His message was that the intensification of therapy in diabetes is crucial. Type 2 diabetes (T2DM) is characterised by early and progressive insulin deficiency. At the time of diagnosis, it is estimated that there is already a 50% loss of beta-cell functioning and over the next several years, it further declines at a rate of about 5%-10% each year. 

Numerous studies, including the United Kingdom Prospective Diabetes Study (UKPDS), showed that oral antidiabetic drug (AOD) therapy has a limited effect on HbA1c reduction and the majority of patients will require insulin therapy. According to Dr Randeree, the addition of insulin therapy should be the rule, rather than the exception.  

Other benefits of early insulin therapy include: 

• The UKPDS study showed that a 1% reduction in HbA1c reduces complications associated with diabetes
• Insulin therapy can reverse glucotoxicity, not only at the pancreatic level, which improves beta cell functions, but also at the periphery, which improves insulin sensitivity
• When insulin therapy is used, beta cell functioning improves in patients failing on maximum tolerated oral antidiabetic
  drugs (OADs) 
• In patient with renal and hepatic impairment, some OADs are contraindicated, but insulin, used judiciously, is a safe option in
  these patients.

Poor glycaemic control increases the risk of micro- and macrovascular complications. To prevent these complications, early initiation of insulin therapy is physiologically rational, because it prevents declining beta-cell functioning, explained Dr Randeree.  

In the long-term, improvement in glycaemic control may provide numerous benefits in the patients with T2DM,  he emphasised.   

INITIATING INSULIN THERAPY  

Basal insulin – once or twice daily – in combination with OADs, is often recommended as first-line insulin therapy because of its simplicity.¹ 

However, several randomised controlled trials have demonstrated that initiating insulin therapy with a modern premixed insulin analogue, such as biphasic insulin aspart 30 can result in better glycaemic control than when initiating with a basal insulin analogue.¹ 

In the Safety and Effectiveness of NovoMix® 30 for the Treatment of Diabetes (IMPROVE™), Valenti et al assessed the safety and efficacy of treatment with premix biphasic insulin aspart 30 in patients with T2DM.¹  

Patients who initiated insulin therapy with, or switched existing insulin therapy to, biphasic insulin aspart 30 in routine care were eligible for this 26-week, non-interventional observational study.^¹  

A total of 52 419 patients were enrolled from three pre-study treatment groups, with the following criteria:¹  

1. No pharmaceutical therapy (n=8 966, diabetes duration two years, baseline HbA1c 9.9%)
2. OADs only (n=33 797, diabetes duration 7.4 years, baseline HbA1c 9.2%)
3. Insulin plus OADs (n=9 568, diabetes duration 10.4 years, baseline HbA1c 9.3%). 

At final visit, HbA1c, fasting and postprandial blood glucose were significantly reduced from baseline in all subgroups (no pharmaceutical therapy: -3.1%, -5.9mmol/l and -9.0mmol/l, respectively. OADs-only: -2.1%, -4.1mmol/l and -6.1mmol/l and insulin plus OADs -2.0%, -3.3mmol/l and -5.1mmol/l.¹  

Major hypoglycaemia rates decreased in all subgroups. Minor hypoglycaemia increased in the insulin-naive groups. There was no mean weight gain across subgroups.¹  

Across all countries, glycaemic parameters and major hypoglycaemia were reduced. Weight increases were seen in some countries. Treatment satisfaction increased in all subgroups and countries following biphasic insulin aspart 30 therapy.¹ 

The authors concluded that initiating insulin with, or switching insulin therapy to, biphasic insulin aspart 30 in routine care resulted in improved glycaemic control, reduced major hypoglycaemia and greater treatment satisfaction.¹ 

The starting dose for insulin-naïve patients, is 10-12 units just before dinner. The short- and long-acting components of biphasic insulin aspart 30 allows for post-prandial, as well as the longer-term control overnight. 

If the single dose at dinner is not adequate (eg that the amount of insulin used is more than 30 units per day or there is loss of daytime control and glycaemic targets have not been met, or a hypoglycaemia event) the dose can be split between breakfast and dinner.    

It is recommended that the dose be split 50:50, taken before meals, and adjusted using fasting blood glucose level as a guide. It is recommended that the dose is uptitrated by two units every two days (the rule of 2) to gradually achieve the glycaemic target.  

“In patients who are not controlled on pre-mix insulin, insulin degludec/insulin aspart, the first combination of a basal insulin with an ultra-long duration of action, and a rapid-acting insulin in a single injection, may be an effective intensification strategy,” said Dr Raderee.  

WHAT THE TRIALS SAY 

Fulcher et al compared insulin degludec/aspart and biphasic insulin aspart 30 in adults with T2DM inadequately controlled with once- or twice-daily pre- or self-mixed insulin with or without OADs.² 

This was a 26-week, randomised, open-label, multinational, treat-to-target trial. Participants (mean age 58.7 years, duration of diabetes 13 years, BMI 29.3 kg/m², and HbA1c 8.4% were exposed (1:1) to twice-daily injections of insulin degludec/aspart (n=224) or biphasic insulin aspart 30 (n=222), administered with breakfast and the main evening meal and dose titrated to a self-measured premeal plasma glucose target of 4.0-5.0mmol/l.² 

After 26 weeks, mean HbA1c was 7.1% for both groups, with insulin degludec/aspart achieving the prespecified noninferiority margin for mean change in HbA1c (estimated treatment difference -0.03% points.²  

Treatment with insulin degludec/aspart was superior in lowering fasting plasma glucose (estimated treatment difference -1.14mmol/L and had a significantly lower final mean daily insulin dose (estimated rate ratio 0.89). Fewer confirmed, nocturnal, and severe hypoglycaemia episodes were reported for insulin degludec/aspart compared with biphasic insulin aspart 30.² 

The authors concluded that insulin degludec/aspart twice daily effectively improves HbA1c and fasting PG levels with fewer hypoglycaemia episodes vs biphasic insulin aspart 30 in patients with uncontrolled T2DM previously treated with once- or twice-daily pre- or self-mixed insulin.² It is recommended that insulin degludec/aspart dosage is split evenly at the two largest carbohydrate meals of the day. The patient’s self-monitored blood glucose values should be taken three days before titrating. 

REFERENCES:

1. Valensi P, Benroubi M, Borzi V, et al. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix® 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE™ observational study. International Journal of Clinical Practice, 2009.  

2. Fulcher GR, Christiansen JS, Bantwal G, et al. Comparison of insulin degludec/insulin aspart and biphasic insulin aspart 30 in uncontrolled, insulin-treated type 2 diabetes: a phase 3a, randomised, treat-to-target trial. Diabetes Care, 2014.