Knowledge Type: Clinical Articles

What is rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that affects the joints and can damage other body systems, including the skin, eyes, lungs, heart, and blood vessels. Unlike the wear-and-tear damage of osteoarthritis, RA is an autoimmune disorder where the immune system attacks the joints. This can result in painful swelling, bone erosion and joint deformity.

Medications include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs);
• Steroids;
• Conventional disease-modifying anti-rheumatic drugs (DMARDs); and
• Biological agents.

What are biological agents?

Biologics are a newer class of DMARDs that may slow or stop inflammation. In people with RA, the immune system mistakenly takes aim at its own tissues, leading to high levels of cytokines that can cause joint inflammation and pain. Biologics work by blocking these substances to diminish the immune response and reduce inflammation, pain and joint damage.

Biologics are made from living cells and tend to work quicker than conventional DMARDs. Conventional DMARDs suppress the overall immune system, whereas biologics block specific parts of the immune system. Biologics are more complex than conventional DMARDs and must be administered parenterally.

According to the Therapeutic Guidelines, biological disease-modifying anti-rheumatic drugs (bDMARDs) are used by specialists if remission is not achieved or significant disease activity persists after trialling conventional DMARDs. Biologicals are usually used in combination with conventional DMARDs.

The guidelines provide the following usual dosages for first-line bDMARDs (listed in alphabetical order):

• Abatacept 500 to 1000 mg intravenously, as a single dose at 0, 2 and 4 weeks, and thereafter every 4 weeks; OR
• Abatacept 125 mg subcutaneously, once weekly; OR
• Adalimumab 40 mg subcutaneously, every 2 weeks; OR
• Certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and thereafter 200 mg every 2 weeks; OR
• Certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and thereafter every 4 weeks; OR
• Etanercept 50 mg subcutaneously, once weekly; OR
• Golimumab 50 mg subcutaneously, every 4 weeks; OR
• Infliximab 3 mg/kg intravenously, as a single dose at 0, 2 and 6 weeks, and thereafter every 8 weeks; OR
• Tocilizumab 8 mg/kg intravenously, every 4 weeks; OR
• Tocilizumab 162 mg subcutaneously, once weekly.

If the response to the initial drug choice is inadequate, the guidelines advise that an alternative first-line bDMARD may be used.

Rituximab is reserved for when first-line bDMARD therapy has failed. The two doses (1g by intravenous infusion) are given two weeks apart. For patients who respond to this initial rituximab course, treatment may be repeated (usually after 6 to 12 months) depending on disease activity.

Different types of biological therapies:

All bDMARDs are associated with an increased risk of infections. The most common infections seen are upper respiratory infections, pneumonia, urinary tract infections, and skin infections. Patients should be advised to contact their doctor if they develop signs of an infection.

Patients should not receive live vaccines when taking biologics.

1. Tumour necrosis factor (TNF) inhibitors = adalimumab, certolizumab, etanercept, golimumab, infliximab

These agents bind to TNF alpha and inhibit its activity. TNF alpha is a pro-inflammatory cytokine produced by macrophages and lymphocytes.

Following initiation of a TNF inhibitor, improvements may be seen within two to four weeks, with further effects over the next three to six months. 

2. T-cell Co-stimulatory blockers

Abatacept (Orencia^®)

Abatacept is a fusion protein that binds to the CD80 and CD86 molecules on the surface of antigen presenting cells. This prevents the interaction of these molecules with CD28 found on T cells, thereby reducing the T cell response.

The onset of effect may be seen within 14 days, with continued improvement over the following 12 months. Discontinuation should be considered if there is no effect after three to four months.

3. B-Cell inhibitors

Rituximab (Rituxan^®)

Rituximab is a monoclonal antibody that binds to the CD20 molecule on the B cell surface, removing B cells from circulation. A single course of rituximab (two infusions of 1,000mg given two weeks apart) leads to a prompt reduction of B lymphocytes in the peripheral blood. This effect is prolonged, with recovery of B cell counts usually beginning six to nine months after completion of therapy.

The onset of action may be slower for rituximab than other bDMARDs, and effects may not be seen for up to three months after an infusion. However, the effects may last six months or longer following a single course.

Rituximab is associated with infusion reactions such as hives, itching, swelling, difficulty breathing, fever, chills and changes in blood pressure. These respond to slowing the infusion rate. Patients receive premedication with intravenous corticosteroids, paracetamol and an antihistamine before each dose.

Rituximab may also be associated with progressive multifocal leukoencephalopathy (PML), a severe and potentially fatal brain infection.

Angina, arrhythmias, heart failure and myocardial infarction, have also been reported in patients treated with rituximab.

4. Interleukin inhibitors

Interleukin-6 (IL-6)

Tocilizumab (Actemra^®)

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors. IL-6 is a pleiotropic pro-inflammatory cytokine involved in various physiological activities, including T-cell activation, immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoiesis. Synovial and endothelial cells can also produce IL-6, leading to local production in joints affected by inflammatory processes.

The usual time to effect is around four to eight weeks.

Caution is required in patients with a history of intestinal ulceration or diverticulitis due to reports of gastrointestinal perforation. Other potential adverse effects include reduced platelet count, elevations in liver transaminases, increased lipid parameters, and neutropenia.

Interleukin-1 (IL-1)

IL-1 is another pro-inflammatory cytokine involved in the pathogenesis of RA. IL1 can cause degradation of cartilage and inhibit its repair. It also stimulates osteoclasts, leading to bone erosion.

Anakinra

Anakinra is an IL-1 receptor antagonist. It is administered as a subcutaneous injection, with a recommended dose of 100mg daily. The usual time to effect is around two to four weeks.

The most common side effects are injection site reactions which may present as erythema, itching, and discomfort. These usually resolve over one to two months, although patients with severe reactions may require discontinuation of therapy.

Anakinra is not available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of rheumatoid arthritis.

Finerenone is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of chronic kidney disease (CKD) with type II diabetes.

Finerenone is a mineralocorticoid receptor antagonist. The mineralocorticoid receptor plays an important role in the regulation of blood pressure and fluid and electrolyte balance. The main ligand for this receptor is aldosterone, a hormone produced in the adrenal glands. Aldosterone acts on mineralocorticoid receptors in epithelial tissues (e.g. kidney and colon) as well as nonepithelial tissues (e.g. heart and vasculature). Activation of mineralocorticoid receptors in the kidney increases sodium and water reabsorption, resulting in increased blood pressure.

