Dulaglutide and empagliflozin: Your questions answered (2)

45 minutes to Delve
Contributor
Dr Ryan Paul
13 October 2021
Dulaglutide Questions and Answers

Following on from presentations in February, this new resource covers discussions from webinars held in August 2021. The content has been edited, and reviewed by Waikato DHB endocrinologist/diabetologist Dr Ryan Paul, and is current at the time of publication (14 October 2021).

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Tips for navigating this Q&A

Content has been grouped into the following sections. Click the headings to be taken straight to that section, or scroll through the content below to view all questions.

  1. Talking with your patient
  2. Dulaglutide or empagliflozin?
  3. Dosing and administration
  4. Use in particular patient groups
  5. Reduced food intake, elective surgery, sick-day management
  6. Funding and Special Authority
  7. General
This resource is the second part of our Q&A series. To view part one, click here.


Talking with your patient

The questions and answers in this section have been taken from our dulaglutide algorithm resource, which can be found here.

What are the expected benefits of dulaglutide?

Dulaglutide:

  • reduces the risk of non-fatal myocardial infarction (heart attack), non-fatal stroke or death from cardiovascular causes by 12% in patients with and without a history of cardiovascular disease1,2,3
  • reduces death from all causes by 11%3
  • reduces blood total cholesterol, low-density lipoprotein cholesterol and triglyceride levels4
  • reduces systolic blood pressure by 2–3mmHg5,6
  • helps preserve renal function (slows decline in GFR and onset of end-stage kidney disease or renal death) – driven largely by a 24% reduction in macroalbuminuria7
  • reduces HbA1c by as much as 14mmol/mol5,8
  • leads to a possible average 1–3kg weight loss3,5,9
  • may delay the need for insulin in the treatment of type 2 diabetes4
  • carries a low risk of hypoglycaemia; this is only usually seen when used in combination with a sulfonylurea or insulin.3,5

(References for the above can be found within our dulaglutide algorithm here.)

What are the potential adverse effects of dulaglutide?

Dulaglutide may cause:

  • nausea, abdominal discomfort and reduced appetite in up to 20% of patients – by far the most common side effects, most pronounced after the initial dose but tending to settle over a few weeks5
  • more severe gastric disturbance, diarrhoea or vomiting, potentially affecting a person’s ability to tolerate dulaglutide (suspend dulaglutide in acute/severe gastrointestinal illness, until it resolves); be alert for persistent, severe abdominal pain with or without vomiting (reports of pancreatitis are rare but its occurrence requires stopping the drug)5,10
  • injection-site reactions such as redness, soreness and swelling, or transient nodules10
  • systemic hypersensitivity reactions (eg, urticaria, oedema) in about 1 in 200 patients – there are also rare, documented cases of anaphylaxis.5

(References for the above can be found within our dulaglutide algorithm here.)

What are the key points to raise with your patients when talking about dulaglutide?

  • Continue your other medicines unless specifically told to stop by your healthcare provider.
  • Don’t be surprised if you are asked to change the doses of your other blood glucose-lowering medicines over the next four weeks.
  • If using dulaglutide and insulin, avoid using the same injection site and time them separately if you can. Avoid using sites where a nodule may have developed.
  • Drink plenty of fluids and stay well-hydrated, particularly in summer and when exercising.
  • Do not over-indulge in alcohol.
  • Talk with your healthcare provider if you plan to make dramatic dietary changes (eg, a large change in carbohydrates).
  • Remember to check your feet and maintain good foot care.
  • Contact your practice if you notice any infections or rashes.
  • Make sure to tell other healthcare professionals that you are taking dulaglutide.
  • Stop the dulaglutide if you have severe gastrointestinal illness; persistent, severe stomach pains with or without vomiting; or experience a hypersensitivity reaction causing swelling or fluid accumulation, particularly around the face, lips or tongue – seek medical advice urgently and contact your own healthcare provider.

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

Refer to NZSSD Type 2 Diabetes Management Guidelines: Sick day management in patients with diabetes: tinyurl.com/nzssd-sick-day

Where can I find information for patients about dulaglutide?

Patient information can be printed from www.healthnavigator.org.nz/medicines/d/dulaglutide


Dulaglutide or empagliflozin?

