Insulin degludec: An optimal choice for diabetes management
Effective long-acting basal insulin analogues offer convenience as initial insulin regimen for diabetes mellitus (DM). Insulin degludec (IDeg) (Tresiba®, Novo Nordisk), an ultra-long-acting basal insulin analogue for the treatment of type 1 and type 2 DM (T1DM and T2DM), has the advantages of lower 24-hour variability in glucose-lowering effect with a lower risk of hypoglycaemia. Dr Bernard Wong, Specialist in Cardiology in private practice in Hong Kong, discusses study findings supporting the use of IDeg in DM management.
IDeg: Ultra-long-acting basal insulin
In theory, basal insulin analogues with a extended duration of action would have reduced peak-to-trough variations in insulin concentration at steady state. (Figure 1) [Clin Pharmacokinet 2014;53:787-800]
IDeg, a human insulin analogue made up of multi-hexameric complexes, is designed to reduce such peak-to-trough variations. [Pharm Res 2012;29:2104-14] Compared with insulin glargine (IGar) U100, once-daily IDeg has a longer half-life (25.4 hours vs 12.1 hours). With a duration of action extending beyond 42 hours, IDeg offers more stable and evenly distributed exposure and glucose-lowering effects across one dosing interval. [Expert Opin Drug Metab Toxicol 2015;11:1193-201; Clin Pharmacokinet 2014;53:787-800]
“IDeg provides smoother and better [glucose] control with reduced risk of hypoglycaemia. Also, with less restriction on the timing of injection, patients have improved compliance with IDeg treatment,” explained Wong.
“The risk of hypoglycaemia must be minimized, particularly in the elderly who have a blunted response to it, because severe hypoglycaemia is associated with an increased risk of adverse CV outcomes in DM patients,” he emphasized.
DEVOTE: Proven CV safety, reduced hypoglycaemia with IDeg
The multicentre, treat-to-target, randomized, double-blind, active comparator-controlled cardiovascular (CV) outcome DEVOTE trial showed that among patients with T2DM at high risk of CV events, IDeg was noninferior to IGar U100 with respect to the incidence of major CV events (death from CV causes, nonfatal MI, or nonfatal stroke) (absolute difference, 0.8 percent; hazard ratio, 0.91; 95 percent confidence interval [CI], 0.78 to 1.06; p<0.001 for noninferiority). [N Engl J Med 2017;377:723-732]
IDeg demonstrated a significantly lower rate of severe hypoglycaemia (defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon or to take other corrective actions) (absolute difference, 1.7 percent; rate ratio, 0.60; 95 percent CI, 0.48 to 0.76; p<0.001 for superiority). (Figure 2) Similarly, the rate of nocturnal severe hypoglycaemia (defined as an episode with an investigator-reported onset between 12:01 AM and 5:59 AM) was also significantly lower with IDeg (rate ratio, 0.47; 95 percent CI, 0.31 to 0.73; p<0.001). (Figure 3) [N Engl J Med 2017;377:723-732]
Severe hypoglycaemia associated with adverse CV outcomes
The DEVOTE investigators subsequently evaluated the associations of severe hypoglycaemia with CV outcomes and mortality in patients randomized to receive IDeg or IGar U100. Results showed a significantly higher risk of CV death at any time following a severe hypoglycaemia event (hazard ratio [HR], 2.14; 95 percent CI, 1.37 to 3.35; p<0.001). Pooled analysis also revealed a 2.5-fold increased risk of all-cause mortality in those who experienced severe hypoglycaemia vs those who did not (HR, 2.51; 95 percent CI, 1.79 to 3.50; p<0.001), with the highest risk occurring in the short term. [Diabetologia 2018;61:58-65]
The investigators also analyzed the associations of day-to-day fasting glycaemic variability with severe hypoglycaemia and CV outcomes in patients in the two treatment groups. Pooled analysis showed that higher day-to-day fasting glycaemic variability, indicated by self-measured blood glucose (SMBG), was significantly associated with increased risks of severe hypoglycaemia (HR, 4.15; p<0.0001) and all-cause mortality (HR, 1.53; p=0.0011) even after adjustments for the most recent HbA1C measurement throughout the trial or baseline characteristics. Patients with high variability had the highest incidence of severe hypoglycaemia (5.0 vs 2.38 vs 1.69 per 100 patient-years of observation), major adverse CV events (5.48 vs 4.49 vs 3.84 per 100 patient-years) and all-cause mortality (3.40 vs 2.61 vs 2.30 per 100 patient-years) compared with those in the medium and low variability groups. (Figure 4) [Diabetologia 2018;61:48-57]
“Patients with DM with high glycaemic variability are more likely to experience hypoglycaemia, particularly severe hypoglycaemia. These data therefore support the use of basal insulin with a low day-to-day variability in DM management,” noted Wong.
Initiating and switching to IDeg in clinical practice
“Lack of knowledge on proper DM management remains a key challenge in Hong Kong. Patients need to understand that the condition should be meticulously treated with effective medications. Patient education and close doctor-patient-nurse relationships are very important to facilitate effective treatment and address patients’ fear of needles and injection-associated pain,” stressed Wong.
The IDeg device delivers up to 80 units of insulin per injection. Its nonextending dose button and low injection force allow injections to be manoeuvered easily regardless of the dose, while the end-of-dose click ensures accurate dosing of insulin. [Tresiba prescribing information]
“In my clinic, patients and their relatives are informed of the rationale and benefits when initiating IDeg. Experienced nurses provide education on proper injection techniques, showing patients the needles and reassuring them that the injection is not that painful. Patients’ response to IDeg are closely monitored for the first 1–2 weeks by SMBG 2–3 times per day, with feedback and suggestions on carbohydrate intake given based on food tracking records. This process enables patients to gradually become more familiar with the injection and food planning.”
“Since IDeg has a longer half-life with more stable glucose-lowering effect, I tend to switch patients from another basal insulin to IDeg without hesitation. Switching is also done to reduce the risk of hypoglycaemia. Since IDeg is more potent, I tend to start patients on a lower dose, with a dose reduction of 5 units or 10 percent if patients are switching from IGar to IDeg.”
Based on the results of the randomized SWITCH 2 clinical trial, patients with T2DM who switched from IGar U100 to IDeg had a significant reduction in rates of both overall symptomatic hypoglycaemia (219.9 vs 271.1 episodes/100 patient-years of exposure [PYE]; rate difference, −19.4; estimated rate ratio [ERR], 0.77; p<0.001) and nocturnal symptomatic hypoglycaemia (72.0 vs 88.4 episodes/100 PYE; rate difference, −4.4; ERR, 0.75; p<0.001) during the full treatment period. [JAMA 2017;318:45-56]
A 70-year-old man with T2DM and a history of angioplasty was previously treated with oral glucose-lowering drugs and IGar. He was switched from IGar to IDeg due to suboptimal glycaemic control (HbA1c >7 percent). His glycaemic control improved over time (HbA1c <7 percent) and he has not experienced any hypoglycaemic events since.
A 70-year-old lady with T2DM and a history of stroke was put on IDeg 12 units on top of her two current oral glucose-lowering drugs due to suboptimal glycaemic control. IDeg was subsequently uptitrated to 33 units according to her SMBG. This resulted in good glycaemic control without hypoglycaemia, and the patient has been taken off one of the oral drugs.