Aldosterone may also contribute to structural changes as a result of hypertrophy and tissue remodelling. Its stimulation of cell proliferation in the kidneys may be an important contributory factor in the progression of CKD. Excessive activation of mineralocorticoid receptors may also result in tissue injury, such as myocardial and vascular fibrosis.

Mineralocorticoid receptor antagonists

Other mineralocorticoid receptor antagonists on the market are spironolactone and eplerenone. These agents may also reduce fibrosis, inflammation, and adverse remodelling in the kidneys and cardiovascular system. However, their use may be limited by the risk of hyperkalaemia. Spironolactone may also be associated with endocrine adverse effects, such as gynaecomastia and menstrual changes.

Of the three mineralocorticoid antagonists currently available, finerenone is the only non-steroidal agent. Compared to steroidal mineralocorticoid antagonists, finerenone is more potent and distributes more evenly between the kidneys and the heart. A comparison of mineralocorticoid receptor antagonists can be seen in Table 1.

Table 1. Comparison of mineralocorticoid receptor antagonists

	Finerenone	Spironolactone	Eplerenone
Indications	CKD with type II diabetes	Hypertension, oedema, primary hyperaldosteronism, hirsutism	Heart failure
Chemistry	Non-steroidal	Steroidal
Distribution	Equal between heart and kidney	Higher concentrations in renal tissue compared to heart
Half maximal inhibitory concentration (IC50)
Mineralocorticoid receptor	18	24	990
Glucocorticoid receptor	≥10,000	2,410	22,000
Androgen receptor	≥10,000	77	21,200
Progesterone receptor	≥10,000	740	31,200

The IC₅₀ values in Table 1 provide an indication of the potency of these agents at different receptor types. These figures signify how much of the drug (in nanomoles) is required to inhibit the receptors by 50% in vitro, i.e. higher values indicate weaker inhibition.

The IC₅₀ values demonstrate that finerenone may overcome some of the selectivity issues associated with spironolactone and the low potency associated with eplerenone. Finerenone has high selectivity for the mineralocorticoid receptor, which is responsible for the desired pharmacological action. Affinity at androgen, progesterone, estrogen, and glucocorticoid receptors is considered insignificant. This higher selectivity avoids some of the adverse effects associated with spironolactone.

Efficacy

The FIDELIO-DKD study investigated the effect of finerenone on kidney and cardiovascular outcomes in patients with CKD and type II diabetes. Patients treated with the maximally tolerated dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) were randomly assigned to receive finerenone or placebo. Finerenone was initiated at 20mg daily, or 10mg daily for patients with an estimated glomerular filtration rate (eGFR) of less than 60 ml/minute/1.73 m². The lower doses could be increased after one month if renal function and serum potassium remained stable.

The primary composite outcome in this study was kidney failure, a sustained reduction in the eGFR of at least 40% from baseline, or death from renal causes. The key secondary composite outcome was death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure. The median follow-up period was 2.6 years.

The incidence of the primary composite outcome was significantly lower in the finerenone group compared to the placebo group (17.8% vs 21.1%), as was the incidence of key secondary outcomes (13.0% vs 14.8%). While the incidence of non-fatal stroke was similar between the groups, all other components of the key secondary outcome were lower for finerenone.

Most of the patients in the FIDELIO-DKD study had advanced CKD, which may limit the generalisability of the results. The more recently published FIGARO-DKD trial sought to address this issue by including patients with a wider range of kidney impairment (stages 1-4 CKD). Patients treated with maximal tolerated doses of an ACE inhibitor or ARB were randomly assigned to receive finerenone or placebo.

The primary outcome in this study was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure. A secondary outcome was a composite of the first occurrence of kidney failure, sustained reduction in eGFR of at least 40%, or death from renal causes. The median follow-up period was longer at 3.4 years.

The incidence of the primary composite outcome was significantly lower in the finerenone group than in the placebo group (12.4% vs 14.2%). This difference was primarily driven by a reduction in hospitalisation for heart failure in the finerenone group. Interestingly, patients with symptomatic chronic heart failure with a reduced ejection fraction were excluded from this trial. As heart failure (new-onset or preexisting) confers a very high risk for hospitalisation and death in patients with CKD and type II diabetes, finerenone may offer benefits in the management of heart failure in this population.

The incidence of the first secondary composite outcome was also lower in the finerenone group compared to placebo (9.5% vs 10.8%), although this did not reach significance.

A comparison of the two trials can be seen in Table 2.

Table 2. Comparison of the FIDELIO-DKD and FIGARO-DKD trials (adapted from KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease)

	FIDELIO-DKD	FIGARO-DKD
Number of participants	5734	7437
Proportion with CVD	45.4%	44.7
eGFR and ACR at enrolment	25–<60 ml/min/1.73 m2 and ACR 30–<300 mg/g OR 25–<75 ml/min/1.73 m2 and ACR 300-5000 mg/g	25–90 ml/min/1.73 m2 and ACR 30–<300 mg/g OR ≥60 ml/min/1.73 m2 and ACR 300–5000 mg/g
Mean eGFR at enrolment	44	68
Proportion with eGFR <60 ml/min/1.73 m2	88.4%	38.2%
Median ACR at enrolment	850mg/g	309mg/g
Proportion with ACR ≥300mg/g	87.5%	50.7%
Median follow-up	2.6 years	3.4 years
Primary outcome	Kidney composite: kidney failure, a sustained decrease ≥40% in GFR, renal death	CV composite: death from CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for HF
Main secondary outcome	CV composite: death from CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for HF	Kidney composite: kidney failure, a sustained decrease ≥40% in GFR, renal death
Kidney composite outcome result	HR: 0.82; 95% CI: 0.73–0.93	HR: 0.87; 95% CI: 0.76–1.01
Cardiovascular composite outcome result	HR: 0.86; 95% CI: 0.75–0.99	HR: 0.87; 95% CI: 0.76–0.98

Adverse effects

In the FIDELIO-DKD study, the incidence of adverse effects was similar in the finerenone and placebo groups. Serious adverse events were reported in 31.9% of the patients in the finerenone group and 34.3% of the placebo group. Hyperkalaemia occurred in almost twice as many patients in the finerenone group compared to the placebo group (15.8% vs 7.8%), although this was only considered serious in 1.6% of the study group (compared to 0.4% in the placebo group). Other commonly reported adverse reactions include hyponatraemia, hypotension, and reduced GFR.

