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Basal insulin intensification in type 2 diabetes: a key role for GLP-1 receptor agonists

Diabetes Metab. 2015 Dec;41(6 Suppl 1):6S1-2.

Intensification of insulin in type 2 diabetes is an important issue in clinical practice but remains in 2015 a difficult question for which we need new and evidence-based therapeutic options. Adding a GLP-1 receptor agonist with a predominant prandial action to basal insulin is one of these therapeutic options. It is discussed in this special issue of Diabetes & Metabolism.

The initiation of insulin treatment in type 2 diabetes is based on the “Treat to target studies” published in the 2000 years. All current guidelines recommend to start insulin with the so-called “basal insulin regimen”: a single daily injection of a long-acting and “flat” basal insulin (glargine is the gold standard) aiming at normalizing blood glucose during the night. The main objective is to reduce fasting blood glucose to near-normal. As a result, related to a global decrease of the 24 hours blood glucose profile, there is a reduction in post meal blood glucose levels as well, but in absolute value whereas blood glucose excursions during meals (post-meal versus pre-meal values) are not directly adressed by basal insulin.

The question of which other treatments have to be maintained in addition to basal insulin when insulin is initiated remains open to debate. Metformin is usually maintained since most of the clinical studies have showed a benefit in terms of both body weight and HbA1c. It is generally recommended to progressively stop sulfonylureas which may limit the titration of insulin by fear of hypoglycaemia. I personally think that it is reasonable to stop GLP-1 receptor agonists (usually long acting) when they were used before the initiation of insulin since why continuing an injectable agent which, by definition in patients switched to insulin, failed to keep blood glucose levels controlled.

A good clinical practice is to simplify the treatment regimen at this step of insulin initiation and to get rid of all the many anti-diabetic agents which have often been accumulated to each others over time before the need for insulin. The simple combination of basal insulin and metformin has been shown in all the “Treat-to-Target” studies to be able to get HbA1c to an average of 7% which means that HbA1c will be below 7.0 to 7.5% in about half of the patients, if an appropriate up-titration of insulin is performed.

The treatment regimen will become more complex in a 2nd step, only in those patients who do not reach the HbA1c target with the simple well titrated basal insulin regimen. This is what we call intensification.

Intensification is required if HbA1c level is above the target value despite up-titration of basal insulin. That means the persistence of an elevated HbA1c level despite a fasting blood gucose normalized by a well-titrated basal insulin to <1.30 g/l. I suggest that intensification may also be needed in the insulin resistant patients who keep a high fasting blood glucose for relatively high doses of basal insulin (an arbitrary figure could be more than 60 to 80 units per day).

What could we propose to these many patients? As everybody knows, it is a difficult clinical situation. The main options are the following:

  • a basal-bolus insulin regimen is the usually recommended option and represents the theoretical gold standard. Since basal insulin does not target post-prandial blood excursions, it is generally considered that this is the main reason why HbA1c is not at target despite a correct fasting blood glucose value. Adding a short-acting insulin before each meal seems logical in this situation to control glucose prandial excursions. In insulin resistant patients, addition of such boluses of a short-acting insulin allows to increase the total daily dose of insulin, in order to overcome insulin resistance. In clinical practice, this basal-bolus option is unfortunately far from being always successful and is associated with a high risk of hypoglycaemia. It is a complex therapeutic regimen for the patient, which requires multiple adjustments of insulin doses in relation to the diet and physical activity, why finally HbA1c often remains high if these doses adustments are not correct;
  • the “basal-plus” option consists in the addition of one injection of a short-acting insulin before the main meal. This is a simplified version of the basal-bolus, which gives good results in some cases. This option might be viewed as an intermediate step between basal insulin and the classical basal-bolus regimen;
  • addition of anti-diabetic oral agents could also be relevant, rather than switching to basal-bolus. Pioglitazone has been shown to be the most efficient option in very insulin resistant patients. However, Pioglitazone has well-known potential adverse-effects, mainly fluid retention and must be used cautiously in addition to insulin. Addition of a DPP-4 inhibitor will reduce post-prandial blood glucose excursions and represents therefore an interesting option with a mean HbAlc reduction of 0.7% in clinical studies, without increasing the risk of hypogycaemia. Adding a SGLT2 inhibitor is a potentially attractive option with a reduction of HbA1c of about 0.7%, without a concomitant increased risk of hypoglycaemia and with a body weight loss. The amazing positive results of the EMPA-REG outcome study (48% of the patients were insulin-treated) showing a 32% reduction of all-causes mortality on empagliflozin will probably make this option still more attractive. However, the question of euglycaemic keto-acidosis occurring mainly in patients on insulin needs to be clarified;
  • addition of a GLP-1 receptor agonist to basal insulin is another option and this the topic of this special issue of the Journal.

