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Introducing Trulicity (Dulaglutide)

By DQ Pharmacist

Donna Itzstein        

 

As of June 1 a new medication, Trulicity, (Dulaglutide) was approved for supply under subsidy through the Pharmaceutical Benefits Scheme (PBS).

 

Trulicity, due to its ease of use, reduced frequency of administration and injection site reactions is an [CT1]  attractive new option for people living with type 2 diabetes.

 

Dulaglutide is a GLP-1 RA that mimics endogenous GLP-1 (glucagon-like peptide 1), administered once weekly.  Dulaglutide produced by Eli Lilly has been available in the US since September 2014 when it was approved by the Federal Drug Administration.  Here in Australia, our drug safety authority, the Therapeutic Goods Administration (TGA) approved its use on 19 January 2015.

 

TGA approval was granted as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus alone, or in combination with Metformin, sulfonylureas, thiazolidinediones or prandial insulin. This new medication is sold as a month's supply (4 pens) at a cost of $130.91 but under PBS subsidy will be supplied at $39.50 (general) and $6.40 for concession patients.

 

Trulicity is available under PBS only under the appropriate authorised circumstances.

  Trulicity Graphic

 

Image 1: Representation of action of GLP-1 agonists

 

Endogenous GLP-1 is a hormone produced by the gut lining in response to food intake. GLP-1 stimulates the secretion of insulin from the pancreas only when glucose levels are elevated. In addition, GLP-1 inhibits glucagon secretion, slows gastric emptying, and reduces appetite promoting weight loss.

 

Endogenous GLP-1 is quickly broken down by the enzyme Dipeptyl-peptidase-4 (DPP4) and then by pass metabolism as it passes through the liver. GLP-1 agonists resist degradation by DPP4 enzyme and as they are injected into the subcutaneous layer of the skin bypass first pass liver metabolism. The effect produces much larger GLP-1 type actions for longer.

 

Image 2

Image2: Representation of chemical structure of Dulaglutide courtesy of Eli Lilly Australia ltd (5).

 

 

Dulaglutide consists of two identical GLP-1 like amino acid parts, which are 90 per cent identical to endogenous GLP-1. These parts have modifications to resist DPP-4 enzyme breakdown. The other part of the molecule is a fragment of human immunoglobulin, which reduces the immune reaction to the molecule. The large size of the molecule leads to less renal clearance. Steady-state concentrations of once-weekly subcutaneous Dulaglutide will occur within 2-4 weeks.

Dulaglutide is broken down by general protein breakdown. (2)

 

Table 1: Comparison Efficacy of HbA1c of Dulaglutide (AWARD) - reduction of HbA1c

Superior to

Non-inferior to

Placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide

liraglutide

 

Phase three AWARD trials 1 and 5 revealed a strong association reduction of fasting blood glucose at week 2 and achieving significant HbA1c reductions at week 26. (3) Practically, this means results, if they are going to happen, will be apparent early by monitoring fasting blood glucose levels. Reductions in blood glucose are significantly better when the dose of Dulaglutide is 1mg or greater. (2)

 

The most common adverse effects in clinical studies were gastrointestinal-related adverse events. The GI adverse events from Dulaglutide were the same as others in this class of medication being nausea, vomiting, diarrhoea and gastroesophageal reflux. The incidence and duration of these effects are similar with symptoms expect to peak around two weeks and decrease with continued use.

 

Other reactions are a class effect increased heart rate and reduction in blood pressure. The evidence indicating increased risk of pancreatitis in this medication group is conflicting; however, production of pancreatic enzymes increases with administration. In rat studies, GLP-1 agonists are associated with thyroid C-cell tumors. This has not translated to human experience; however, Dulaglutide is contraindicated in human patients with thyroid C-cell tumors.

 

The rate of site reactions found in Dulaglutide 0.7% much lower than the incidence for Exenatide. This can be attributed to the similarity of the molecule to endogenous GLP-1 and the extra immunoglobin portion attached. Unlike Bydureon (Exenatide) which is a microsphere encapsulated suspension injectable, no nodules are formed under the skin. The formulation is required to reach room temperature before injection. Storage requirements are refridgeration (2-8 degees celcius) until the expiry date, however be stored for up to 14 days at 30 degrees celcius before use.