The incidence of adverse effects was similar in the FIGARO-DKD study. Hyperkalaemia was less commonly reported (10.8% for finerenone and 5.2% for placebo), with serious hyperkalaemia occurring in only 0.7% of patients receiving finerenone. This may reflect the higher mean eGFR in this trial.

Hyperkalaemia can occur in advanced CKD and type II diabetes. It may also be exacerbated by medications such as ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists. The Mineralocorticoid Receptor Antagonist Tolerability Study helps put the risk of hyperkalaemia in perspective. The incidence of hyperkalaemia in patients taking finerenone (10mg daily) was compared to patients taking spironolactone (25-50mg daily). Finerenone was associated with a significantly lower risk of hyperkalaemia (4.5% vs 11.1%).

Place in therapy

Diabetes is a significant cause of CKD. The KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease provides recommendations for the care of patients with type II diabetes and CKD, including:

• Lifestyle measures (diet, exercise, weight control, smoking cessation);
• First-line medication options (metformin, ACE inhibitor or ARB, sodium-glucose cotransporter 2 (SGLT2) inhibitor, statin); and
• Additional drugs with heart and kidney protection (non-steroidal mineralocorticoid receptor antagonists).

Finerenone is the only non-steroidal mineralocorticoid receptor antagonist currently approved for use in Australia. It is indicated to delay the progressive decline in kidney function in patients with CKD associated with type II diabetes.

PBS Criteria

Patients with CKD and type II diabetes may qualify for PBS-subsidised finerenone therapy if they meet the following criteria:

• No known significant non-diabetic renal disease prior to initiating treatment;
• eGFR of at least 25 mL/min/1.73 m² prior to initiating treatment;
• Urinary albumin-to-creatinine ratio of at least 200 mg/g (22.6 mg/mmol) prior to initiating treatment;
• Stabilised for at least four weeks prior to initiation of finerenone on either an ACE inhibitor or ARB, unless medically contraindicated;
• The treatment must be in combination with an SGLT2 inhibitor unless medically contraindicated or intolerant;
• Treatment must not be in combination with another selective non-steroidal mineralocorticoid receptor antagonist, a renin inhibitor, or a potassium-sparing diuretic;
• The patient must not have established heart failure with reduced ejection fraction with an indication for treatment with a mineralocorticoid receptor antagonist; and
• Finerenone treatment must be discontinued prior to initiating renal replacement therapy (i.e. dialysis or kidney transplant).

Immunotherapy and targeted treatment of melanoma have drastically improved prognosis. Well established in the metastatic melanoma setting, studies have proven PD1 inhibition in the adjuvant setting for high-risk resectable melanoma, and this is now a PBS-funded treatment. High-risk resectable melanoma is classified as stage 3B to 3D according to the AJCC TNM staging system for melanoma. AJCC TNM measures thickness of primary tumour, ulceration, mitotic rate, and lymph nodal involvement. Other risk factors that influence prognosis and treatment include BRAF mutation status and patient characteristics such as age, comorbidities, and treatment preferences.

There is evidence for improved survival with neo-adjuvant treatment of high-risk resectable melanoma, and the suggested mechanism behind this is that tumour load has an impact with regard to immunotherapy response. Hence if you remove the tumour prior to therapy (adjuvant), it has been proposed to be less effective than if you treat the tumour up front and then undergo surgery (neo-adjuvant).

The primary endpoint of the SWOG 1801 study was event-free survival (EFS), a study that compared the PD1 inhibitor pembrolizumab in both the adjuvant (18 doses post-surgery) and neo-adjuvant (3 doses pre-surgery and then 15 doses post-surgery) settings. Three hundred thirteen participants with resectable stage IIIB to IV melanomas were included. The neo-adjuvant group experienced better control than the adjuvant group (HR 0.58, P=0.004). At 2 years, the neo-adjuvant group EFS was 72% compared to 49% for the adjuvant group, representing a significant reduction. All participants underwent recommended surgery to remove the primary tumour regardless of response to the neoadjuvant treatment. It should be noted that the control group was statistically planned to have a 64% reduction in EFS compared with the 49% reduction that was observed during this study and therefore the results may be magnified.

The PRADO trial assessed stage IIIB to IIID melanoma neoadjuvant treatment with Nivolumab 3mg/kg and Ipilimumab 1mg/kg for 6 weeks prior to surgery. Personalised response directed therapy was also assessed by measurement of response in an index node (largest lymph node metastasis at baseline) after neo-adjuvant treatment. In previous studies, it has been shown that using an index node to measure response was a reliable indicator of response in the total tumour bed.

Therapeutic lymph node dissection (TLND) usually is indicated for high-risk resectable melanoma and is associated with significant morbidity. There is also a risk of side effects when treating a patient with adjuvant immunotherapy or MEK/BRAF inhibition. The risk that when a patient no longer responds to adjuvant therapy, it can’t be used in the “arsenal” as part of treatment if relapse occurs is also a factor. Therefore, it would be optimal to only treat those patients with additional surgery and adjuvant treatment when necessary, and it has been suggested in preliminary studies that those patients who respond strongly to neoadjuvant therapy can forgo TLND and subsequent adjuvant treatment.

In the PRADO study, patients who had a major response (≤ 10% viable tumour in index node after 2 cycles) to neoadjuvant Nivolumab and Ipilimumab did not undergo major TLND and did not receive additional adjuvant treatment. Patients who had a partial response (>10% to ≤50% viable tumour after 2 cycles) received TLND without adjuvant treatment. Patients with minimal response (≥50% viable tumour after 2 cycles) received both a TLND and adjuvant immunotherapy or BRAF/MEK inhibition if BRAF^V600E/K-mutated tumours present for 12 months. Primary endpoints included pathological Response Rates, 24-month relapse-free survival and 24-month relapse-free survival in patients with minimal response after neoadjuvant therapy.

Pathological responses were recorded in 72% of patients who successfully underwent ILN resection and analysis. Major pathological response occurred in 61% of patients, and partial responses in 11% of patients ILN successfully analysed. PD1 expression was the only tumour or patient characteristic that showed definitive predictive value in response, with the higher PD1 expression associated with higher neoadjuvant response rates.

The relapse-free survival rate after 2 years for patients with major pathological response was 93%, with all 4 patients who had relapsed harbouring a BRAF^V600E/K-mutation and multiple lymph node involvement. Patients with partial pathological response who underwent TLND was 64%, and patients with minimal pathological response who received both TLND and adjuvant therapy was 71%. Grade 3-4 immune-related adverse effects occurred in 22% of patients, with the most common grade 3-4 adverse effects being increased transaminases and diarrhoea/colitis. 10% of patients received only one dose of neoadjuvant therapy due to adverse effects. A flowchart of the outcomes and interventions in the study is below here.

