Makindo Medical Notes

At a glance

• Class: Ultra–long-acting (basal) insulin analogue
• Brand name: Tresiba®
• Drug name: Insulin degludec
• Route: Subcutaneous injection (pre-filled FlexTouch pens; 100 units/mL & 200 units/mL)
• Indications (UK): Diabetes mellitus in adults, adolescents and children ≥1 year (type 1 and type 2), including basal component of MDI or basal-only regimens
• USP: Very long half-life (~25 h) and duration of action >42 hours ⟶ extremely flat, stable basal profile with flexible timing.

What is insulin degludec? 🧬

Insulin degludec is a basal insulin analogue engineered to provide a very prolonged and stable background insulin level. Structurally, it is a modified human insulin molecule in which the B29 lysine is acylated with a fatty acid side chain via a glutamic acid spacer and the B30 threonine is omitted. These apparently small tweaks dramatically change how molecules interact in the subcutaneous tissue and circulation.

After injection, degludec forms long multi-hexamer chains in the subcutaneous depot. Zinc ions dissociate slowly, breaking the chains down so that insulin monomers are released at a near-constant rate. There is also reversible albumin binding in the bloodstream. The combination of multi-hexamer depot + albumin buffering gives degludec its ultra-long, “peak-less” profile.

How does Tresiba work? ⏱

• Subcutaneous depot: On injection, degludec forms soluble multi-hexamers. As zinc diffuses away, individual insulin monomers are slowly released.
• Ultra-long duration: The slow, continuous release gives a duration of action >42 hours at steady state, far longer than glargine or detemir.
• Half-life: Around 25 hours, compared with about 12 hours for glargine, which means:
  • Very low day-to-day variability in effect.
  • A true “flat and stable” basal profile.
• Glucose effects: As with other basal insulins, it:
  • Suppresses hepatic gluconeogenesis and glycogenolysis.
  • Promotes peripheral glucose uptake.
  • Inhibits lipolysis and ketogenesis in a dose-dependent way.

Pathophysiology link: In type 1 diabetes, there is absolute insulin deficiency, so you must replace both basal and prandial insulin. In type 2 diabetes, basal hyperglycaemia often reflects insufficient overnight/fasting insulin to counter hepatic glucose output – ultra-long basal analogues like degludec are particularly good at “flattening” this fasting component.

When do we use Tresiba? (UK context) 🇬🇧

Indications

• Type 1 diabetes – as the basal component of a basal–bolus regimen in adults and children ≥1 year.
• Type 2 diabetes – as basal insulin, either:
  • In addition to oral agents ± GLP-1 RA, or
  • As part of a full basal–bolus regimen in more advanced disease.
• Specialist situations:
  • Patients with very erratic control or problematic nocturnal hypoglycaemia on other basal insulins.
  • Those needing flexibility in injection timing (shift workers, confused dosing schedules).

Positioning in UK practice

• Most UK formularies still start basal therapy with NPH or a less expensive glargine biosimilar in type 2 diabetes.
• Degludec is increasingly used when:
  • There is recurrent hypoglycaemia (especially nocturnal) on other basals.
  • Marked day-to-day variability in glucose despite good adherence.
  • Patients are being switched from Levemir or glargine and still struggle with hypos or variability.
• In type 1 diabetes, it’s often chosen by specialist teams for people with:
  • Brittle control.
  • Irregular lifestyles or meal patterns.
  • Significant dawn phenomenon not controlled with other basals.

Dosing and regimens 💉

General principles

• Administered once daily at any time, preferably the same time each day – but there is more flexibility than with other insulins (you can vary timing by up to ~8 hours in many protocols without major issues).
• Available as:
  • 100 units/mL FlexTouch pen.
  • 200 units/mL FlexTouch pen for high-dose users, delivering the same “units” in half the volume.
• Injection sites: abdomen, thigh, upper arm. Rotate within and between sites to avoid lipohypertrophy.

Starting doses (teaching ballpark)

• Type 2 diabetes (basal add-on):
  • Often start at 10 units once daily or 0.1–0.2 units/kg.
  • Increase by 2 units every 3–4 days until fasting glucose in target, assuming no hypoglycaemia.
• Type 1 diabetes (basal–bolus):
  • Total daily insulin usually ~0.5–0.7 units/kg/day, of which ~40–50% basal and 50–60% bolus.
  • Degludec provides the basal portion once daily; adjust based on fasting and pre-meal readings.

Exam angle: You don’t need to know exact numbers but should know that degludec is used once daily, titrated based on fasting glucose, and “units” are equivalent in potency to human insulin units.

Pharmacology and PK highlights 📈

• Onset: Within a few hours, but clinical effect is about the very long, steady state rather than rapid action.
• Duration: >42 hours at therapeutic doses – meaning there is still basal effect if a dose is delayed.
• Steady state: Reached in ~2–3 days; titration should not be too rapid because you need time to see full effect.
• Day-to-day variability: Lower than with glargine and detemir ⟶ smoother fasting glucose and less “glucose noise”.
• Albumin binding: Contributes to the buffering of free insulin levels; helps with the flat pharmacodynamic profile.

