New diabetes medicines funded: empagliflozin and dulaglutide

More tools for the diabetes management toolbox

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have been recommended internationally in type 2 diabetes management guidelines for some time, but, until now, have been inaccessible to most people in New Zealand due to cost. Empagliflozin (with and without metformin), an oral SGLT-2 inhibitor, has been available fully funded with Special Authority approval since 1 February, 2021 (see: “Initiating funded treatment”).¹ As of 1 September, 2021, Dulaglutide, an injectable GLP-1 receptor agonist, has also been available fully funded with Special Authority approval. Both medicines will be the sole subsidised brands until at least 2024.¹

SGLT-2 inhibitors lower blood glucose levels by inhibiting glucose reabsorption in the renal tubule. In contrast, GLP-1 receptor agonists lower blood glucose levels by stimulating insulin secretion after meals. When added to metformin, SGLT-2 inhibitors and GLP-1 receptor agonists may reduce HbA_1c levels by a further 7 to 15 mmol/mol.^2–4

For further information on the decision to fund these medicines, see: https://pharmac.govt.nz/news-and-resources/consultations-and-decisions/decision-to-fund-two-new-medicines-for-type-2-diabetes/

People at high risk of cardiovascular and renal complications will benefit

Several large randomised controlled trials (RCTs) have shown that treatment with a SGLT-2 inhibitor or GLP-1 receptor agonist provides significant cardiovascular benefit to people with type 2 diabetes.⁵ A recent meta-analysis of 764 RCTs including 421,346 people with type 2 diabetes found that both medicine classes reduced:⁶

• All-cause mortality
• Cardiovascular mortality
• Non-fatal myocardial infarction
• Kidney failure

The mechanism by which these medicines reduce adverse cardiovascular outcomes remains uncertain; trials are currently underway to explore the pathways involved, including investigating reductions in oxidative stress and cardiac pre-load.⁷

Table 1 describes the estimated absolute difference in outcomes with SGLT-2 inhibitors and GLP-1 receptor agonists compared with placebo per 1,000 people with type 2 diabetes with moderate or very high cardiovascular risk.^{6 *}

^*Moderate risk defined as people with cardiovascular disease; very high risk defined as people with both cardiovascular disease and chronic kidney disease

Funding criteria is intended to help reduce inequities

For the first time, Māori and Pacific peoples have been specifically identified within Special Authority criteria for funding (see: “Initiating funded treatment” for the full criteria). The prevalence of type 2 diabetes is two to three times higher in these ethnic groups than others.⁸ Māori and Pacific peoples with type 2 diabetes have worse health outcomes compared to Europeans.^{9, 10} Improved access to medicines with established cardiovascular and renal benefits is hoped to reduce the inequities in diabetes health outcomes in these vulnerable populations.

Table 1. Estimated absolute differences in outcomes with SGLT-2 inhibitors and GLP-1 receptor agonists compared with placebo per 1,000 people with type 2 diabetes with moderate and very high cardiovascular risk, treated for five years. Adapted from Palmer et al, (2021).⁶

^*Moderate risk defined as people with CVD; very high risk defined as people with both CVD and chronic kidney disease

The place of empagliflozin and dulaglutide in type 2 diabetes management

Type 2 diabetes management follows a stepwise progression. Lifestyle interventions and metformin are the cornerstone of type 2 diabetes management (Step 1). If a sufficient reduction in HbA_1c levels is not achieved with metformin, treatment is typically escalated by reinforcing the importance of diet and exercise to induce weight loss, and adding a second non-insulin pharmacological treatment (Step 2a). If further intensification is required, a third non-insulin pharmacological treatment can be added (Step 2b) or insulin can be initiated (Step 3).

N.B. Consider starting at Step 2 at diagnosis for patients with HbA_1c levels > 64 mmol/mol, i.e. two pharmacological treatments (e.g. metformin and vildagliptin) and lifestyle management.¹¹ Consider initiating insulin at diagnosis if very high HbA_1c levels, e.g. > 80 – 90 mmol/mol^*, or significant symptoms of hyperglycaemia.¹¹ Insulin may be withdrawn once HbA_1c levels are controlled.