 

Patients with lower renal function experience an increase in systemic exposure to Dulaglutide; however, no dosing adjustments are required. No dosing adjustments are required for other factors, such as hepatic function, age, sex, race, or weight. As Dulaglutide delays gastric emptying, there is the potential for drug interactions with respect to the absorption of orally administered medications; however, no relevant drug interactions have been reported. (2)

 

During the AWARD studies, patients naïve to injections were surveyed regarding ease of use of the Trulicity pen device. Nearly all patients found it easy to use and 97% of patients were able to administer placebo successfully via the dulaglutide pen device. Patients appreciated that the needle did not have to be touched or seen with the device. Fear of self-injecting significantly decreased over the 4-week study. During Trulicity administration, an audible click further distracts from injection time.  (2)

 

Reports based on a study of a large UK cohort in routine clinical practice reveal adding a GLP-1 (exenatide, liraglutide, or lixinatide) to insulin therapy may reduce risk of cardiovascular events and all-cause mortality but not the risk of hospitalization for heart failure in overweight patients with type 2 diabetes.  (4)

 

Table 2 compares Trulicity with Bydureon its nearest comparator on the Australian market.

 

Table 2: A comparison of  Bydureon (exenatide) and Trulicity (Dulaglutide)as reported in prescribing information

 

Bydureon (Exenatide)

Trulicity (Dulaglutide)

Frequency

Single use prefilled syringe- weekly

Single use prefilled syringe- weekly

Consistency

Extended release microspheres that require intensive premixing. Must be at room temperature to mix.

Chains of GLP-1 agonist linked to an immunoglobin portion, which allows it to be soluble but slows absorption and renal clearance. No premixing can be injected straight out of the fridge

Site reactions

High rates of injection site pruritus (47%), Erythema (24%), Nodules (19%) and pain (6%)

90 % homologous and linked chain is human immunoglobulin (modified) which reduces immune response to this large molecule- site reaction (0.7%)

Pen device

Larger bore needle required due to suspension.

Fine auto injector pen - the needle will not be seen. Audible click distracts from time of injection.

renal

Cease if renal clearance  <30ml/min

No dose adjustment

Efficacy

HbA1c reduction similar - superior to exenatide twice daily

HbA1c reduction similar - superior to exenatide twice daily

Weight reduction

Weight reduction up to 5kg in those with nausea and vomiting, up to 3kg with no nausea

Up to 3kg in one year - weight reduction will depend on other therapies administered.

Gastro intestinal adverse reactions

Nausea 20% vomiting 8% diarrhoea 13%. Most episodes of nausea were mild to moderate and with continued therapy, the frequency decreased in most patients.

Nausea 21% vomiting 13% diarrhoea 13%

Peaks during first 2 weeks and rapid decline by 4 weeks

 

Patients may confuse Trulicity with being a replacement for insulin injections. This is understandable as until the introduction of Byetta (Exenatide) in recent times, all injectables for diabetes were insulin. As with other GLP-1 agonists, Dulaglutide must be used with caution in patients with severe gastrointestinal disease.  Due to its capacity to promote weight loss risk in patients in or below their ideal, weight range must be considered.

 

References

 

1. Eli Lilly Australia. Public Summary Document- November 2017 PBAC Meeting: 5.06 Dulaglutide solution for injection, Trulicity. Pharmaceutical Benefits Scheme. [Online] November 2017. [Cited: May 31st, 2018.] http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd/2017-11/dulaglutide-psd-november-2017.

 

2. Advances in the treatment of type 2 diabetes: impact of dulaglutide. Angela M. Thompson, Jennifer M. Trujillo. s.l. : Dove medical press limited, 2016, Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol. 9.

 

3. Early fasting glucose measurements can predict later glycaemic response to once weekly dulaglutide. G. Grunberger, T. Forst, V. Pechtner, R. sHaginian, N. Jia, S. Gough. 3, March 2016, Diabetic Mediicine, Vol. 33, pp. 391-394.

 

4. Effect of adding GLP-1RA on mortality, cardiovascular events, and metabolic outcomes among insulin-treated patients with type 2 diabetes: A large retrospective UK cohort study. Uchenna Anyanwagu MD, Jil Mamza BSc, PhD, Richard Donnelly MD, PhD, Iskandar Idris. February 2018, American Heart Journal, Vol. 196, pp. 18-27.

 

5. Eli Lilly Australia Ltd. Prescribing Information : Trulicity (Dulaglutide rch). Guild link. [Online] [Cited: May 31st, 2018.] http://www.guildlink.com.au/gc/ws/lilly/pi.cfm?product=lyptruli10218.

 

 

 

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