We know SGLT2 inhibitors and carbohydrate-restricted diets do not mix. Is it safer for erratic eaters or people trying fad diets to use dulaglutide instead?

Due to the risk of diabetic ketoacidosis (DKA), it is safer to use dulaglutide than empagliflozin in people whose diets have less than 130g of carbohydrate per day, which includes intermittent fasting such as the five and two diet. However, patients who fast throughout the day but still have adequate daily carbohydrate intake, such as during Ramadan, do not appear to be at a greater risk of DKA with SGLT2 inhibitors. If there is any doubt over carbohydrate intake it would be sensible to refer the patient to a dietitian and use dulaglutide rather than empagliflozin in the interim.

Click here to download a PDF of the NZSSD Position Statement on Ketogenic or Very-Low-Carbohydrate Diets and the Use of SGLT2-inhibitors in Adults with Type 2 Diabetes

A 41-year-old female patient with renal failure and eGFR of 31ml/min/1.73m2 has stopped empagliflozin twice because of UTIs and returned to a small dose of insulin. Would dulaglutide be a suitable option instead of empagliflozin?

Dulaglutide would be a suitable alternative, given the woman has had UTIs and has a borderline eGFR for using empagliflozin. It may be possible to get her off insulin again by using dulaglutide.

If dulaglutide is a good second-line medication, what would be third-line if someone still has suboptimal blood glucose control?

Empagliflozin, if it is not contraindicated. Unfortunately, it will not be funded with concomitant dulaglutide, so you may need to try pioglitazone or a sulfonylurea as your next option if patients cannot self-fund empagliflozin.

If a patient needs renal protection (very high ACR, high HbA1c and eGFR 30–39ml/min/1.73m2), would empagliflozin, dulaglutide, or both be preferable?

Empagliflozin would be preferred, at this stage, based on the patient’s renal disease and function. If the HbA1c remains above target then adding dulaglutide would be useful, particularly as they are likely at high risk for cardiovascular disease. However, at present, there is no evidence to confirm that dual empagliflozin-dulaglutide therapy will further reduce renal disease. If both empagliflozin and dulaglutide were used, empagliflozin (the cheaper of the two medicines) would require self-funding.

Why is high alcohol consumption a factor favouring the use of dulaglutide over empagliflozin?

Chronic high alcohol intake is a risk factor for diabetic ketoacidosis. In these people, dulaglutide would be preferred over empagliflozin.

How do you go about switching someone from empagliflozin to dulaglutide?

There are no concerns medically and no ‘washout period’ is required; patients can simply start on dulaglutide when it suits them. Empagliflozin and dulaglutide can be taken concurrently, so the patient may continue taking their remaining supply of dispensed empagliflozin. However, once the Special Authority for dulaglutide is approved, any remaining empagliflozin scripts will need to be self-funded, if filled.

Which treatment is better for patients with atrial fibrillation: dulaglutide or empagliflozin?

Studies suggest that empagliflozin is likely a better agent to use if there is atrial fibrillation, but this is very unlikely to be the sole factor in your decision making between the two agents. Other comorbidities such as heart failure or renal disease (empagliflozin likely better option) or cardiovascular disease (dulaglutide potentially better option) will influence your decision.

Exercising care with dulaglutide in the over-75's is suggested and empagliflozin has similar warnings, yet they seem ideal for such patients who commonly have CHF. Can they be used in these patients?

Age is not a contraindication to these medicines, but it is a precaution, because with increasing age there are typically increased risks of comorbidities, frailty, and adverse effects. Either medicine could be tried but always be aware – probably more so with empagliflozin – of the potential for adverse effects and the requirements of sick-day management. Studies have either not been performed in the very elderly or are limited, so we do not really know the safety or benefit of dulaglutide and empagliflozin in this group.

Can either dulaglutide or empagliflozin be used when patients are having chemotherapy?

Dulaglutide: It is probably safe to continue dulaglutide in a patient who is already taking it and tolerating it well. Consider the adverse effects of chemotherapy (eg, nausea, vomiting, diarrhoea) and recognise that dulaglutide can make these worse, with the potential for acute renal injury if a patient becomes very dehydrated. Therefore, consider withholding the dulaglutide if it is associated with gastrointestinal adverse effects pre-chemotherapy.