This PRADO trial investigated an exciting development in personalised treatment of melanoma that is tailored to the response from 6 weeks of neo-adjuvant therapy. Although the outcomes achieved for the major pathological response cohort are consistent with previous investigational studies, the small sample sizes, particularly in the partial and non-responsive subgroups, limit the certainty of any outcomes. It should also be noted that PRADO did not randomise TLND versus lymph node dissection, only allowing for indirect comparisons with historical studies. Also of note is that although previous studies have shown that the Index node response can be translated to the entire tumour bed, in two of the patients with multiple node involvement, there was a non-response in a small non-index node that did not alter the response subgroup in the entire TLND tumour bed. The authors speculate that less responsive sub-clones in a minority of patients may be the reason for the increased risk seen with patients with multiple nodal involvement.

The NADINA trial is currently investigating if neoadjuvant with standard TLND versus adjuvant will add to the body of work being pursued in the neoadjuvant treatment of advanced stage 3 melanoma. As TLND is associated with morbidity and poor quality of life outcomes and the burden of yearly adjuvant immunotherapy or targeted therapy, those with major pathological response to neoadjuvant therapy could forgo both TLND and adjuvant therapy according to the results from the PRADO trial.  Those in the partial response group should definitely be considered for yearly adjuvant therapy as well due to the unfavourable results in this subgroup (2 year relapse-free survival 64%). A larger randomised trial comparing TLND and index lymph node dissection is necessary to draw any conclusive evidence.

The Therapeutic Goods Administration (TGA) has issued a medicines safety update regarding oral anticoagulants and the potential for anticoagulant-related nephropathy (ARN).

Anticoagulant-related nephropathy is a recently recognised form of acute kidney injury. First described in 2009 in association with warfarin, there is now growing evidence implicating direct oral anticoagulants (DOACs). Patients with ARN can experience a rapid deterioration of renal function which may lead to irreversible kidney damage and death. Early identification of this adverse event is critical.

To increase awareness of this serious adverse event, a warning has been added to the product information of all oral anticoagulants. This includes warfarin, apixaban, rivaroxaban, and dabigatran. Warnings have not been added to parenteral anticoagulants as these agents are generally used in a hospital setting for shorter periods.

Presentation:

The presentation of ARN depends upon the severity. Severe cases may be associated with hypertension, reduced urine output, and signs of fluid overload. Haematuria was present in all patients studied in the initial case reports. However, more recent evidence suggests that the absence of haematuria may not preclude a diagnosis of ARN. This may be related to patients experiencing transient microscopic haematuria that is no longer present when seeking medical care.

Anticoagulant-related nephropathy is associated with a significant increase in mortality rate. Brodsky et al. (2011) conducted a study in patients taking warfarin who experienced an INR greater than 3. Patients who developed presumptive ARN were compared to those who did not experience ARN. The authors found that the hazard ratio for death in the ARN group was 3.65 at one week after the supratherapeutic INR was recorded (95% CI 2.81-4.75). The hazard ratio then progressively reduced, reaching non-significance six months later.

Pathogenesis:

The mechanisms behind ARN are complex. However, glomerular haemorrhage related to over-anticoagulation is thought to be the initial trigger. Chen et al. (2023) describe the following factors:

• Disruption of the glomerular filtration barrier, which causes red blood cells to fill Bowman’s space and the renal tubules;
• Formation of erythrocyte casts in the distal nephron, which could obstruct the passage of urine; and
• Intratubular lysis of red blood cells leading to a localised release of heme-containing molecules and catalytic (or labile) iron. This can lead to tubular and interstitial damage due to increased production of hydroxyl radicals.

While ARN is considered rare, it is also likely to be underdiagnosed for several reasons. Firstly, kidney biopsies are not commonly performed in patients requiring therapeutic anticoagulation. This is due to concerns regarding the risk of thrombotic complications while the anticoagulant is withheld as well as concerns regarding haemorrhage, particularly in patients with recent excessive anticoagulation. Secondly, as ARN often occurs in patients with multiple risk factors for acute kidney injury, extensive diagnostic evaluation may not always be performed.

Risk factors

The major risk factor identified for ARN is moderate or severe coagulopathy. In the case of warfarin, this can be identified by a high International Normalized Ratio (INR). Studies suggest that the risk of ARN is highest in the first three months after initiating warfarin.

Other potential risk factors for ARN include:

• Underlying chronic kidney disease;
• Glomerulonephritis (particularly with nephrotic syndrome);
• Age > 80 years;
• Male sex;
• Diabetes mellitus; and
• Cardiovascular factors (heart failure, hypertension).

Prevention:

Prevention of ARN should consider ways to minimise the risk of excessive anticoagulation. Drug interactions are an important factor to consider.

Warfarin interacts with many medicines. Medications that may increase exposure to warfarin include those that inhibit the CYP450 isoenzymes 2C9, 1A2, and 3A4. Some examples of these agents are amiodarone, metronidazole, aciclovir, verapamil, and alprazolam. It is recommended that the INR be monitored more carefully whenever drug treatment is changed, including when a new medicine is started or when an existing medicine is ceased or has a dose change.

Apixaban plasma levels may increase when given with dual inhibitors of CYP3A4 and P-glycoprotein (P-gp). Apixaban is contraindicated with strong inhibitors of CYP3A4 and P-gp, such as ritonavir and systemic azole antifungals (e.g. itraconazole and voriconazole). Co-administration with medicines that are not strong inhibitors of CYP3A4 and P-gp is expected to increase plasma levels to a lesser extent and is not considered clinically relevant.

Dabigatran plasma levels can be increased by P-gp inhibitors (e.g. amiodarone, verapamil, quinidine, ticagrelor, and clarithromycin). The manufacturer contraindicates concomitant treatment with systemic ketoconazole, cyclosporin, itraconazole or dronedarone; initiation of verapamil is also contraindicated in some settings.

Rivaroxaban levels may be increased when given with inhibitors of CYP3A4 or P‑gp. The manufacturer contraindicates the combination with strong inhibitors of both CYP3A4 and P‑gp. In patients with moderate renal impairment, caution is required with moderate inhibitors of CYP3A4 or P‑gp.

Comprehensive information on potential drug interactions can be found in the relevant product information.

