targets and other risk factors.

In a patient with low blood pressure (100mmHg systolic or less) and heart failure, and on the maximum dose of carvedilol, ACE inhibitor and frusemide, can I still start an SGLT2 inhibitor?

Yes, this is possible, but particular awareness of the risk of hypotension is required. The patient must be warned to look out for this and to make sure they are adequately hydrated before starting the SGLT2 inhibitor. This is an example of where the dose of frusemide and/or their antihypertensives could be reviewed and reduced or possibly stopped before starting empagliflozin, to reduce the risk of hypotension. In most patients the reduction in BP is minimal.

How do you recommend a patient up-titrates when starting metformin? How slow should one go?

There's never a time that metformin must be started urgently – except, perhaps, during pregnancy. Normally up-titration is slow, and the rate may be influenced by whether the patient has been on metformin previously and has any adverse effects. The dose can usually be doubled weekly if the patient has no adverse effects. A young patient who may be expected to tolerate it well can be started on 500mg twice a day. In principle, the starting dose and titration rate is individualised and if there are concerns about tolerance, the dose can be started at 250mg once or twice a day, and doubled every week up to 2 g per day. I do not use doses of metformin more than 2 g per day as there is very little benefit, but patients do develop more adverse effects. [Dr Ryan Paul, endocrinologist and diabetologist, Waikato DHB]

With several combination products available containing metformin, I guess you have to be careful about double dosing of metformin?

Yes, this is an important concern, the total daily metformin dose needs to be considered. Jardiamet (empagliflozin and metformin) can be prescribed, for example, when replacing the daily metformin dose with the addition of empagliflozin. However, if the patient is already taking Galvumet (vildagliptin and metformin), start with Jardiance (empagliflozin).

How long does it take to see full therapeutic benefit from empagliflozin? Do you taper sulfonylureas at that point?

A fairly good idea of therapeutic benefit is evident within the first two weeks as the glucose-lowering effects occur relatively quickly. When there is concern about the risk of hypoglycaemia, the dose of sulfonylurea should be lowered on starting empagliflozin. After a few weeks the sulfonylurea dose may be increased, once certain there is no risk of hypoglycaemia.

When would you stop a sulfonylurea on starting an SGLT2 inhibitor?

If there is a risk of hypoglycaemia. These are typically the patients with an HbA1c <64mmol/mol. In all patients the aim is to get them off sulfonylureas if possible.

Why consider empagliflozin as a second-line agent if there is no renal disease or cardiovascular disease, and it is not a primary preventer?

Of all the other glucose-lowering agents we have available, vildagliptin is probably the best but it is weight-neutral, whereas empagliflozin tends to cause weight loss. Pioglitazone, sulfonylureas and insulin all lead to weight gain. One of the biggest issues we have in our patients is obesity and its associated complications. Therefore, if there is concern about weight gain and hypoglycaemia – the most important adverse effects of our diabetes medicines – SGLT2 inhibitors such as empagliflozin are a good second-line option.

Are the renal and cardiovascular benefits of empagliflozin dose-related? For example, if the HbA1c level indicates good glycaemic control on 10mg of empagliflozin, would you increase the dose further?

Base the empagliflozin dose primarily on glycaemic control and leave it at 10mg daily if glycaemia is well controlled. The only caveat would be if the intent is to get someone off insulin or sulfonylureas, because the aim is to limit the use of these if possible. There may be benefits in increasing the dose of empagliflozin in this scenario.

How does empagliflozin compare with vildagliptin, and what would make you choose one over the other?

Empagliflozin will probably provide greater glucose-lowering effect than vildagliptin. For example, the mean reduction in HbA1c with vildagliptin is about 5mmol/mol; slightly more (about 10mmol/mol) may be achieved with empagliflozin. In addition, vildagliptin is weight-neutral, and evidence to date suggests it has no benefits on cardiovascular or renal disease over and above glycaemic control.

Do you think the standard is going to end up being metformin, empagliflozin, vildagliptin then insulin?