^*This is a higher level than in previous guidance (75 mmol/mol) due to the availability of more medicines to manage hyperglycaemia¹²

Treatment options at Step 2 (typically added to metformin) include:

• Empagliflozin (oral, funded with Special Authority – see: “Initiating funded treatment” and “Prescribing empagliflozin”), taken either as separate metformin and empagliflozin tablets, or a combination empagliflozin + metformin formulation
• Dulaglutide (injectable, funded with Special Authority – see: “Initiating funded treatment” and “Prescribing dulaglutide”)
• Vildagliptin (oral, funded), taken either as separate metformin and vildagliptin tablets, or a combination vildagliptin + metformin formulation
• A sulfonylurea (oral, funded), such as gliclazide or glipizide
• Pioglitazone (oral, funded)

The decision about which medicine to use should take into account any contraindications, cardiovascular co-morbidities, risk of hypoglycaemia, effects on weight, medicines interactions, adverse effects and eligibility for funding (Table 2 and “Initiating funded treatment”).⁵

Empagliflozin or dulaglutide are preferred at Step 2 for people with or at high risk of CVD, diabetic kidney disease or heart failure, regardless of their HbA_1c levels; currently only people with HbA_1c levels > 53 mmol/mol are eligible for funded treatment (see: “Initiating funded treatment”).¹¹ Both medicine classes can be used together with likely additive benefits, however, dual treatment with empagliflozin and dulaglutide is not funded.¹¹ There is little risk of hypoglycaemia with these medicines without concomitant use of sulfonylureas or insulin.

N.B. A SGLT-2 inhibitor or GLP-1 receptor agonist are also preferred in some international guidelines if there is a need to minimise weight gain or promote weight loss, however, they are not funded for these indications in New Zealand.^5,13

Vildagliptin is recommended at Step 2 for people with type 2 diabetes who are not eligible for funded SGLT-2 inhibitor or GLP-1 receptor agonist treatment (also see: “Clinical scenarios where empagliflozin or dulaglutide are recommended, but not funded”).¹¹ Vildagliptin is particularly useful in older patients, either combined with metformin or alone if metformin is contraindicated or not tolerated.

A new type 2 diabetes management guideline published by the New Zealand Society for the Study of Diabetes and the Ministry of Health is available here: https://t2dm.nzssd.org.nz/

Table 2. Effects of diabetes medicines (excluding insulin) on HbA_1c, cardiovascular co-morbidities, progression of kidney disease, weight and risk of hypoglycaemia and diabetic ketoacidosis. Adapted from the American Diabetes Association (2021) and NZSSD (2021).^{5, 11}

CVD = cardiovascular disease,     HF = heart failure,     DKD = diabetic kidney disease,     DKA = diabetic ketoacidosis

Initiating funded treatment

To initiate funded empagliflozin or dulaglutide treatment, patients must meet either of the following criteria:¹

1. Have type 2 diabetes; and
2. Have at least one of the following characteristics:
   • Māori or any Pacific ethnicity; or
   • Pre-existing CVD or risk equivalent^*; or
   • An absolute five-year CVD risk of ≥ 15% according to a validated cardiovascular risk assessment calculator; or
   • A high lifetime cardiovascular risk due to being diagnosed with type 2 diabetes during childhood or as a young adult; or
   • Diabetic kidney disease^†; and
3. Have an HbA_1c level > 53 mmol/mol despite the regular use of at least one blood-glucose lowering agent (e.g. metformin, vildagliptin or insulin) for at least three months^**

Or

Have previously received an initial approval for a SGLT-2 inhibitor if the current application is for a GLP-1 agonist, or vice versa

^*Defined as: prior cardiovascular disease event (i.e. angina, myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, transient ischaemic attack, ischaemic stroke, peripheral vascular disease), congestive heart failure or familial hypercholesterolaemia

^†Defined as: persistent albuminuria (albumin:creatinine ratio greater than or equal to 3 mg/mmol, in at least two out of three samples over a 3 – 6-month period) and/or eGFR less than 60 mL/min/1.73m² in the presence of diabetes, without alternative cause

^** If HbA_1c is very high at diagnosis, e.g. > 64 mmol/mol, they would not be eligible for funded treatment with empagliflozin or dulaglutide until they have been treated with at least one glucose-lowering agent for three months; patients with high HbA_1c at diagnosis could be initiated on metformin + vildagliptin or, if HbA_1c are very high at diagnosis, metformin and insulin (which could then be withdrawn once HbA_1c has stabilised)

Applications can be made by any relevant practitioner and are valid without further renewal (unless notified) for eligible patients. Dual SGLT-2 inhibitor/GLP-1 receptor agonist treatment is not currently funded.

