Diabetes Queensland

By Donna Itzstein

DQ Pharmacist

Ryzodeg was added to the Pharmaceutical Benefits Scheme (PBS) on August 1, 2018, after an "early experience program" with direct supply by prescribing endocrinologists (1).

The Novo Nordisk combination product containing 70 percent Insulin Degludec (rys) and 30 percent Insulin Aspart (rys) gained approval by the Therapeutic Goods Administration (TGA) in November 2017 (2).

Degludec is an ultra-long acting insulin whereas Aspart is a very rapid acting insulin. The introduction of analogue insulins, such as this product, has significantly improved the predictability compared to human and bovine insulins.

Figure 1 compares the profiles of various insulins commonly used in Australia.

Compared to other basal insulins, Detemir (20 hours) and Glargine (24 hours), Degludec has a duration of action beyond 42 hours. Tresiba (single ingredient insulin Degludec) has been available in the UK and USA since 2015. It was approved for use in adults by the Australian TGA at the same time as Ryzodeg in November 2017; however, Tresiba is not yet subsidised by the PBS.

Figure 2 compares the action profiles of Ryzodeg (70 percent Degludec, 30 percent Aspart) and Tresiba (Degludec)  (3) (4).  Insulin Degludec provides a long flat profile, which with the recommended 24 hour injections, insulin levels stabilise into a steady state after two to three days. Dosage adjustments are recommended only after three to four days of current dose use.

Ryzodeg contains 30 percent very short acting insulin (Aspart) which is administered immediately before a meal with sufficient carbohydrate.

The pharmacodynamics of Ryzodeg 70/30 (image 1) is the result of the action profiles of the individual components; the ultra-long acting Degludec and the rapid acting Aspart.

The Degludec component forms soluble multi-hexamers when subcutaneously injected, whereas the Aspart dissociates and is quickly absorbed into the bloodstream.

After Aspart dissociates into the bloodstream, a depot remains from which the Degludec is continuously and slowly absorbed into the circulation, leading to a flat and stable glucose-lowering effect.

The actions of the individual insulins in this co-formulation are independent. Insulin Degludec is highly protein bound in the bloodstream; however, the rate-limiting step for entry into the bloodstream is disassociation of the multi-hexamers. Its action is unlikely to be affected by protein displacement by other drugs.

The ultra-long action of Degludec (as a single component of Ryzodeg) compared to other basal insulins reduces variability in the glucose-lowering effect. A study in patients with type 1 diabetes, comparing insulin Degludec to insulin Glargine, found that the variability of the glucose-lowering effect was much less, regardless of the time of day (5)(Figure 3).

Please note Ryzodeg's safety and efficacy is not established in paediatric, pregnant or breastfeeding populations.

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Type 1 diabetes

Ryzodeg, due to the large basal component, is administered in type 1 diabetes once daily with the largest carbohydrate meal of the day. This may change from meal to meal as long as it is administered in an 8-hour window. Other meals will require bolus (insulin Aspart) doses according to the carbohydrate content of the meal. This allows Ryzodeg to be dosed with lunch instead of breakfast or dinner.

Pros:

• Reduced variability of the glucose-lowering effect.
• The flexibility of changing the timing of the daily dose of Ryzodeg within 8 hours as long as the meal contains enough carbohydrate for the insulin Aspart dose.
• It may be an option for adults who have very little dietary variation from day to day, as it reduces the number of daily injections by one.
• Studies reveal the risk of nocturnal hypoglycaemia is reduced compared to insulin Detemir, due to the reduced variability and the long flat profile of insulin Degludec (6).

Cons:

• Less flexibility regarding mealtime insulin dosing. Ryzodeg assumes the carbohydrate-containing meal will match the insulin Aspart dose.
• Due to the ultra-long action of the insulin Degludec component, dose changes will require two to three days to take effect.
• Basal insulin requirements change during a 24-hour period in everyone. In this regard, Ryzodeg will be less flexible than insulin Detemir taken twice daily or an insulin pump.
• Having mealtime insulin combined with a basal insulin may cause confusion among patients.