Empagliflozin: Be very cautious continuing empagliflozin in someone about to start chemotherapy. Consider the potential adverse effects and the risks of renal injury or diabetic ketoacidosis. If the patient tolerates empagliflozin well enough during the first cycle of chemotherapy, it will likely be fine to keep it going.

It may be best not to start new treatment with dulaglutide or empagliflozin in a patient about to undergo chemotherapy.


Dosing and administration

It is possible to take the weekly dulaglutide injection up to three days late. When do you then time the next dose?

If less than three days late with an injection, the patient can still take the following injection when it was originally due (ie, they can continue with their normal regimen as long as dulaglutide isn’t injected twice within 72 hours). This helps with developing a routine – one day of the week is injection day.

Does dulaglutide cause lipohypertrophy if you fail to rotate injection sites, as with insulin?

Long term injection site reactions such as persistent nodules or lipohypertrophy are rare with dulaglutide, but transient injection site reactions such as redness etc. are not uncommon so rotating injection sites is still advised.

When starting dulaglutide and reducing daily insulin dose by 15 to 20 per cent, does that include rapid-acting, pre-meal insulins, or do we stop these to see how dulaglutide works for the patient?

There is no single answer to this question: insulin dose adjustment must be driven by the patient’s glucose levels. The 15 to 20 per cent insulin reduction is a ballpark figure, and further reductions may be needed.

Both long and short-acting insulins may need to be reduced - the greatest effect on blood glucose will be seen after meals but fasting glucose levels may also be affected. If the patient’s HbA1c is on target, or close to target, and they are on minimal insulin (eg, <5U with meals), it is reasonable to stop insulin altogether. However, a person who requires 20U or 30U of insulin with meals is unlikely to be able to cease insulin altogether, but a 15-20% dose reduction would be a reasonable starting point.

How do you go about switching someone from empagliflozin to dulaglutide?

There are no concerns medically and no ‘washout period’ is required; patients can simply start on dulaglutide when it suits them. Empagliflozin and dulaglutide can be taken concurrently, so the patient may continue taking their remaining supply of dispensed empagliflozin. However, once the Special Authority for dulaglutide is approved, any remaining empagliflozin scripts will need to be self-funded, if filled.

In terms of the initial injections, is it possible to administer a smaller dose of dulaglutide from the device?

There is no demonstrated way to do that. From the studies, there is little difference in adverse effects between the dulaglutide 0.75mg and 1.5mg doses, and that is part of the reason New Zealand has funded the one dose. It is advisable to go with the 1.5mg dose.

Does starting dulaglutide at a lower dose make any difference? And, if needed, is it permitted to double the dose using the currently funded device?

Dulaglutide comes as single-use injectable devices, pre-filled with a 1.5mg dose, and would be very tricky to administer at a different dose. Studies have not shown any significant differences in adverse effects between the 0.75mg and 1.5mg doses so, for now, staying with the one 1.5mg dose makes it easier as we get used to using it.

What is the purpose of the higher dose formulations of dulaglutide?

Only the 1.5mg dosing unit is available in New Zealand currently. The higher doses of dulaglutide (3mg and 4.5mg) available internationally are associated with greater reductions in HbA1c and more weight loss.

Although we do not yet have any higher doses of dulaglutide in New Zealand, when would dose-escalation be appropriate?

At present, Medsafe advise that the 1.5 mg injections of dulaglutide should not be administered more than once per week.


Use in particular patient groups

Can either dulaglutide or empagliflozin be used when patients are having chemotherapy?

Dulaglutide: It is probably safe to continue dulaglutide in a patient who is already taking it and tolerating it well. Consider the adverse effects of chemotherapy (eg, nausea, vomiting, diarrhoea) and recognise that dulaglutide can make these worse, with the potential for acute renal injury if a patient becomes very dehydrated. Therefore, consider withholding the dulaglutide if it is associated with gastrointestinal adverse effects pre-chemotherapy.