Summary:

As oral anticoagulants are commonly prescribed medicines, it is important to be aware of this serious adverse event. A diagnosis of ARN should be considered in patients with excessive anticoagulation who present with acute kidney injury. Early detection and intervention are essential for minimising morbidity and mortality associated with ARN.

Suspected adverse events can be reported to the TGA using the online form.

Sepsis is a medical emergency which, if left untreated, can progress to septic shock, multi-organ failure and death. Pathogens responsible for sepsis can be bacterial, viral or fungal. Any person who acquires an infection is at risk of developing sepsis. Sepsis is the leading cause of death in hospitals and is related to 20% of all deaths.

High levels of lactate in tissue is an indication of tissue hypoxia. Tissue hypoxia for a long time can cause irreversible damage to the tissue resulting in its death and organ failure. Organ failure is a common feature seen in septic shock patients. Multi-organ failure is the last stage of uncontrolled sepsis, which can result in death. Septic shock is a subset of sepsis associated with profound circulatory, cellular and metabolic abnormalities.

Groups at a higher risk of developing sepsis are:

• The very young and old;
• Immunocompromised;
• Hospitalised patients; and
• Pregnant or recently pregnant women.

The following measures can reduce the risk of a person acquiring an infection:

• Vaccination;
• Hand hygiene;
• Sanitation measures;
• Infection control within healthcare; and
• Pandemic response measures.

A delay in the treatment of sepsis or inadequate treatment can reduce the patient’s chance of survival. For every hour of delay in commencing antibiotics, there is a 7.6% decrease in survival over the first 6 hours. The time to initiation of antibiotics is a key factor in patient survival.

Treatment

Evidence-based guidelines (e.g. The Hour-1 Bundle) should be initiated within the first hour of the patient presenting with sepsis. The following is recommended:

• Measure lactate level. Remeasure if initial lactate is >2mmol/L. Serum lactate helps in identifying a patient progressing into septic shock.
• Obtain blood cultures prior to administration of antibiotics. However, antibiotic administration should not be delayed in order to obtain blood cultures.
• Administer broad-spectrum antibiotics.
• Begin rapid administration of a minimum of 30ml/kg crystalloid for hypotension or lactate ≥4mmol/L. A crystalloid solution such as 0.9% sodium chloride is the most frequently used fluid.
• Apply vasopressors if the patient is hypotensive during or after fluid resuscitation to maintain mean arterial blood pressure (MAP) ≥65mmHg

Patients who remain hypotensive despite adequate fluid administration are said to be in septic shock. These patients require vasopressor infusions. Noradrenaline is the first-line treatment in septic shock. Metaraminol and phenylephrine are alternatives. Vasopressin is often administered second-line to replete the relative vasopressin deficiency, which occurs in septic shock and allows for a reduction in noradrenaline requirements.

Steroids may be administered to patients with septic shock. The 2018 ADRENAL trial did not show a mortality benefit with a 200mg daily intravenous infusion of hydrocortisone but did show improvements in secondary outcomes of time off ventilation and length of ICU stay.

If prolonged hypotension occurs, blood flow to the kidneys will reduce, and organ dysfunction will begin. Sepsis is the leading cause of acute kidney injury.

Initial antibiotics used to treat sepsis should be broad-spectrum to cover the potential infecting pathogen. Considerations to be taken into account to determine the most appropriate antibiotic are:

• The most likely source of infection;
• Local antibiotic resistance patterns;
• Recent antibiotic exposure;
• Patient allergies;
• Individual patient factors (e.g. recent hospitalisations, immunosuppression, and overseas travel); and
• Any known multi-resistant organism (MRO) colonisation.

A medication history should be taken with a particular focus on allergies, vaccination history and any recent antibiotics received. If a patient has been taking antibiotics prior to presentation, then antibiotics from a different class, or higher doses, may need to be considered. The antibiotic choice needs to be reviewed and rationalised in response to changes in patient condition and the results of microbiological cultures as they become available. Patients in septic shock can experience pathophysiological changes, which in turn can affect the pharmacokinetics of medicines. Therefore, these changes need to be taken into consideration when dosing. Antibiotic treatment should be reviewed if the patient’s condition deteriorates.

Patients with septic shock may require their regular medicines to be withheld. Other medications may require dose adjustment based on any organ failure. Hospitalised patients should receive venous thromboembolism (VTE) prophylaxis, as septic patients are at a high risk of developing blood clots.

Absorption from the gastrointestinal tract (GIT) is reduced in septic shock, as blood supply is diverted away from the GIT to the essential organs (brain, lungs and heart). Hence, oral administration of antibiotics is less likely to be effective due to delayed or reduced absorption. The Intravenous (IV) route of administration is therefore preferred for septic patients. If unable to obtain IV access, then intraosseous (IO) administration is the second-line option.

Drug metabolism can decrease in septic shock as hepatic blood flow reduces. If liver function is significantly reduced, then dosage adjustments to hepatically cleared medications may be needed.

The Therapeutic Guidelines advise that the following features are indicators of life-threatening organ dysfunction and are associated with a significant risk of deterioration or death:

• Impaired consciousness
• Tachypnoea (respiratory rate 22 breaths/minute or more) or hypoxaemia
• Hypotension (systolic blood pressure less than 90 mmHg)
• Blood lactate concentration more than 2 mmol/L

Life-threatening organ dysfunction is also indicated by the following features:

• Poor peripheral perfusion or mottled skin;
• Acute oliguria or elevated serum creatinine (above baseline);
• Low platelet count; and
• Elevated serum bilirubin (above baseline).

 

Self-management is an important aspect of chronic disease management. This approach requires patients to actively participate in their recovery in order to encourage survival, well-being and overall health and reduce the negative impacts of treatments. It involves patients working collaboratively with health professionals and their carers so as to:

• Devise a plan of self-care and monitor it;
• Participate in activities that promote and enhance health, by concentrating on prevention and timely intervention;
• Manage and monitor signs and symptoms;
• Cope with the bearing of the condition on mental health, physical health and social interactions;
• Understand the condition and the options for treatment and management that are available, and participate in decision-making; and
• Develop the confidence and ability to access supports and services.

To facilitate this, it is of value to employ the following supports for patients:

• Provision of tailored information to patients
  • To enhance knowledge and help the patient with behaviour change.
  • Tailor self-management support to the patient’s ability to do so, taking into account skill level and confidence of the patient.
• Promote self-efficacy
  • Involve patients in behaviour change, g. through an action plan.
  • Assist patients to understand the multiple causes of their symptoms to encourage trying new self-management techniques.
  • Maintain a collaborative approach and encourage this with other health professionals involved in care, to aid patients in taking responsibility for their health.

