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Drug Evidence Review:
Tresiba (insulin degludec) vs. Lantus (insulin glargine)
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Actionable Intelligence: Tresiba (insulin degludec), the FDA- Insulin therapy is a critical part of treatment regimen for patients with approved long-acting injectable insulin analog, seems to have a type 1 diabetes and for many with advanced type 2 diabetes. Current similar safety profile to its comparator Lantus (insulin glargine), insulin preparations have various limitations like hypoglycemia, based on their matching labeled serious adverse events (AEs). In weight gain, rigid dosing schedules, and concerns over inter-patient head-to-head clinical trials comparing these two insulin analogs, differences in insulin levels after injection. Tresiba (insulin degludec)
Tresiba (insulin degludec) was statistically non-inferior to Lantus is a novel basal insulin with improved pharmacokinetic and (insulin glargine) in reducing glycosylated hemoglobin levels, fasting pharmacodynamic properties compared to other insulin preparations, glucose levels confirmed hypoglycemic episodes, but the rate of including a long half-life of 25 hours and a duration of action greater nocturnal hypoglycemic events were significantly reduced especially than 42 hours at steady state, providing a flat and stable blood in type 2 diabetes patients treated with Tresiba (insulin degludec). glucose-lowering effect when injected once daily. Tresiba (insulin
Both the drugs had similar rates of serious AEs through the clinical degludec) offers a broad dosing window, allowing for a flexible dose trials. Based on real-world adverse events reported for Lantus (insulin regime, thereby likely improving patient compliance. glargine), our analytics have identified: non-labeled Active RxSignals for serious events such as liver transplant, cerebral thrombosis, and myelitis transverse; an RxScore of 43.88; and an RxCost per prescription of $1.62.
The approval of Tresiba (insulin degludec) was based on data from the BEGIN® clinical trial program, which includes randomized, controlled, treat-to-target, open-label trials in patients with type 1 and type 2 diabetes from over 40 countries. Table 1 below shows the details of these clinical trials.
Drugs Covered: Tresiba (insulin degludec), Lantus (insulin glargine
[rDNA origin] injection)
Indications Covered: Diabetes Mellitus, Type 2; Diabetes Mellitus,
Efficacy: Through clinical trials in patients with type 1 diabetes,
Tresiba (insulin degludec) was statistically non-inferior to Lantus
(insulin glargine) in reducing the glycosylated hemoglobin (Hb1Ac) and fasting Plasma Glucose (FPG) levels. Similarly, there was no significant difference between Tresiba (insulin degludec) and Lantus
(insulin glargine) in the rate of overall confirmed hypoglycemic episodes, although it was slightly higher in Tresiba (insulin degludec) compared to Lantus (insulin glargine). However, the nocturnal confirmed hypoglycemic episodes were consistently lower in Tresiba (insulin degludec) treated patients through the trials.
Clinical trials in subjects with type 2 diabetes confirmed that Tresiba
(insulin degludec) was statistically non-inferior in reducing HbA1c concentrations, and FPG levels compared to Lantus (insulin glargine). A meta-analysis of all the trials found that the rates of overall and nocturnal confirmed hypoglycemia were significantly reduced in Tresiba (insulin degludec) compared to Lantus (insulin glargine) in both insulin-naïve and insulin-experienced diabetes type
2 subjects. In another real-world observational study on diabetic patients with recurrent hypoglycemic episodes (who were excluded from all the above clinical trials), Tresiba (insulin degludec) showed an improvement in the glycemic control and patient treatment satisfaction.
Drug Classes Covered: Insulins and analogues for injection, longacting
MoA Covered: Insulin Receptor Agonists
On September 25, 2015, FDA approved Tresiba (insulin degludec,
Novo Nordisk), a long acting insulin analog, to treat adults with type
1 and type 2 diabetes mellitus by improving their glycemic control.
Tresiba (insulin degludec) is available at two dosages, 100 units/mL and 200 units/mL, and is administered subcutaneously once daily.
FDA concurrently approved Ryzodeg, a 70/30 combination of longacting insulin degludec and rapid-acting insulin aspart analogs, and European Medicines Agency (EMA) approved Xultophy, a combination of Tresiba (insulin degludec) and Victoza (liraglutide,
Novo Nordisk), a Glucagon-like peptide-1 agonist to treat diabetes type 2.