Vildagliptin is like a “poor cousin” of the GLP-1 receptor agonist, so there will be a place for a GLP-1 receptor agonist (dulaglutide) as well. Vildagliptin is still a good agent to use in the elderly or in patients with an eGFR <30mL/min/1.73m². They are a group that is really going to benefit. If a patient has no evidence of diabetic renal disease or cardiovascular disease, and they're of normal weight, there's no real benefit for an SGLT2 inhibitor over vildagliptin. So there is still a large group of patients where vildagliptin will be the preferred second-line agent. If a patient is starting empagliflozin and they are already on vildagliptin, it is important not to stop it.

Is empagliflozin contraindicated in patients with abnormal but relatively stable liver function tests due to severe fatty liver disease?

Dose adjustment of empagliflozin is not required in hepatic impairment. It is advisable to avoid empagliflozin in patients with marked hepatic decompensation, but in all other patients it is safe to use. Fatty liver usually improves; obviously, if glycaemic control is improved, fatty liver disease is improved.

Does empagliflozin have any effect on the “dawn phenomenon”?

The dawn phenomenon, the rise in early-morning glucose levels, is likely due to nocturnal increases in levels of cortisol, growth hormone and testosterone. Although empagliflozin lowers glucose levels, any specific effect on the dawn phenomenon is undetermined and doubtfully would completely prevent it. Generally, the dawn phenomenon is less likely to be significant in type 2 diabetes.

Can you go straight to an empagliflozin dose of 25mg daily?

Best practice is to start on 10mg daily and increase to 25mg daily if necessary and tolerated.

Is there any increase in lower extremity amputation rate with empagliflozin as there was with canagliflozin?

Initial studies with canagliflozin did show an increased risk of amputation, but this hasn’t been seen in phase IV studies for canagliflozin or any other SGLT2 inhibitors. Peripheral vascular disease should not be a contraindication to using SGLT2 inhibitors.

Where can I find patient information on sick-day management for empagliflozin?

NZSSD is having ongoing discussion with empagliflozin manufacturer Boehringer Ingelheim about changing sick-day management in their patient information. NZSSD is aiming to develop a standard sick-day management plan for everyone with diabetes in New Zealand, regardless of which medication a patient is on. The main advice to patients is, if they have nausea, vomiting or abdominal pain while on empagliflozin, to get their blood ketone levels checked, regardless of glucose level.

Patient information, including sick day management is available here:

Where can I get the Jardiance (empagliflozin) and the Jardiamet (empagliflozin and metformin) booklets?

The branded booklets are only available through Boehringer Ingelheim pharmaceutical representatives, and are being made available in English, Tongan, te reo Māori and Samoan. Other printable patient information on these medicines is readily available from Health Navigator and Medsafe.

For a patient on insulin and empagliflozin 10mg with good glycaemic control, can the insulin be stopped?

Yes, but stopping insulin may result in a return to hyperglycaemia. If a patient is on empagliflozin and more than 10 units of insulin a day with good glycaemic control without hypoglycaemia then it is probably best to leave as status quo. You could consider stopping insulin in patients who are on doses less than this. If the patient is having hypoglycaemia then you should be reducing the dose of insulin. However, you may be able to stop the insulin before you start empagliflozin if they have good glycaemic control (eg, HbA1c < 60 mmol/mol) and they are on less than 15 – 20 units of insulin per day. These patients will need a reduction in the dose of their insulin regardless. The most important aspect of management is frequent monitoring of blood glucose levels to guide necessary titration of insulin. Once dulaglutide becomes available, you may be able to get patients off insulin who are on less than 40 units per day.

If a patient is female and of childbearing age, would you still commence empagliflozin?

Yes, but contraception should be discussed. There are no data on the safety of empagliflozin in pregnancy and it is unknown if it is safe or unsafe. However, as many of these patients are already on an ACE inhibitor and perhaps a statin, which are contraindicated in pregnancy, they should be on appropriate contraception anyway. If a woman becomes pregnant during treatment with empagliflozin, it should be stopped immediately.

As dehydration increases the risk of adverse effects with SGLT2 inhibitors does that mean we need to stop them as our patients get older?