The promotion of behaviour change is central to patient autonomy and success in self-management of their chronic disease. Various techniques can be employed by health professionals to facilitate behaviour change such as:

• Goal setting and planning
  • Help patients to concentrate on a particular issue, set achievable goals and devise a tailored action plan to work towards achievement.
  • Usually, goals are SMART (Specific: simple and focused; Measurable: goal has a measurable outcome; Achievable: the patient must have the ability to achieve; Realistic: the patient is capable of achieving the goal, and during the consultation identify any barriers to doing so; and Timely: define a date and time for achievement of the goal).
• Open questioning
  • Enables patients to discover their issues and devise their own motivation to change.
• Reflective listening
  • Is an active process to mirror the message the patient has just imparted, and further emboldens the patient to articulate their own reasons to change.
• Articulating follow-up requirements
  • Help patients to adhere to planned care strategies, deliver emotional care, and lead behaviour change.
• Problem solving
  • To recognise and analyse issues together with the patient, understand how the issue impacts on their life, work through barriers to change behaviour, and resolve clinical problems, as well as help the patient to do so as well, by effectively using resources and time available.
• Assertiveness
  • Important in handling patients who may be aggressive or defensive, and assists the health professional in approaching challenging issues and tackling people about change.
• Assessing a patient’s willingness to change
  • Will aid a patient to then adhere to the strategies needed to work through the change process.

Motivational interviewing is a technique that promotes a patient’s motivation to change. It is based upon a combined therapeutic relationship where the patient’s autonomy is prioritised, and the health professional identifies the tools required for change. The health professional assumes a supportive approach to facilitate the patient’s journey towards changing their behaviour. The approach of ‘The Five A’s Model of Self-Management Support’ involves the use of essential skills such as reflective listening, goal setting and planning, and open questioning and consists of the following five steps:

1. Assessment – of the patient’s habits, beliefs, knowledge, and the health professional’s review of clinical data.
2. Advise – the health professional aims to improve a patient’s knowledge, provide tailored information, and resolve any misconceptions.
3. Agreement – a collaborative approach with the patient to set specific, achievable goals and develop an ensuing action plan.
4. Assist – help the patient to recognise apprehensions and obstacles to change, and develop strategies to assist in working through these, and achieve these goals.
5. Arrange – follow-up consultation either by phone or in person with the patient to reflect on progress against goals, and reiterate the action plan and goals to be achieved.

Motivational interviewing is successful when the health professional is able to:

• Empower the patient to talk
• Develop self-motivational dot points for the patient
• Handle opposition from the patient
• Inspire the patient to change
• Discuss and devise a plan in collaboration with the patient

The health professional should adopt a patient-centred approach, rather than try to rectify a problem, advise or persuade. The strategy should involve asking the following questions:

1. Why do you want to make this change?
2. How might you go about being successful in changing?
3. What are the three key reasons for you to change?
4. On a scale of 0-10, how important is it for you to make this change?
5. Why have you chosen x rather than a lower number?

After closely listening to the answers, the health professional needs to reflect a concise summary of the information gathered, then ask the patient what they think they will do. Patients should be stimulated to speak their minds in order to help the health professional foster a willingness for change, work through resistance, formulate a plan, develop motivation and take action.

Ogunbayo et al. conducted a study into patient opinions regarding self-care in chronic medical conditions and their reliance on community pharmacies. It was found that healthcare professionals were thought to be passive and incomplete providers of information, and not helpful in effecting behaviour change. Patients reported that sources outside the healthcare realm (i.e. friends, family, carers, the internet) were significant in catering for such voids, in particular with regard to lifestyle measures. Patients’ recognition of community pharmacies as an opportunity for self-care support provision in chronic disease management and, in turn, their utilisation of and perceived need for community pharmacies was found to be minimal, with little cognisance of the potential for the abilities and role of a community pharmacist, with a primary focus on just medication supply. This study demonstrated that community pharmacists should consider patient perception of the lack of contribution to self-care support in chronic conditions, and inter-professional collaboration may be of benefit.

It is clear from widespread documented evidence (beyond the scope of this article) that the clinical pharmacist plays an important role in a multidisciplinary team and can make a significant impact upon patient care, provide a ready resource of drug information and advice for colleagues and patients alike with regard to therapies, monitoring, and toxicity, as well as cost savings and beneficial pharmacoeconomic outcomes. Medications are clearly a vital part of patient therapy, and accordingly, a methodical and careful methodology in assisting patients to manage their medications can simplify matters and positively impact upon therapeutic outcomes. Accordingly, pharmacists can contribute significantly to patient care and represent a dynamic and essential part of the answer to providing care for the growing number of patients in our communities. By applying a systematic, sequential practice combining the fundamental ideologies of pharmaceutical care to each patient’s clinical situation, circumstances and therapeutic goals, then ultimately keeping at the forefront the value for patients, is fundamental to motivating the application of new collaborative initiatives and extended scope of responsibility involving pharmacists in supporting patients on their journey to wellness.

Supportive care in cancer is a collective term used to indicate services that may be needed by cancer patients and their close networks. It consists of self-help and support in the realms of psychology and spirituality, information provision, symptom management, rehabilitation, palliative care and bereavement care. In summary, supportive care in cancer refers to the following five areas of need:

• Psychological;
• Spiritual;
• Social needs;
• Physical; and
• Informational.

Supportive care offered by all members of the multidisciplinary team, as well as help from family, friends, support groups, volunteers and other community-based organisations, make a vital difference to the quality of supportive care. Healthcare systems with a strong primary care component have been demonstrated to be more cost-effective than those which are predominantly led by hospital specialists.

Pharmacists, as primary care professionals, can make a contribution to supportive and survivorship care in the following areas:

• Symptom management;
• Health promotion and wellness;
• Assist patients to make informed decisions about health improvement;
  • Focus areas can include diet, exercise, alcohol use, smoking cessation, etc.
• Act as an interface between the patient/survivor, primary healthcare professional, oncology team, and any other providers involved;
• Facilitate guidance as to what services should be offered as components of care and indicate who is responsible for managing these; and
• Support patient self-management.

Communication skills are central to providing supportive and survivorship care. This broadly involves the pharmacist effectively:

• Pinpointing the needs of the person;
• Establishing a therapeutic relationship with the patient;
• Meeting the informational needs identified in relation to diagnosis and treatment plans;
• Reducing distress and anxiety; and
• Developing the patient’s self-management skill set.