© 2016 Advera Health Analytics 1 Safety: For Tresiba (insulin degludec) (the most common side effects observed in the clinical trials of type 1 (T1) and type 2
(T2) diabetes were nasopharyngitis (23.9 % in T1/ 12.9 % in T2), upper respiratory tract infection (11.9 % in T1/8.4 % in
T2), headache (11.8 % in T1/8.8 % in T2), sinusitis and gastroenteritis (5.1 % in T1), diarrhea (6.3% in T2), peripheral edema (0.9% T1/ 3.0% in T2) and injection site reactions (3.8% in T1 and T2). Through the clinical trials, the serious AE rate in Tresiba (insulin degludec) seemed comparable to Lantus (insulin glargine). Consolidated data analysis of 21 Phase
2/3 trials from our proprietary analytic platform, Evidex™ showed a slightly higher rate of serious AEs in Tresiba (insulin degludec) treated arms (9.08% vs. 7.74% in control arms (p=0.59)). Noteworthy, a pre-specified meta-analysis of major cardiovascular events (MACE) as per FDA 2008 CV Risk Guidance recommendations showed the incidence rates of MACE in Tresiba (insulin degludec) treated groups was 1.48 events per 100 Patient Year Exposure (PYE) vs. 1.44 events per 100
PYE of Lantus (insulin glargine).
DEVOTE, a clinical trial to further assess the cardiovascular safety profile of Tresiba (insulin degludec) is presently ongoing. The results of this trial and post-marketing surveillance reports will provide a better look into the safety of this drug in future.
In the present article, we compared the safety profile of Tresiba (insulin degludec) with Lantus (insulin glargine). Both drugs have similar labels with sections alerting patients on the side effects associated with insulin usage. Tresiba (insulin degludec) seems to have a similar safety profile to Lantus (insulin glargine), with 11 Important Medical Event (IME) terms (according to EudraVigilance Expert Working Group (EV-EWG)) like anaphylactic reactions, cardiac failure, lipodystrophy and loss of consciousness overlapping between the drugs. Table 2 shows the IME-serious AEs found in Tresiba (insulin degludec) and Lantus (insulin glargine) drug labels, and their corresponding incidence rates in clinical trials and FAERS reports. Our
RxSignal1 analytic identified 7 Active Signals and 13 Watchlist signals for Lantus (insulin glargine), which include liver transplant, cerebral thrombosis, and myelitis transverse. Table 3 shows the RxSignals associated with Lantus (insulin glargine) and their corresponding incidence in clinical trials and post-marketing surveillance data from FAERS. Based on the post-market reporting of adverse events to FAERS, we calculated an additional RxCost3 burden of $1.62 per prescription associated with Lantus (insulin glargine) which adds up to a downstream annual medical expense of $30,040,000. Lantus
(insulin glargine) has an RxScore4 of 43.88, which is slightly higher than the average RxScore of 38.87 of the long-acting
Insulins and analogues.
Safety Comparison to Existing Treatments
Table 1A and 1B below gives a detailed overview of the clinical trials of Tresiba (Insulin degludec) vs Lantus (insulin glargine).
The side-by-side tabulation is done to simplify presentation across trials that are all conducted in differing trial designs. The data of individual trials was procured from the www.clinicaltrials.gov and the references indicated therein.
© 2016 Advera Health Analytics 2
© 2016 Advera Health Analytics 3
Table 2 shows the IME serious AEs that are found in the clinical trials and the latest label of Tresiba (Insulin degludec) and Lantus (insulin glargine). An ROR5 value of 1.0 indicates that there is a higher than expected reporting rate for a given AE / drug combination. A red Designated Medical Event (DME) tag indicates that the AE is on FDA’s DME list, which are inherently serious, often drug-related.
Tresiba (Insulin degludec) and Lantus (insulin glargine) does not have any boxed warning on their labels.
Tresiba (Insulin degludec) and Lantus (insulin glargine) do not have any REMS associated with their usage.
Table 3 below shows the Active and Watchlist RxSignals for Lantus (insulin glargine). Any signal tagged with “DR” indicates an AE that could potentially be related to the disease the medication is FDA-approved to treat.
© 2016 Advera Health Analytics 4
Our proprietary RxCost algorithm calculates downstream medical costs associated with AE/drug combinations. In this way, we alert our clients early on about unforeseen medical costs linked to serious AEs that are not listed in the drug’s FDA-approved prescribing information. Table 4 below shows the top 5 costliest non-labeled and labeled AEs associated with Lantus (insulin glargine.