The rationale of this combination is easy to understand: GLP receptor agonists are powerful anti-diabetic agents, which do not induce hypoglycaemia when used alone and which favour weight loss, an appreciated added value when combined to insulin therapy. The recently updated ADA/EASD position statement endorsed this option of adding a GLP-1 receptor agonist to basal insulin as one of the prefered ones which could represent for many patients a intermediary step between a basal insulin regimen and a basal-bolus regimen.

The remaining question, when it is decided to intensify the insulin regimen by adding a GLP1-receptor agonist on the top of basal insulin, is which GLP-1 receptor agonist to choose?

Is it better to choose a long acting “basal” GLP-1 receptor agonist such as liraglutide or once weekly GLP1-receptor agonists which will surimpose their basal action to the basal action of basal insulin?

Or is it better to choose a short-acting “prandial” GLP-1 receptor agonist which will have a complementary effect to that of basal insulin, to reduce post-prandial blood glucose excursions not adressed by basal insulin? The mechanistic rationale of such a combination is strong, it is now well evidence-based in clinical studies and the cardio-vascular safety of at least one of the short-acting GLP1-receptor agonist has been demonstrated. This issue of the journal explores in detail this later option.

There are two GLP-1 receptor agonists with a predominant prandial action, both of reptilian origin: lixisenatide, given once a day, and exenatide, given twice a day. They have a relatively short duration of action with an elective potent inhibitory effect on gastric emptying which explains a predominant prandial effect with a strong reduction of post-prandial blood glucose excursion, at the difference of what is shown for the long acting GLP-1 receptor agonists which are potent agents but which do not impact, or slightly, gastic emptying,.

The rationale of adding lixisenatide or exenatide to basal insulin appears strong in those patients with a fasting plasma glucose near normalized by a well titrated basal insulin but in whom HbA1c remains above target due to high post-prandial blood glucose levels. The rationale is more or less similar to the rationale of the basal-bolus insulin therapy but with many advantages in clinical practice: no need for dose adjustment of the GLP-1 receptor agonist, smaller risk of hypoglycaemia, potential benefits on body weight.

In the 4B trial, the combination of exenatide twice a day to basal insuli had a similar effect on glycaemic control as a traditional basal bolus with three short-acting insulin injections, but with less weight gain and less hypoglycaemias. This option appears therefore more attractive for type 2 diabetic patients than the classical basal bolus.

Addition of lixisenatide once a day to basal insulin in the Getgoal clinical program, mainly the Getgal duo 2 trial, had shown an almost similar HbA1c reduction efficacy as compared to a basal bolus regimen and a similar efficacy as compared to a basal plus regimen, with a superiority for body weight and hypoglycaemia. Such a combination thus seems to be a more attractive option than at least the basal plus option. Adding lixisenatide once a day to basal insulin can be viewed as the “modern basal plus”.

Furthermore, lixisenatide is currently the only GLP-1 receptor agonist which has proven its cardiovascular and global safety in a randomized clinical outcome study (ELIXA study) in type 2 diabetic patients at very high cardio-vascular risk.

The different papers in this supplement propose to review the physiopathological knowledge and the level of clinical evidence supporting the use of a GLP-1 receptor agonist with a predominant prandial action in patients in whom basal insulin alone fails to get HbA1c to target. This scientific contribution highlights the clinical relevance of renewing insulin therapy options in type 2 diabetes.

Footnotes

University of Nantes

* Correspondence

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