There is no clear guidance at present; it is dependent on clinical judgement. If there is concern about a patient being at increased risk as they become frailer, with multimorbidity and polypharmacy, stopping the SGLT2 inhibitor should be considered. This is also in line with the general principle to step down treatment as patients get older or frail as the benefits on cardiovascular or renal outcomes become less significant compared with potential harms of treatment.

If you need to decrease insulin after starting empagliflozin, do you decrease the basal, the short-acting insulin or both?

It may be necessary to decrease both, particularly if there is concern about hypoglycaemia. However, many patients are on too much basal versus short-acting insulin and just reducing the basal may be enough.

Are specific guidelines available for the use of SGLT2 inhibitors and GLP-1 receptor agonists in patients of Indian ethnicity, given their diabetes risk and prevalence is similar to that of Pacific peoples?

In the New Zealand setting, there's no evidence any of these medications are more or less effective based on ethnicity alone. However, the risk of diabetic complications in Māori, Pacific and Indian peoples is a lot higher. These are the groups that will really benefit from these medicines as cardiovascular and renal risk are being targeted in addition to the other measures. This is not a pharmacogenomic decision based on ethnicity, it is based on cardiovascular and renal risk.

What about young patients with type 2 diabetes who have low cardiovascular risk based on their age. How do these medicines fit with this group?

One of the problems with cardiovascular risk assessment in young people is that, by virtue of their age, the calculated 5-year CVD risk is not usually high. Although there is no evidence that SGLT2 inhibitors are beneficial in primary prevention of cardiovascular events, it is important to look at the whole picture to help in decision making. For example, most young patients with type 2 diabetes are overweight or obese and will benefit from SGLT2 inhibitors long term. It is also important to realise that type 2 diabetes in young people is almost a different disease than that in older people; it is a lot more progressive and associated with complications a lot earlier.

If a patient is well-controlled on Galvumet (vildagliptin plus metformin), would you consider switching to Jardiance (empagliflozin)?

Yes, if they have renal or cardiovascular disease, but I would continue the metformin and switch the vildagliptin to empagliflozin. Also consider switching if the patient is overweight. If they are well controlled with no renal or cardiovascular disease, they can stay on Galvumet. You may also choose to add empagliflozin to Galvumet, particularly if their HbA1c is above target as you will not increase their risk of hypoglycaemia.

Is a SGLT2 inhibitor contraindicated in the fasting month of Ramadan?

If the person is not fasting all day and if the person is still getting enough carbohydrate intake – it should be fine to continue the patient on the SGLT2 inhibitor. It is important to discuss with the patient and weigh up carbohydrate intake and the risks of dehydration. Patients can decide to opt out of fasting, particularly if they have advanced diabetes. Reassuringly, there is no increased prevalence of DKA in Muslim populations during Ramadan.

Do SGLT2 inhibitors reduce uric acid?

Yes, this is an exciting benefit of SGLT2 inhibitors. Studies in terms of their effects on gout are underway. To date, there's no evidence SGLT2 inhibitors conclusively reduce gout, but there's very good evidence they reduce uric acid levels. Watch this space.

Is an SGLT2 inhibitor best taken mane or nocte?

Any time of day is fine, although taking it in the morning may be more convenient in terms of the dysuria effect.

Should weekend binge drinkers stop taking their SGLT2 inhibitor over the weekend?

This must be assessed case by case. Many patients will be absolutely fine. Consider stopping the SGLT2 inhibitor if there is concern about the risk of diabetic ketoacidosis due to heavy alcohol intake or other factors.

Does the weekly injection of the GLP-1 agonist, dulaglutide, have any advantages compared with SGLT2 inhibitor empagliflozin?

In terms of the evidence base, dulaglutide reduces the risk of non-fatal stroke or cerebrovascular disease, which SGLT2 inhibitors don't do, to date. Dulaglutide also causes greater weight loss and probably better improves glycaemic control than empagliflozin.

Can empagliflozin be used as monotherapy if metformin is not tolerated?

Yes

Should Jardiance be stopped peri-operative for 3 days?