Empagliflozin: Be very cautious continuing empagliflozin in someone about to start chemotherapy. Consider the potential adverse effects and the risks of renal injury or diabetic ketoacidosis. If the patient tolerates empagliflozin well enough during the first cycle of chemotherapy, it will likely be fine to keep it going.

It may be best not to start new treatment with dulaglutide or empagliflozin in a patient about to undergo chemotherapy.

Can dulaglutide be used by patients who have had bariatric surgery?

Yes, dulaglutide is still beneficial in patients who have persistent T2D following bariatric surgery and it may help with some bariatric surgery-induced complications such as dumping syndrome.

Is dulaglutide appropriate for type 2 diabetes in patients with polycystic ovary syndrome?

Definitely. Dulaglutide may induce ovulation in patients with polycystic ovarian syndrome, over and above its effects on glycaemic control and weight loss. Ensure these women are using contraception, particularly since there are no safety data for dulaglutide use in pregnancy.

Are there potential issues with dulaglutide and significant GORD? What about patients on acid suppression – would you use it in that instance?

It is reasonable to try dulaglutide in patients with GORD - if it makes things worse, you can always stop it. Patients with mild GORD may need to take an antacid for the week of the first dulaglutide injection and, if symptoms are too bad, not have any further injections. With more significant GORD, an approach might be to start acid suppression first with a proton-pump inhibitor and, once under control, start dulaglutide – this might only delay dulaglutide by a few weeks. However, it is not advised to use dulaglutide in patients with severe GORD.

Can dulaglutide be started in someone who has deranged liver function test results, and are LFTs part of monitoring when starting patients on dulaglutide?

Dulaglutide can be used safely in a patient with deranged LFTs but not in patients with end-stage liver disease or acute liver failure, as safety data are lacking. A sizeable proportion of patients with T2D have fatty liver disease (and, thus, deranged LFTs), which can be improved with dulaglutide up and above its effects on glucose control. Routine LFT monitoring is not required during treatment with dulaglutide.

Are there any special considerations with using dulaglutide for heart or kidney transplant patients?

Diabetes is very common in post-transplant patients and can contribute to accelerated atherosclerotic disease in the grafts, so diabetes treatment should be aggressive in this group. There are no additional precautions to using dulaglutide in this group.

If a patient with ischaemic heart disease is euglycaemic on metformin, should they be encouraged to self-fund dulaglutide?

Dulaglutide is likely to be beneficial in such a patient, so it would be good to provide them with the treatment option, even if they do not meet the Special Authority funding criteria.

Which treatment is better for patients with atrial fibrillation: dulaglutide or empagliflozin?

Studies suggest that empagliflozin is likely a better agent to use if there is atrial fibrillation, but this is very unlikely to be the sole factor in your decision making between the two agents. Other comorbidities such as heart failure or renal disease (empagliflozin likely better option) or cardiovascular disease (dulaglutide potentially better option) will influence your decision.

A 70yo Māori man, HbA1c 56 on Galvumet 50/1000 once daily, dyslipidaemia, BMI 33, no CVD or renal disease. If we add dulaglutide, should we stop metformin (since HbA1c would be expected to fall further)?

If dulaglutide was started, you would need to stop vildagliptin. Ideally, you’d want to continue metformin at 1g once daily if possible (for it’s likely additional reductions in cardiovascular disease and weight). If the metformin is not tolerated/accepted, this patient’s HbA1c would likely remain < 53 mmol/mol on dulaglutide alone.


Reduced food intake, elective surgery, sick-day management

We know SGLT2 inhibitors and carbohydrate-restricted diets do not mix. Is it safer for erratic eaters or people trying fad diets to use dulaglutide instead?

Due to the risk of diabetic ketoacidosis (DKA) it is safer to use dulaglutide than empagliflozin in diets with less than 130g of carbohydrate per day, which includes intermittent fasting such as the five and two diet. However, patients who fast throughout the day but still have adequate daily carbohydrate intake, such as during Ramadan, do not appear to be at a greater risk of DKA with SGLT2 inhibitors. If there is any doubt over carbohydrate intake it would be sensible to refer the patient to a dietitian and use dulaglutide rather than empagliflozin in the interim.

