Dulaglutide and empagliflozin: Your questions answered (2)

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 disease^1,2,3
• reduces death from all causes by 11%³
• reduces blood total cholesterol, low-density lipoprotein cholesterol and triglyceride levels⁴
• reduces systolic blood pressure by 2–3mmHg^5,6
• 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/mol^5,8
• leads to a possible average 1–3kg weight loss^3,5,9
• 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

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

• 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.

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

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

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}

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

If dulaglutide was started, you would need to stop vildagliptin (Galvumet is metformin + 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.

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}

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.

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.

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.

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:

• dulaglutide application for subsidy by Special Authority
• liraglutide application for subsidy by Special Authority
• empagliflozin; empagliflozin with metformin application for subsidy by Special Authority

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.

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.’

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.

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

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).

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.

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.

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.

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.

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.

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.

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.

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

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.

1. Lilly Investors. Trulicity® (dulaglutide) significantly reduced major cardiovascular events for broad range of people with type 2 diabetes [News Release]. Indianapolis: Eli Lilly and Company, 9 June 2019. https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-significantly-reduced-major
2. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394(10193):121–30. doi: 10.1016/S0140-6736(19)31149-3
3. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7(10):776–85. doi: 10.1016/S2213-8587(19)30249-9
4. Edwards KL, Minze MG. Dulaglutide: an evidence-based review of its potential in the treatment of type 2 diabetes. Core Evid 2015;10:11–21. doi: 10.2147/CE.S55944
5. Australian government. Therapeutic Goods Administration. Australian Product information - Trulicity (dulaglutide RCH) autoinjector. vA6.0 July 2020. https://apps.medicines.org.au/files/lyptruli.pdf
6. Kugler AK, Thiman ML. Efficacy and safety profile of once-weekly dulaglutide in type 2 diabetes: a report on the emerging new data. Diabetes Metab Syndr Obes 2018;11:187–97. doi: 10.2147/DMSO.S134960
7. Greco EV, Russo G, Giandalia A, et al. GLP-1 receptor agonists and kidney protection. Medicina (Kaunas) 2019;55(6):233. doi: 10.3390/medicina55060233
8. Mody R, Yu M, Grabner M, et al. Dulaglutide shows sustained reduction in glycosylated hemoglobin values: 2-Year US real-world study results. Clin Ther 2020;42(11):2184–95. https://www.sciencedirect.com/science/article/pii/S0149291820304616
9. Edwards KL, Minze MG. Dulaglutide: an evidence-based review of its potential in the treatment of type 2 diabetes. Core Evid 2015;10:11–21. doi: 10.2147/CE.S55944
10. New Zealand Society for the Study of Diabetes (NZSSD), Ministry of Health. Type 2 diabetes management guidance. 2021. https://t2dm.nzssd.org.nz (Accessed July 2021).
11. Pharmac. Decision to fund two new medicines for type 2 diabetes – Amended with Q&A. 29 January 2021. https://pharmac.govt.nz/news-and-resources/consultations-and-decisions/decision-to-fund-two-new-medicines-for-type-2-diabetes
12. Trulicity – dulaglutide injection, solution. Instructions for use. Eli Lilly and Company, September 2020. Version 38, revised April 2021. https://uspl.lilly.com/trulicity/trulicity.html#ug (Accessed July 2021).

• 3 October 2023: Hyperlinks to SA application forms added