Jardiance should be stopped for 2 days before surgery and the day of surgery. It can be restarted once the patient is well and eating drinking and normally.

If a patient is on vildagliptin and empagliflozin, and you switch the empagliflozin to dulaglutide, should you then stop the vildagliptin?

Yes. Patients should not be on vildagliptin (Galvus) and a GLP-1 agonist due to the likely no additional benefit, but increased risk of adverse effects.

In long-duration T2D patients on insulin, is there any benefit of C-Peptide testing before starting an SGLT2?

I suspect it wouldn’t change your management at all as you know they are very likely to be insulin deficient and the risk of DKA is still rare, so I wouldn’t bother. However, these are the patients you want to ensure are well informed on sick day management and who are not on low carb diets.

What other medications may benefit a 40yo Māori man who has had T2D for 7 years; on Galvumet 50/1000 and insulin 30mg; HbA1c 99 mmol/mol; weight 120 kgs; minimal exercise and poor nutrition?

Based on the limited history given, it appears he would be a good candidate for metformin, empagliflozin and dulaglutide (unfortunately dual empagliflozin and dulaglutide therapy is not funded) given his likely obesity and high HbA1c. You may also consider pioglitazone depending on the circumstances. Regardless, he will likely need to continue on his insulin therapy unless major changes to his lifestyle are made.

A lot of patients are fasting for two days a week; for example, with the five-and-two diet. Can they use empagliflozin and stop it on those days?

Yes, that would be reasonable. There's no blanket rule, and care must be taken as reduced carbohydrate intake can increase the risk of diabetic ketoacidosis. But if a patient has a known risk of DKA – and by default they have to be relatively insulin-deficient to have DKA – and is on insulin and a low-carbohydrate diet, it is best to steer clear of empagliflozin in these situations. For other patients it should be fine, but caution is required.

What advice would you give for a type 2 diabetic patient who runs marathons? Stop empagliflozin two days prior?

There is a risk of diabetic ketoacidosis, so the best advice if they are going to run a marathon is to stop empagliflozin. Empagliflozin could be restarted when the patient is well hydrated and eating normally, probably 24 hours or so after the marathon.

Should we be more cautious about starting an SGLT2 inhibitor if the patient has had uncontrolled type 2 diabetes for a long period (ie, pancreatic beta cells are likely to have died and there is a risk of diabetic ketoacidosis)?

Yes, more caution is needed, particularly due to the significant glycosuria patients will develop. However, in this scenario, particularly if they have poor blood glucose control (eg, HbA1c >100mmol/mol), it is probably necessary to start insulin first or at least concomitantly to achieve better glycaemic control. But these patients will still greatly benefit from empagliflozin.

Cardiovascular

Apparently SGLT2 inhibitors lower blood pressure – is this an effect of their use alone?

Some cardiologists are using empagliflozin off-label for heart failure, in patients without diabetes. There are reductions in systolic BP with empagliflozin but they are modest, in the order of 2–4mmHg.

Are the renal and CV benefits of empagliflozin dose-related? For example, if the HbA1c level indicates good glycaemic control on 10mg empagliflozin, would you increase the dose further?

Base the empagliflozin dose primarily on glycaemic control and leave it at 10mg daily if glycaemia is well controlled. The only caveat would be if the intent is to get someone off insulin or sulfonylureas, because the aim is to limit the use of these if possible. There may be benefits in increasing the empagliflozin dose in this scenario.

In a patient with low blood pressure (100mmHg systolic or less) and heart failure, and on the maximum dose of carvedilol, ACE inhibitor and frusemide, can I still start an SGLT2 inhibitor? 

Yes, this is possible, but particular awareness of the risk of hypotension is required. The patient must be warned to look out for this and to make sure they are adequately hydrated before starting the SGLT2 inhibitor. This is an example of where the dose of frusemide could be reviewed and reduced or possibly stopped before starting empagliflozin, to reduce the risk of hypotension. In most patients the reduction in BP is minimal.

To be eligible for empagliflozin, CVD risk needs to be greater than 15 per cent; is this clinical cardiovascular risk or calculated risk?