Click here to download a PDF of the NZSSD Position Statement on Ketogenic or Very-Low-Carbohydrate Diets and the Use of SGLT2-inhibitors in Adults with Type 2 Diabetes

What advice do we give someone experiencing nausea and reduced oral intake for the first couple of weeks after starting dulaglutide, particularly if taking insulin?

When starting dulaglutide, patients should be given advice on when to contact the practice eg, if they have significant side effects, particularly vomiting and/or reduced oral intake, or hypoglycaemia. In such cases the insulin (and/or sulfonylurea) doses will likely need to be further reduced.

Most patients tolerate dulaglutide well, particularly if they have been advised to expect some nausea and that it will pass. The most important thing the patient can do is stay well-hydrated without excess fluid intake (that can make the nausea worse). The nausea is not usually so bad that it stops patients eating altogether.

Are there any recommendations or precautions with dulaglutide use in the peri-operative period or when people are unwell?

Being a weekly injection, dulaglutide may already be in the patient’s system prior to unplanned surgery or becoming unwell. However, if possible, it would be appropriate to withhold the dose for a patient who is about to have gastrointestinal surgery or who has a gastrointestinal illness. There is no risk of diabetic ketoacidosis with dulaglutide, so there are not the pre-procedural worries there are with empagliflozin - follow normal sick-day diabetes management.

Do patients need to stop dulaglutide before surgery if they have a pre-planned procedure?

For planned gastrointestinal surgery, it is likely prudent to withhold dulaglutide. For other surgeries it is probably safe to continue dulaglutide, noting that hypoglycaemia is only a risk if insulin or a sulfonylurea are also being used. Dulaglutide does not appear to affect the quality of bowel prep or impair colonoscopy, so does not routinely need to be stopped before a colonoscopy. However, if the patient is still experiencing gastrointestinal adverse effects from the dulaglutide then it would be reasonable to withhold the dulaglutide before the bowel prep and colonoscopy.


Funding and Special Authority

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

How do you complete the Special Authority (SA) now both dulaglutide and empagliflozin are available?

There are separate SA forms for each medicine - funding is allowed for only one at a time. If you wish to change a patient from one to the other, you simply tick the box stating the patient has previously received approval for funding for one of the two agents.

For patients already self-funding dulaglutide, how do we apply for a Special Authority (SA) exemption?

If the person has been previously using a GLP1RA unfunded, they may no longer meet the initial access criteria. If you can show that the person met the access criteria before they started taking the medicine, they may be eligible for a waiver.

There is no separate waiver form – you will need to download a PDF of the dulaglutide Special Authority form from the Pharmaceutical Schedule and provide additional information to explain any criteria that are not met. This may be hand-written onto the Special Authority form (then scanned and returned to Pharmac by email/fax) or provided by way of additional email and/or clinic letter.

You can find more information here.

The 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.’

Is the cost of dulaglutide something to work out with the pharmacy if patients are self-funding?

The mark-up for unfunded dulaglutide will vary between each community and online pharmacy, so it may be useful for someone who is self-funding dulaglutide to shop around to find the best price. For patients who are on both empagliflozin and dulaglutide and eligible for one of these to be funded on Special Authority, it is cheaper for them to receive funded dulaglutide and self-fund the empagliflozin.

Is dulaglutide currently restricted only to people with type 2 diabetes?

For funded dulaglutide, yes. Using it for other types of diabetes should not be considered without specialist discussion.


General

How quickly are the effects of dulaglutide seen on blood glucose and HbA1c?

Blood glucose levels improve quite rapidly - effects are likely to be seen within 2 or 3 weeks, or immediately if dulaglutide affects the person’s appetite with a subsequent reduction in their carbohydrate intake. Lowering of blood glucose levels continues over the next few weeks. Be aware that patients with rapid changes in dietary intake may need more vigorous action regarding their doses of insulin and sulfonylureas.

HbA1c takes around 3 months to show a meaningful change (because the lifespan of red blood cells is about 120 days – new red cells contain no HbA1c and old cells have the most).

How quickly can we expect to see weight loss with dulaglutide, if a patient is going to lose weight?