A calculator to assess cardiovascular disease risk in people with type 2 diabetes is available here: https://www.nzssd.org.nz/cvd/

Choosing between empagliflozin and dulaglutide

The decision to initiate a SGLT-2 inhibitor versus a GLP-1 receptor agonist is based primarily on the predominant co-morbidity, i.e. CVD, heart failure or diabetic kidney disease, and patient preference, particularly regarding the route of administration (Figure 1).¹¹ If heart failure or diabetic kidney disease predominates, a SGLT-2 inhibitor (i.e. empagliflozin) is preferred. Otherwise either a SGLT-2 inhibitor or a GLP-1 receptor agonist (i.e. dulaglutide) is recommended; GLP-1 receptor agonist treatment will likely lead to greater improvements in glycaemic control and greater weight loss than SGLT-2 inhibitor treatment (although SGLT-2 inhibitors are still associated with weight loss).¹¹

An interactive decision support tool is available here: https://magicevidence.org/match-it/200820dist/#!/

Dulaglutide is administered as a once weekly injection

Patients may be reluctant to take dulaglutide as it is an injectable treatment rather than an oral medicine. However, unlike insulin, which requires one or more daily injections, dulaglutide is administered once weekly. Furthermore, self-monitoring blood glucose is not necessary for patients taking dulaglutide, unless their regimen also includes a sulfonylurea or insulin. Providing patients who are hesitant about initiating an injectable treatment with this information may help them to feel more confident with this treatment option. A treatment trial of dulaglutide may be very useful before initiating insulin.

Figure 1. An overview of management of patients with type 2 diabetes. Adapted from the New Zealand Society for the Study of Diabetes type 2 diabetes guideline (2021).¹¹

Prescribing empagliflozin

When initiating empagliflozin, reinforce lifestyle advice, i.e. dietary and exercise interventions, and offer support as required. Metformin should be continued unless it is contraindicated or not tolerated; combination empagliflozin + metformin formulations are available (Table 3).¹¹ Other glucose-lowering treatments (e.g. vildagliptin, a sulfonylurea, dulaglutide,^* or insulin) should be continued if needed for glycaemic control or cardiovascular or renal protection.¹¹ If the patient is taking insulin or a sulfonylurea, the dose may need to be reduced; a reduction of 15 – 20% of the daily total insulin or 50% of the sulfonylurea dose is recommended as a starting point.¹¹ People with a HbA_1c > 75 mmol/mol do not usually require a reduction in insulin or sulfonylurea, unless they have a history of hypoglycaemia.¹¹ Patients taking SGLT-2 inhibitors must discontinue treatment during an acute illness or two days before an elective medical procedure.¹¹

^*Dual empagliflozin and dulaglutide treatment is not currently funded under the Special Authority criteria

For further information on sick-day management, see: https://t2dm.nzssd.org.nz/Section-95-Sick-day-management-in-patients-with-diabetes

Table 3. Key empagliflozin prescribing information.^{11, 14, 15}

^*It may assist kidney function, but this has not been definitively proven

Contraindications and cautions to empagliflozin treatment

Empagliflozin is currently contraindicated in people with severe renal impairment; it is ineffective at lowering glucose if eGFR < 30 mL/minute/1.73 m². Empagliflozin is not recommended for use in people who:¹¹

• Are aged < 18 years
• Are pregnant or breastfeeding
• Have a history of severe genitourinary infections
• Are on a ketogenic diet (due to the increased risk of diabetic ketoacidosis – see below)

N.B. Use of empagliflozin in people with nephrolithiasis/recurrent renal calculi was previously not recommended in the NZSSD guidance. However, updated advice is that empagliflozin may be used with caution in patients with a history of renal calculi if good hydration is ensured; extra caution is needed in those with recurrent calculi.

For further information, refer to the New Zealand Formulary: https://www.nzf.org.nz/nzf_70809

Discuss potential adverse effects before initiating treatment

Adverse effects of SGLT-2 inhibitors such as empagliflozin include:¹¹

• Polyuria – consider reducing diuretics before initiating treatment
• Genitourinary infections, e.g. urinary tract infection, vaginal thrush, balantitis – this is thought to be due to the increased urinary excretion of glucose. Ensure patients are given information on hygiene measures and the rare risk of necrotising fasciitis of the perineum (Fournier’s gangrene).
• Hypotension – consider reducing antihypertensive medicines before initiating treatment or before a dose increase
• Diabetic ketoacidosis (DKA) – increased risk (see below)

SGLT-2 inhibitor use is associated with an increased risk of severe DKA

People taking SGLT-2 inhibitors are at increased risk of DKA, particularly in the first few months of treatment or peri-operatively.¹¹ This can occur with normal blood glucose levels (euglycaemia).¹¹ While this is a rare adverse effect (ranging from one in 1,000 to one in 3,000 people), this should be discussed with patients before initiating treatment, with advice provided on the symptoms and signs of DKA and when to seek medical attention to get their blood ketones checked (i.e. if they experience nausea, vomiting or abdominal pain).¹¹ In general, it is advisable to temporarily stop empagliflozin if patients are unwell and febrile, especially if they are not eating or vomiting.

