GLP-1 agonist dulaglutide is an injectable synthetic hormone that increases first-phase insulin response (insulin released in response to food ingested) and second-phase (glucose-dependant) insulin secretion. It inhibits glucagon secretion and slows gastric motility so can reduce appetite while increasing satiety.8,19
GLP-1 agonists can reduce HbA1c by 13–15mmol/mol and average weight loss is equitable to that of SGLT2 inhibitors (2–5kg), according to studies.8,19,20 However, in clinical practice, much greater weight and HbA1c reduction has been observed – in some cases weight loss of ≥ 15kg and HbA1c reduction of 20mmol/mol.5 Early weight loss after treatment initiation is a strong predictor of significant weight and HbA1c reduction.20 GLP-1 agonists may reduce systolic BP by 2–5mmHg.6,19
GLP-1 agonists are associated with a significant reduction in cardiovascular events and albuminuria, and likely afford long-term protection against eGFR decline.5,6 In the REWIND trial, dulaglutide demonstrated a 12 per cent reduction in the primary outcome (non-fatal myocardial infarction, non-fatal stroke or death from cardiovascular causes) in patients with and without a history of CVD.5,21
The underlying mechanisms accounting for the decrease in cardiovascular and renal outcomes is thought to be related to a composite of actions: body weight, BP and postprandial triglyceride reduction, and effects on inflammatory processes that contribute to endothelial dysfunction.6
Generally, dulaglutide is well tolerated. The main side effects are described here, but refer to the Medsafe data sheet or the New Zealand Formulary for comprehensive information on side effects and contraindications.
Abdominal discomfort, nausea and reduced appetite are by far the most common side effects and are primarily related to reduced gastric motility, which is greatest after the initial injection and tends to settle over a few weeks.6,8 Some patients may experience more extreme gastric disturbance, diarrhoea or vomiting and not be able to tolerate a GLP-1 agonist.
When used in combination with insulin or sulphonylureas there is an increased risk of hypoglycaemia. Pre-emptive dose reductions of these medications may be necessary, depending on baseline HbA1c.8
Injection-site hypersensitivity reactions may occur in 0.5 per cent of patients – most commonly pruritus, which is transient and generally tolerated without the need to discontinue treatment.8
Medications with narrow therapeutic index
Because dulaglutide slows gastric emptying, closer monitoring of drugs with a narrow therapeutic index may be required (eg, warfarin, digoxin, lithium, phenytoin and others).8
Thyroid and endocrine cancers
GLP-1 agonists are contraindicated in patients with a personal or family history of medullary thyroid cancer.19,22
The risk of pancreatitis associated with GLP-1 agonists has recently been invalidated; however, a subclinical rise in amylase and lipase levels has been observed and so many healthcare providers consider avoiding dulaglutide in patients with a history of pancreatitis.5
Severe gastric disease
Because of gastrointestinal (GI) side effects and the direct effects of GLP-1 agonists on gastric emptying, these agents are not recommended for patients with a history of gastroparesis, Crohn disease and other severe forms of gastric disease.5,8
All GLP-1 receptor agonists can be used without dose adjustment in patients with mild renal impairment, and dulaglutide does not require dose adjustment even in patients with severe renal impairment. However, postmarketing reports for GLP-1 agonists have identified instances of acute renal failure – some in patients with no known underlying renal disease – and worsening of chronic renal failure. Most events occurred in patients who had experienced nausea, vomiting, diarrhoea or dehydration. Because these reactions may worsen renal function, caution is required when initiating or escalating GLP-1 agonists in patients with renal impairment, and close monitoring of renal function should occur in those who report severe GI reactions.22,23