The stated mean 2kg weight loss is at 2 years for dulaglutide 1.5 mg weekly (greater weight loss is seen at higher does). A ‘useful response time’ used with anything obesity-related is 12 weeks. If a patient has not responded to pharmacotherapy by then, they are unlikely to lose weight – you should see it within 3 months of starting Duromine, Contrave and Xenical as well. Weight loss is our number one tool for managing T2D and preventing progression from pre-diabetes to T2D. As with any pharmacotherapy aiming for weight loss, it is important to re-emphasise the importance of lifestyle interventions to achieve weight loss with dulaglutide.

Does dulaglutide have any impact on renal function?

Dulaglutide slows down the decline in eGFR in those with diabetic renal disease, but it is different to empagliflozin, which causes a transient reduction in eGFR before stabilisation in eGFR. Dulaglutide does not typically cause any deterioration in renal function but has rarely been associated with acute kidney injury in those patients with significant vomiting and hypovolaemia. Therefore, it is important to encourage patients to stay well hydrated if they experience gastrointestinal adverse effects. Dulaglutide is safe to use with an eGFR >15ml/min/1.73m² (but there are no studies in people on dialysis), while empagliflozin cannot be used with an eGFR <30ml/min/1.73m². Dulaglutide is now another tool in the armoury for patients with an eGFR 15–30), in addition to low-dose metformin, low-dose vildagliptin and insulin.

What is the expected timeframe for accrual of CV/renal benefits?

It is hard to give an exact answer to when a patient may obtain any benefits from primary prevention of cardiovascular events, but they may become apparent from 2-3 years.

Are there any drug interactions to watch out for with dulaglutide?

Any drug interactions are typically due to the action of dulaglutide, with the main interaction being the potential risk of hypoglycaemia when used in combination with insulin and/or sulfonylureas. Potentially, dulaglutide may also make the gastrointestinal adverse effects of other medications worse. Otherwise, dulaglutide does not have any clinically significant interactions listed in the Medsafe datasheet.

How is dulaglutide excreted from the body?

Dulaglutide is excreted by proteolytic degradation so it can be safely used in liver and renal impairment. However, the safety of dulaglutide is not known in people with an eGFR <15 ml/min/1.73m2 and/or in end-stage liver disease/acute liver failure, so it is not indicated and should not be used in these groups. Otherwise, it is a well-tolerated medication, considering the patient groups in which it is used.

If dulaglutide is a good second-line medication, what would be third-line if someone still has suboptimal blood glucose control?

Empagliflozin, if it is not contraindicated. Unfortunately, it will not be funded with concomitant dulaglutide, so you may need to try pioglitazone or a sulfonylurea as your next option if patients cannot self-fund empagliflozin.

Is it good practice to store a three-month supply of dulaglutide in the fridge?

Definitely, and with lockdowns we may be forced to do this. It is fine to store dulaglutide in the fridge for three months but remember not to leave the whole pack of four injections at room temperature because that is only recommended for up to 2 weeks.

Why is high alcohol consumption a factor favouring the use of dulaglutide over empagliflozin?

Chronic high alcohol intake is a risk factor for diabetic ketoacidosis. In these people, dulaglutide would be preferred over empagliflozin.

Can patients with a history of gastrointestinal adverse drug reactions with vildagliptin sometimes tolerate dulaglutide?

Vildagliptin is usually very well tolerated and, often, the gastrointestinal side effects are actually due to the metformin, when used in combination. If a patient has not tolerated vildagliptin, they would probably have worse adverse gastrointestinal effects with dulaglutide. However, the adverse effects of nasal stuffiness and congestion, which can occur and are specific to vildagliptin, will not arise with dulaglutide.

Does liraglutide have similar benefits to dulaglutide?

Liraglutide is effective in diabetes but not registered for this indication in New Zealand. It is used privately, off-label, for patients with type 2 diabetes and obesity. Dulaglutide is a very good agent within its class – one of the best in reducing cardiovascular disease and cerebrovascular disease. Liraglutide may have an advantage for weight loss, given we can use the higher 3mg/day dose, whereas we only have the 1.5mg dose for dulaglutide. Dulaglutide provides a funded option, whereas liraglutide, at $500 a month on the 3 mg/day dose, is too expensive for most patients. The two agents must not be used together.