N.B. Patients with type 2 diabetes taking a SGLT-2 inhibitor do not currently qualify for a funded CareSens Dual glucometer (measures both blood glucose and blood ketone levels).

For further information on SGLT-2 inhibitors and DKA, see: https://diabetessociety.com.au/documents/ADS_DKA_SGLT2i_Alert_update_2020.pdf

Prescribing dulaglutide

When initiating dulaglutide (Table 4), reinforce lifestyle advice and offer support as required, and provide information on how to administer treatment (see below). Metformin should be continued unless it is contraindicated or not tolerated.¹¹ Dipeptidyl peptidase-4 (DPP-4) inhibitors (i.e. vildagliptin) must be stopped before initiating a GLP-1 receptor agonist as they have similar mechanisms of action.¹¹ Other glucose-lowering treatments can be continued if needed for glycaemic control or cardiovascular or renal protection, with the dose of insulin or a sulfonylurea reduced to prevent hypoglycaemia, if required (see: “Prescribing empagliflozin” for guidance on dose reduction).¹¹ Advise patients to stop treatment if they have an acute gastrointestinal illness (and resume treatment once they have recovered).¹¹

Table 4. Key dulaglutide prescribing information.^{11, 16}

^*Other non-funded GLP-1 receptor agonists approved in New Zealand include liraglutide, exenatide and exenatide extended release (soon to be withdrawn from the local market)

Dulaglutide administration guide:¹⁶

• Dulaglutide is administered once weekly, at any time of day, with or without food
• Patients can inject dulaglutide in the abdomen, thigh or upper arm
• Injection sites should be rotated with each dose
• If a dose is missed, it should be administered as soon as possible if there are ≥ 3 days until the next scheduled dose; if < 3 days until the next dose, the missed dose should not be taken, and the next dose taken at the normal time
• If the regimen includes insulin, these should be administered as separate injections, i.e. not mixed. If injected in the same body region, ensure the injections are not next to each other.
• The single-use pen should be disposed of in a specified sharps container or a closable puncture-resistant container, i.e. not in the household rubbish^*

^*Community pharmacies and some Diabetes NZ branches offer sharps disposal services; patients can return their sharps in a specified sharps container (available to purchase) or other suitable container.

Patient instructions for use of dulaglutide (with images) are available from: https://uspl.lilly.com/trulicity/trulicity.html#ug

Contraindications and cautions to dulaglutide treatment

Dulaglutide is contraindicated in people with personal or family history of medullary thyroid carcinoma or a personal history of multiple endocrine neoplasia syndrome type 2.^{11, 16} Rodent studies have shown an increased incidence of thyroid C-cell adenomas and carcinomas with GLP-1 receptor agonist treatment.¹⁷ While a causal relationship has not been established and there is no evidence of increased prevalence of any form of thyroid cancer in humans with long-term use, dulaglutide is not recommended for use in people at increased risk of thyroid cancer, e.g. due to family history, radiation exposure.¹¹ Advise patients prescribed dulaglutide to seek medical advice if they develop any symptoms that could indicate thyroid cancer, e.g. a mass in the neck, dysphagia, dyspnoea, persistent hoarseness.¹⁶

Dulaglutide is not recommended for people:¹¹

• Aged < 18 years
• Who are pregnant or breastfeeding
• With severe gastrointestinal disease, including gastroparesis
• With previous pancreatitis

Mild adverse effects with dulaglutide are usually transient

Common adverse effects of GLP-1 receptor agonists include gastrointestinal disturbance (nausea [most common], vomiting, anorexia and diarrhoea) and injection site reactions (e.g. nodules, pruritus, bruising, erythema).^{11, 18} These are usually transient and improve with continued treatment.¹¹ Rare adverse effects include pancreatitis, myalgias and muscle weakness, Stevens-Johnson’s syndrome and thrombocytopaenia.¹¹

Reviewing treatment and ongoing monitoring

Regular review of treatment is necessary for all patients with type 2 diabetes to optimise individual goals and ensure medicine regimens remain appropriate. Nutrition, physical activity and body weight monitoring should be discussed with patients at all stages of management. HbA_1c levels should be checked every three months if they are above target and the treatment regimen has changed.¹¹ Once target HbA_1c levels have been achieved, repeat measurement every six months and complete a diabetes review annually.¹¹ Renal function should be assessed at least annually in patients taking empagliflozin (with or without metformin) and prior to initiating any medicines that may reduce renal function.¹⁴ No additional monitoring is required for patients taking dulaglutide.