Successfully working within interdisciplinary teams – establishing rapport with others and participating in positive partnership and synchronisation, while having an understanding and level of respect for the purpose and role of all stakeholders and assimilating facets of care by engaging those in other sectors, as well as employing good communication skills and timely initiation of services is key. The skills required by the pharmacist in order to achieve these attributes include the following:

• Strong communication skills;
• Health promotion knowledge and an awareness of resources, services and supports available and accessibility to these;
• Psychosocial support and assessment skills;
• Cultural sensitivity;
• Ability to assess various health risk factors;
• Utilisation of peer support;
• Assess the self-management ability of the patient; and
• Care planning in cooperation with other stakeholders.

Pharmacists can use the following checklist for ensuring effective patient interaction⁷:

• Active listening;
• Open questioning;
• Good eye contact;
• Open body language;
• Appropriate environment;
• Use of timing;
• Alertness to verbal and non-verbal cues;
• Allow the patient time to speak;
• Use of silence appropriately;
• Sensitivity in handling uncomfortable situations;
• Recognise one’s own distress;
• Clarify patient concerns; and
• Inquire about the patient’s home circumstances and feelings.

The role of primary care generally in cancer control is increasingly recognised as a vital part of cancer services in Australia. This arm of healthcare plays an important role across the cancer continuum: in primary cancer prevention, discussing and delivering cancer screening tests, accurately diagnosing people with cancer when they present in the community, providing supportive care during and after treatment, and at the end-of-life. Cancer prevalence is rising due to improvements in survival and the ageing population. Therefore, primary care will, in turn, need to play a growing role in managing survivorship to ensure cancer care is sustainable.

Urinary tract infections (UTIs) are one of the most frequently occurring bacterial infections in women, and at least 50-60% of women will develop a UTI in their lifetime. The most common organism causing UTIs is the bacteria Escherichia coli. The urinary tract is usually a sterile environment. However, bacteria may transfer from the perianal region, causing a UTI and leading to symptoms such as painful urination and increased urinary urgency.

The definition of a recurrent UTI (rUTI) is having three or more UTIs showing positive cultures during a 12-month period or at least two UTIs showing positive cultures in the previous six months.

UTIs can be classified into various categories, including uncomplicated infections, where the urinary tract is structurally and physiologically normal, and complicated infections where there are abnormalities of the urinary tract. Early investigations, including cystoscopy and urinary tract imaging, should be considered for women with complicated UTIs and those with uncomplicated UTIs who also show atypical features or are not responding to treatment. UTIs can also be classified as being unresolved, where therapy fails due to bacterial resistance or due to infection by two different bacteria; reinfection, where the infection clears after treatment but then the same organism regrows at least two weeks after therapy or a different microorganism grows during any period of time; and relapse, when the same microorganism causes a UTI within two weeks of therapy. Accurately diagnosing and categorising a UTI can help correct complicating factors that predispose someone to an rUTI and guide treatment. Recurrences of UTIs generally occur within three months of the original infection, and 80% of rUTIs are reinfections. Common risk factors for rUTIs are listed in Table 1.

Table 1: Risk factors for rUTIs

In Pre-Menopausal Women	In Post-Menopausal Women
●      Sexual intercourse ●      Use of spermicides or diaphragm for contraception ●      New sexual partners in the last 12 months ●      Early age of first UTI (less than 15 years of age) ●      Maternal history of UTI ●      Recent antimicrobial use	●      Atrophic vaginitis ●      Cystocele ●      Incontinence ●      Catheterisation ●      Declining functional status ●      History of pre-menopausal UTI ●      Incomplete emptying

General non-antibiotic strategies to prevent rUTIs include drinking plenty of water in order to urinate more frequently to help flush bacteria from the bladder, cleaning the genital areas prior to and after having sex, wiping from front to back to reduce the spread of E.coli from the perigenital area to the urethra, and avoiding multiple sexual partners. Avoidance of products such as spermicides, diaphragms, vaginal douching, bubble bath liquids, bath oils, deodorant sprays or soaps is recommended as they may irritate the vaginal and urethral areas and encourage colonisation of bacteria within the urinary tract or alter the vaginal flora, which could lead to a UTI.

The Therapeutic Guidelines recommend antibiotic prophylaxis for rUTIs in those who have frequent symptomatic infections (i.e. two or more infections within six months, or three or more infections within 12 months). Antibiotic prophylaxis strategies (see Table 2) are effective ways of managing rUTIs and include either continuous prophylaxis or intermittent postcoital prophylaxis. Acute self-treatment may also be considered. Urine culture and sensitivity analysis should be performed at least once while the patient is symptomatic, and a midstream technique needs to be used when collecting the urine sample in order to reduce the risk of vaginal and skin contamination. The results of urine cultures confirm the diagnosis, provide antibiotic sensitivities, allow for targeted treatment of the UTI and guide the choice of antibiotics for prophylaxis.

Table 2: Antibiotic regimes for recurrent UTIs in non-pregnant women

Strategy	Antibiotic dose, frequency and duration	Pros/Cons and notes
Continuous prophylaxis	Trimethoprim 150mg orally at night for 6 months; or Cefalexin 250mg orally at night for 6 months; or Nitrofurantoin 50mg orally at night for 6 months	Higher incidence of side effects and antibiotic resistance compared to other strategies.   Nitrofurantoin is associated with an increased risk of adverse effects when used long-term, and includes pulmonary toxicity, hepatotoxicity and peripheral polyneuropathy. Regular spirometry, liver function tests and kidney function tests should be performed if the decision is used to start nitrofurantoin long-term.
Intermittent postcoital prophylaxis	A single dose of one of the above antibiotics is taken within the 2 hours after sexual intercourse occurs	This strategy is generally adopted when the rUTI is related to sexual activity. The incidence of side effects with this strategy is lower than when using the daily prophylaxis strategy.
Acute self-treatment	Involves the patient taking a standard 3-5 day course of recommended antibiotics at the onset of symptoms. Therapeutic dose of the antibiotic should be used after midstream urine testing is performed. Trimethoprim 300mg daily for 3 days; or Cefalexin 500mg every twelve hours for 5 days; or Nitrofurantoin 100mg every six hours for 5 days	Decreases overall antibiotic intake for those who are not suitable candidates for long-term daily prophylaxis. Patients should seek medical review if symptoms do not resolve within 48 hours of completing treatment.