It is calculated risk, but any ischaemic heart disease, or cardiovascular disease or event, will provide eligibility; for example, transient ischaemic attack, angina or previous stent placement. Familial hypercholesterolaemia, although rare, also qualifies, with or without cardiovascular risk calculation.

Is the benefit in HF both for reduced and preserved ejection fraction?

The main known benefit is for those with reduced ejection fraction because that has been the inclusion criteria for the studies. However, I would have no hesitation in using empagliflozin in those with preserved ejection fraction.

Doesn’t having T2D automatically increase your CVD risk to >15% anyway - so anyone with T2D would theoretically be eligible for empagliflozin?

Diabetes does not automatically increase your CVD risk to > 15%, particularly in younger patients. The older CVD risk calculators likely overestimated risk, so you will still need to check the CVD risk if required.

Does rheumatic heart disease count as CVD for the funding criteria?

Heart failure (including reduced ejection fraction from valvular heart disease) is considered part of CVD for the Special Authority criteria.

Are there any contraindications to starting these new meds immediately post MI? Is metformin still contraindicated immediately post MI and for how long?

There are no contraindications if the patient is stable post MI, but I would not start empagliflozin in an unwell patient (including heart failure). Similarly, I would not start metformin in a patient with heart failure or who was going to have an angiogram/angioplasty post MI, due to the risk of contrast-induced renal injury. However, I would have no problems starting metformin in a patient who is stable post MI with no planned interventions.

What about young patients with type 2 diabetes who have low cardiovascular risk based on their age. How do these medicines fit with this group?

One of the problems with cardiovascular risk assessment in young people is that, by virtue of their age, the calculated 5-year CVD risk is not usually high. Although there is no evidence that SGLT2 inhibitors are beneficial in primary prevention of cardiovascular events, it is important to look at the whole picture to help in decision making. For example, most young patients with type 2 diabetes are overweight or obese and will benefit from SGLT2 inhibitors long term. It is also important to realise that type 2 diabetes in young people is almost a different disease than that in older people; it is a lot more progressive and associated with complications a lot earlier.

Ketoacidosis

What are the primary symptom presentations you see in ketoacidosis? What should we watch out for?

Nausea, vomiting and abdominal pain. Patients will be breathing fast or there will be a smell of ketones and, generally, they always will be feeling unwell. Always check for capillary ketones, as ketoacidosis can occur with normal glucose levels in patients on SGLT2 inhibitors.

Do people still use urine ketone testing if ketoacidosis is suspected?

Testing for urinary ketones is not recommended as SGLT2 inhibitors decrease the urinary excretion of ketones and may provide ‘falsely reassuring’ results. Always check for capillary ketones, as ketoacidosis can occur with normal glucose levels in patients on SGLT2 inhibitors.

Do practices have the ability to measure blood ketones?

If practices are not able to measure point-of-care capillary ketones then they can get a free CareSens Dual meter and strips to measure capillary ketone levels.

How often do you test serum ketones in asymptomatic patients on empagliflozin?

It is not necessary to regularly test for ketones. Only test when ketoacidosis is suspected.

I thought diabetic ketoacidosis only occurred in people with type 1 diabetes?

Diabetic ketoacidosis can occur in any form of diabetes. In type 2 diabetes, it typically only happens in end-stage disease. Remember, when most patients are diagnosed with type 2 diabetes, they've already lost 50 per cent of their pancreatic beta cells and the remaining beta cells continue to die over the next 10 to 15 years. Most patients with type 2 diabetes, if they get to end-stage disease, will be at risk of diabetic ketoacidosis.

Is there a risk of ketoacidosis in a patient with normal glucose levels?

Yes, particularly with SGLT2 inhibitors but it can also occur in pregnancy or after significant exercise. Glucose levels may be absolutely normal and the patient may still have ketoacidosis. Don’t base the testing of ketone levels on blood glucose, base it on patient condition.

A lot of patients are fasting for two days a week; for example, with the five-and-two diet. Can they use empagliflozin if they're just going to stop it on those days?

