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.