© 2016 Advera Health Analytics 5
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The inclusion of a particular company, drug, adverse event, class or indication in this report is determined wholly by our quantitative signaling and analytic systems along with our qualitative analysis work. The inclusion or exclusion of any drug, company, adverse event, class or indication has not, and will not, be influenced by any third party, including any clients of Advera Health.
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The inclusion of a particular company, drug, class or indication in this report is determined wholly by our quantitative signaling and scoring systems along with our qualitative analysis work. The inclusion or exclusion of any drug, company, or indication has not, and will not, be influenced by any third party, including any clients of Advera Health.
© 2016 Advera Health Analytics 6 RxFilter results, disproportionality measures, RxSignals, RxScores, RxCosts, and Outcome rates change over time as a result of new case report procurement. As a result, the data you see in this report might not reflect the latest update. Clients may access updated results through their Evidex™ subscription. If you are not a client, you can contact us for more information.
1RxSignal uses a refined version of disproportionality analysis (DA) in order to make predictions regarding future FDA label changes. The key issue for developing a relevant signaling platform is being able to properly identify and track AEs that are of significant interest to FDA. RxSignal was developed by identifying key AEs from over one thousand past FDA alerts.
An Active RxSignal term must be an RxSignal-eligible term that is not listed on the drugs prescribing information. Our new methodology closely monitor 3 AEs - progressive multifocal leukoencephalopathy, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which are noted by the FDA as inherently serious and often drug-related DMEs. An Active RxSignal is triggered for these adverse reactions with at least 1 primary suspect case.
For all other RxSignal-eligible AEs, an Active RxSignal is generated when at least 5 primary suspect cases are reported and the ROR is 2.0 or greater, or when the primary suspect case count is between 2 and 5, and the lower end of the 95% confidence interval for the ROR is 2.0 or greater. We use ROR values of 2.0 and above as a benchmark for an Active RxSignal to help avoid false positive signals.
A Watchlist RxSignal has the same criteria with the exception of having an ROR value between 1.0 and 2.0, if the AE has at least 5 primary case reports. When the primary suspect case count is between 2 and 5, a Watchlist RxSignal is generated if the lower end of the 95% confidence interval for the ROR value is between 1.0 and 2.0.
2ROR is a disproportionality analysis known as the Reporting Odds Ratio. An ROR score greater than 1 indicates that there is a higher than expected reporting rate for a given AE/drug combination. While there is no widely accepted benchmark regarding the numerical level at which disproportionality analysis yields a safety signal, many in the drug industry assume that results above 2.0 warrant attention.
Occasionally, disease-related (DR) symptoms are listed in the “adverse event” field by the person who submitted the FAERS case report. When such events are clearly related to the underlying disease those “AEs” are designated as DR and excluded from further analysis, including our RxCost and RxScore methods. Additionally, when an AE could reasonably be associated with 1) the disease itself, 2) the administration of a drug to treat the disease, or 3) unknown causes, we designated such AEs as
"potential DR" and they are included in our cost and scoring methods. While we are careful to omit all DR AEs from analysis, it cannot be stated that our methods identify and exclude them all.
RxFilter makes post-marketing adverse event (AE) case reports contained in FDA's Adverse Event Reporting System (FAERS) accessible by using a combination of computer algorithms and in-house data analysis. The system accurately standardizes and normalizes ~5 million AE case reports, from 1997 on, linked to over ~2,000 FDA approved drugs and feeds those clean data into our other analytics.
© 2016 Advera Health Analytics 7 RxScore is a proprietary algorithmic model that ranks the potential risk of each drug in our coverage universe on a 1-100 scale. The model is based on the average downstream cost of serious AEs and outcomes per patients exposed to a particular medication.
RxCost is a proprietary algorithm that calculates downstream medical costs associated with AE/drug combinations. We obtained FAERS case reports of all the AEs that occurred during the previous five year period, pertaining to a particular drug.
These AEs were mapped to MedDRA (Medical Dictionary for Regulatory Activities) terms and the MedDRA terms were matched to the corresponding ICD-9 codes (International Statistical Classification of Diseases and Related Health Problems).
An average RxCost per AE is calculated by normalizing the five-year cost of treating a particular AE listed according to
Healthcare Cost and Utilization Project (HCUP).
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