Pros and cons ⚖️

Advantages

• Ultra-long, flat profile – excellent for steady basal control.
• Reduced hypoglycaemia – large trials (e.g. BEGIN, SWITCH) show lower rates of nocturnal and overall hypos versus glargine U100 at similar HbA1c, especially in high-risk patients.
• Flexible dosing time – helpful for shift workers, chaotic lifestyles, or adherence issues.
• Useful in “brittle” diabetes and in people with marked dawn phenomenon or variable day-to-day control.

Disadvantages

• Cost – more expensive than NPH and glargine biosimilars; often reserved for patients who clearly benefit.
• Prolonged action means that:
  • Hypoglycaemia can be prolonged if overdosed.
  • Dose adjustments take longer to fully manifest (you can’t “fix” a problem overnight).
• Not usually first-line basal in straightforward type 2 diabetes according to many local UK formularies.

Adverse effects and safety 🚨

• Hypoglycaemia – the key risk for all insulins.
  • Evidence suggests fewer nocturnal and overall hypos versus glargine U100 at equivalent glycaemic control, but hypos still occur and may be prolonged.
  • Patients must know “4 is the floor” (BG <4 mmol/L) and how to treat hypos.
• Weight gain – similar to other basal analogues; any insulin that improves control may increase weight by reducing glucosuria.
• Injection site issues: Pain, erythema, lipohypertrophy. Check sites regularly and teach rotation.
• Allergic reactions – rare; can present as local or systemic reactions.
• Driving and DVLA: Standard insulin rules apply – regular testing, awareness of hypos, and following DVLA guidance for group 1 and 2 licences.

Special situations

Elderly and frail patients

• Reduced renal clearance ⟶ lower insulin requirements, higher hypo risk.
• Degludec’s stable profile can be helpful in avoiding swings, but you must:
  • Use conservative doses.
  • Accept higher target glucose ranges (e.g. fasting 7–10 mmol/L).
  • Prioritise safety over tight HbA1c targets.

Renal and hepatic impairment

• No specific dose adjustment is mandated in the SmPC, but in practice:
  • Insulin requirements fall as renal function worsens.
  • Very careful titration and frequent CBG monitoring are essential.

Peri-operative care

• Basal insulin is usually continued but at a reduced dose (e.g. 75–80% of usual) depending on local policy.
• Because of the long half-life, degludec provides basal cover even if the patient is fasted; variable rate insulin infusions may still be required for major surgery.
• Always follow local peri-operative diabetes protocols.

Switching to Tresiba 🔄

With Levemir being withdrawn and some patients struggling on other basals, you will increasingly see switching to degludec. In practice, dose conversion is guided by local protocols and diabetes teams, but key concepts for exams and ward work are:

• From another once-daily basal analogue (e.g. glargine U100):
  • Often start degludec at the same unit dose, sometimes with a small reduction (e.g. 80–100%) in high-risk patients.
  • Titrate every 3–4 days based on fasting glucose and hypos.
• From twice-daily basal (e.g. Levemir):
  • Sum the total daily basal dose; start degludec at around this dose, or slightly reduced in frailer patients.
  • Switch to once-daily injections.
• High-risk patients (recurrent hypos, older adults, CKD):
  • Err on the side of a slightly lower starting dose and careful titration.
  • Engage the diabetes specialist team early.

Key learning point: Because of the ultra-long half-life, avoid large rapid dose changes; give each titration step several days to stabilise before the next adjustment.

Quick comparison: Degludec vs other basal insulins

Insulin	Type	Duration	Dosing	Notes
Degludec (Tresiba)	Ultra-long analogue	>42 h	Once daily	Very flat profile; flexible timing; fewer hypos vs glargine in trials.
Glargine U100	Long-acting analogue	~24 h	Once daily	Common first-line basal analogue; cheaper biosimilars widely used.
Glargine U300	Ultra-long analogue	>24–30 h	Once daily	Flatter than U100; often comparable to degludec in practice.
Detemir (Levemir)	Long-acting analogue	12–24 h	Once or twice daily	Being discontinued; many patients moving to degludec or glargine.
NPH insulin	Intermediate-acting	12–18 h	Once or twice daily	Cheaper but more variable, more nocturnal hypos.

Key take-home points for students and juniors 🎓

• Insulin degludec (Tresiba) is an ultra-long-acting basal analogue with duration >42 hours and a very flat profile.
• Used once daily in type 1 and type 2 diabetes as the basal component of therapy, particularly useful in patients with recurrent hypoglycaemia or marked glucose variability.
• Mechanism is based on multi-hexamer formation in the subcutaneous depot plus albumin binding, leading to very slow and stable insulin release.
• Trials show similar HbA1c to glargine with fewer nocturnal and overall hypos, but at a higher drug cost, so UK formularies usually reserve it for selected patients.
• When you see Tresiba on a drug chart, think “once-daily ultra-long basal”: check fasting glucose trends, hypo history, injection sites, and whether doses are being titrated slowly enough to reflect its long half-life.