Type 2 diabetes

Ryzodeg may be initiated in type 2 diabetes in insulin-naïve patients with a starting dose of 10 units and titrated up in once daily dosing or split into twice daily dosing. This will depend on the mealtime insulin needs of the individual patient. Advice regarding switching from basal or premix insulins can be found in the Ryzodeg product information (4).

Pros:

• No premixing. Ryzodeg contains two analogue insulins, which are clear and soluble, giving a consistent predictable result.
• Studies comparing twice daily Novomix (30 percent insulin aspart, 70 percent insulin aspart protamine) to twice daily Ryzodeg revealed that Ryzodeg had lower rates of hypoglycaemia (especially nocturnal), required lower total daily doses and fasting blood glucose levels were reduced (7). 
• Comparing once daily dosing of Ryzodeg 70/30IU/ml at the largest carbohydrate meal of the day and insulin Glargine 100IU showed no increase in rates of nocturnal hypoglycaemia (8).  
• If a patient misses a dose, it can be taken with the next main meal as long as the carbohydrate content is sufficient.

Cons:

• Making changes to dosing to account for things like change in diet, exercise, other medications can take up to three days to take effect.
• Clear guidance is required if a patient cannot eat or keep down fluids. Compared to an insulin Glargine dose, Ryzodeg has a very rapid acting dose, which may cause hypoglycaemia without sufficient carbohydrates.

Ryzodeg is available in cartridges and disposable pens. The device has an audible click upon completion of the injection after which a count of six seconds is required to stop dose regurgitation. The push button action is easy, enabling easy use with arthritis. 

This is another step forward and an option for some to improve their diabetes management.

For more information regarding this article, please contact us at Diabetes Queensland on 1300 136 588.

References

1. Australian Government, Department of Health. Pharmaceutical Benifits Scheme. PBS online. [Online] August 1st, 2018. http://www.pbs.gov.au/medicine/item/11417X.

2. Therapeutic Goods Administration. Prescription medicines: registration of new chemical entities in Australia, 2017. Therapeutic goods administration. [Online] July 2018. [Cited: August 1st, 2018.] https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2017.

3. Novo Nordisk. Product information Tresiba. Therapeutic goods administration. [Online] May 22, 2018. https://www.tga.gov.au/sites/default/files/auspar-tresiba-180522-pi.pdf.

4. Product information Ryzodeg 70/30. Therapeutic Goods Administrtion. [Online] November 17, 2017. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2017-PI-02728-1&d=201808051016933.

5. Insulin degludec: four times lower pharmacodynamics availability than insulin glargine under steady state conditions in type 1 diabetes. Heise, T, et al. 2012, Diabetes, Obesity and Metabolism, Vol. 14, pp. 859-864.

6. Insulin degludec/insulin aspart administered once daily at any meal, with insulin aspart at other meals versus a standard basal-bolus regimen in patients with type 1 diabetes: a 26-week, phase 3, randomized, open-label, treat-to-target trial. Hirsch, I B, et al. 11, s.l. : Diabetes Care, 2012, Vol. 35.

7. Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomized, treat-to-target trial. Fulcher, Gregory R, et al. 8, s.l. : Diabetes Care, 2014, Vol. 37.

8. Efficacy and safety of once-daily insulin Degludec/Insulin aspart versus insulin glargine (U100) for 52 weeks in insulin-naïve patients with type 2 diabetes: A randomized controlled trial. Kumar, A., Franek, E., Wise, J., Niemeyer, M., Mersebach, H., & Simó, R. 10, s.l. : PLoS One, 11, 2016, Vol. 11.

9. Superior glycaemic control with once‐daily insulin degludec/insulin aspart versus insulin glargine in Japanese adults with type 2 diabetes inadequately controlled with oral drugs: a randomized, controlled phase 3 trial. Onishi, Y., et al. 9, s.l. : Diabetes, Obesity and Metabolism, 2013, Vol. 15.