Yes, that would be reasonable. There's no blanket rule, and care must be taken as reduced carbohydrate intake can increase the risk of diabetic ketoacidosis. But if a patient has a known risk of DKA – and by default they have to be relatively insulin-deficient to have DKA – and is on insulin and a low-carbohydrate diet, it is best to steer clear of empagliflozin in these situations. For other patients it should be fine, but caution is required.

What advice would you give for a type 2 diabetic patient who runs marathons? Stop empagliflozin two days prior?

There is a risk of diabetic ketoacidosis, so the best advice if they are going to run a marathon is to stop empagliflozin. Empagliflozin could be restarted when the patient is well hydrated and eating normally, probably 24 hours or so after the marathon.

Should we be more cautious about starting an SGLT2 inhibitor if the patient has had uncontrolled type 2 diabetes for a long period (ie, pancreatic beta cells are likely to have died and there is a risk of diabetic ketoacidosis)?

Yes, more caution is needed, particularly due to the significant glycosuria patients will develop. However, in this scenario, particularly if they have poor blood glucose control (eg, HbA1c >100mmol/mol), it is probably necessary to start insulin first or at least concomitantly to achieve better glycaemic control. But these patients will still greatly benefit from empagliflozin.

Special Authority funding

To see an abbreviated version of the Special Authority criteria for empagliflozin and dulaglutide click here.

If a patient has self-funded empagliflozin, and responded well, will they still be eligible for Special Authority now?

Yes, if the patient’s HbA1c level was above 53mmol/mol before they self-funded and it is now to target, it is still fine to apply for the Special Authority.

If a patient has completed a three-month trial of dapagliflozin and has an HbA1c level under 53mmol/mol, can they be changed to funded empagliflozin (Jardiance)? Their HbA1c level prior to starting was in the 70s.

Yes, this is correct interpretation of the Special Authority criteria. When switching from dapagliflozin, which only comes in one dose (10mg) daily, it's recommended to switch to 10mg daily of empagliflozin initially and increase to 25mg daily if necessary and tolerated.

Empagliflozin Special Authority criteria mention type 2 diabetes onset as a young-adult patient – what is the definition of this?

In a supporting document, PHARMAC states disease onset under 25 years of age could be defined as meeting this criterion. However, a patient in their early thirties may still be considered as a young adult (the CDC defines young adults in relation to diabetes as those aged 19-34y).

PHARMAC guidance states: ‘We have been unable to identify an internationally accepted definition of young-onset type 2 diabetes. In general, we consider that a person with onset of disease under the age of 25 could be defined as meeting this criterion. However, we know you will use your clinical judgement.’

Do you lose the Special Authority for Jardiance (empagliflozin) if the patient wants to self-fund dulaglutide?

No, Special Authority will apply to one of them, either empagliflozin or dulaglutide. As empagliflozin is cheaper, it would make sense to apply for a Special Authority for dulaglutide and have the patient self-fund empagliflozin.

Are there any clinical concerns about using dulaglutide in combination with empagliflozin, or is it purely a funding decision?

It's a funding decision – only one of these agents may be funded on Special Authority for a patient at any time. There are likely 250,000 New Zealanders with diabetes who may benefit from these agents but as a small country New Zealand has finite resources. In an ideal world, clinicians would probably prescribe metformin, empagliflozin and dulaglutide to many patients with type 2 diabetes.

To be eligible for empagliflozin, cardiovascular risk needs to be greater than 15 per cent; is this clinical cardiovascular risk or calculated risk?

It is calculated risk, but any ischaemic heart disease, or cardiovascular disease or event, will provide eligibility, for example, transient ischaemic attack, angina or previous stent placement. Familial hypercholesterolaemia, although rare, also qualifies, with or without cardiovascular risk calculation.

Will I be able to switch a patient from funded empagliflozin to funded dulaglutide (once it’s available) if clinically appropriate?

PHARMAC will have one Special Authority for both new agents, so it will be straightforward to switch from empagliflozin to dulaglutide when it is available. It will be beneficial to start patients on empagliflozin if there are no contraindications, rather than just waiting a few months and not doing anything. They can be switched to dulaglutide later if indicated.