Urine culture and sensitivity results should guide the choice of antibiotic wherever possible, and regional antibiotic resistance patterns, patient preferences and tolerance should also be considered. If UTIs recur despite prophylactic treatment, specialist expert advice should be sought.

Adjunct treatments may also be considered. Intravaginal estrogen in post-menopausal women has been shown to have beneficial effects on vaginal flora and reduces the incidence of rUTIs in small randomised controlled trials. Cranberry products did not show sufficient evidence of benefit in preventing UTIs and thus are not recommended for the prevention of UTIs. Methenamine hippurate has a bacteriostatic effect in the urine and may reduce the incidence of symptomatic UTIs in women without urinary tract abnormalities. However, evidence for the prevention of UTIs is poor and inconsistent. It has also not been shown to be effective for the prevention of UTIs in those with urinary tract abnormalities. D-mannose is thought to have antibacterial activity by inhibiting bacteria’s adherence to urothelial cells. Limited studies demonstrate a reduction in the rate of UTI recurrence in women. However, further studies are required. Other treatments, such as probiotics, immunostimulants, vaccines, and acupuncture, have been investigated. However, further evaluation is required.

Enerzair^® Breezhaler^® is a triple therapy fixed dose combination inhaler containing an inhaled corticosteroid (ICS), an ultra-long-acting beta-agonist (LABA), and a long-acting muscarinic antagonist (LAMA), namely mometasone furoate, indacaterol and glycopyrronium. It is indicated for maintenance treatment of severe asthma in those who have inadequate control from using a combination of ICS and LABA. Studies show that the Enerzair^® combination has demonstrated superiority to treatment with indacaterol and mometasone combination alone, in terms of change from the baseline forced expiratory volume in one second (FEV1) after 26 weeks of treatment and other measures of lung function.

The inhaler comes in two strengths: either indacaterol 114mcg, glycopyrronium 46mcg, mometasone furoate 68mcg or as indacaterol 114mcg, glycopyrronium 46mcg, mometasone furoate 136mcg (2). The dose is delivered using the Breezhaler^® device, with inhalation of the content of one capsule once daily being the recommended dose. As with other Breezhaler^® devices, the administration instructions are detailed below in Figure 1 below. 

Figure 1: Instructions for using Breezhaler® device (adapted from Asthma Australia)

*Wash hands before using inhaler device* Open device Remove cap Flip mouthpiece to open Load capsule Remove capsule from blister and place in the chamber Close mouthpiece until it clicks Press side buttons in once and release Inhale single dose Breathe out gently away from the inhaler Put the mouthpiece between teeth without biting and close lips to form a good seal Breathe in quickly and steadily, so the capsule vibrates. Continue to breathe in until comfortable Hold breath for about 5 seconds or as long as is comfortable Remove the inhaler from your mouth while holding your breath Breathe out gently away from the inhaler Close device Open mouthpiece and remove the capsule Close the mouthpiece and replace the cap Rinse your mouth out with water after use Other important points: ●      Only use the capsules provided in the pack with the inhaler ●      Keep capsules in the blister until you need them ●      Peel the blister back to retrieve the capsule, don’t push the capsule through the blister

Mild side effects are common when using the Breezhaler^® device and include changed voice, sore or dry mouth, sore throat, and muscle pain. As with other inhaler devices containing corticosteroids, the patient should be reminded to rinse their mouth with water, gargle and spit out after each use. An asthma action plan should also be developed so that the patient is aware of what steps to take and when a presentation to the emergency department is warranted. Inhaler technique should also be checked regularly by either the GP or pharmacist.

Enerzair^® Breezhaler^® is currently listed on the Pharmaceutical Benefits Scheme (PBS) under a streamlined authority, with the clinical criteria being patients who are 18 years of age or older and having had at least one severe asthma exacerbation in the last 12 months prior to having first commenced treatment for severe asthma which required systemic corticosteroid treatment despite each of i) receiving optimised asthma therapy, ii) being assessed for adherence to therapy, and iii) being assessed for correct inhaler technique. Optimised asthma therapy includes adherence to the maintenance combination of an ICS of at least 800mcg budesonide per day or equivalent, and a LABA.

 

Tirzepatide is a new drug for the treatment of type 2 diabetes mellitus (T2DM). While it is not yet available in Australia, it has recently gained Therapeutic Goods Administration (TGA) approval for adults with insufficiently controlled T2DM as an adjunct to diet and exercise, where monotherapy with metformin alone has not been tolerated or contraindicated, or in addition to other pharmacotherapies for the treatment of T2DM (1). Though not yet TGA approved for the indication of obesity, tirzepatide also offers promising outcomes in substantially reducing body weight.

It is a unique and “first in its class” medication as it is both a glucagon-like peptide–1 (GLP-1) receptor agonist, as well as a long-acting glucose-dependent insulinotropic peptide (GIP) receptor agonist. Its action on the GLP-1 receptor stimulates insulin secretion in hyperglycaemic states, suppresses glucagon secretion, delays gastric emptying and decreases appetite. GIP receptors are widespread in adipose tissue and also have a role in increasing insulin sensitivity. Thus this dual mechanism functioning on both the GLP-1 and GIP incretins significantly reduces glycaemic levels and improves insulin sensitivity, whilst reducing body weight and improving lipid metabolism. Its C20 fatty-diacid moiety, which can bind to albumin, prolongs its half-life, enabling it to be dosed once a week via subcutaneous injection.

The pre-filled subcutaneous pen is presented in multiple different strengths, as the starting dose is 2.5mg once weekly and increasing to 5mg once weekly after four weeks. The dose can be increased in further 2.5mg increments after a minimum of four weeks, with the recommended maintenance doses being either 5mg, 10mg or 15mg, with the maximum dose being 15mg once weekly. Common side effects of tirzepatide are comparable to other GLP-1 agonists and include gastrointestinal side effects such as nausea, vomiting and diarrhoea, and the incidence of hypoglycaemia appears to be low.

Compared to semaglutide, which is currently on the market, studies have shown that tirzepatide has significantly superior therapeutic efficacy. A higher percentage of those using tirzepatide reached the glycated haemoglobin (HbA1c) target level of less than 7% compared to those on semaglutide, and the patients who received tirzepatide 15mg attained almost twice the weight loss of those who received semaglutide 1mg.

Thus, tirzepatide is an emerging and promising option for those with T2DM and obesity, showing superior effects compared to semaglutide.