Antidiabetic treatment: Though lovers be lost, love shall not

Abstract

The new position statement of the American Diabetes Association and the European Association for the Study of Diabetes on the management of type 2 diabetes mellitus represents a paradigm shift in our understanding of antidiabetic treatment. It emphasises the necessity to individualise management based on patient needs. Glycaemic targets should also be pursued on an individualised basis. New therapeutic combinations are discussed, and the uncertainty surrounding the ideal choice is acknowledged. Above all, it is the mindful and experienced clinician who will implement the best available evidence towards flexible and efficacious treatment. Some areas of uncertainty may ensue, but it is expected that the new position statement will improve patient healthcare and treatment satisfaction. This now remains to be seen in practice.

Key Words: Diabetes mellitus; Guidelines; Insulin; Oral agents; Treatment

INVITED COMMENTARY ON HOT ARTICLES

We read with great interest the recent article by Inzucchi et al[1] providing the new position statement of the American Diabetes Association and the European Association for the Study of Diabetes on the management of type 2 diabetes mellitus (T2DM). This new consensus statement is very important, because it represents a paradigm shift in seven issues and is, thereby, anticipated to induce considerable progress in these areas.

This the first, to the very best of our knowledge, consensus statement emphasising the need to individualise treatment, based on patient preferences and characteristics. The pivotal role of individualisation is characteristically expressed in the title describing this approach as “patient-centered”[1]. For example, in patients less willing to perform multiple daily blood glucose monitoring at home, the clinician may consider a slightly less intensive regimen, which is, at the same time, safer in terms of hypoglycemia. Similarly, patients with virtually no meals during daytime and a large dinner may respond well to meglitinide or an injection of premixed insulin at dinner. Individualised therapeutic decisions should also pay attention to age, weight, comorbidities, and, possibly, gender and racial/ethnic differences[1]. In this way, the need for improved guidelines incorporating patient characteristics[2] is realised at last. Such individualised approach would also ensure improved patient empowerment, in accordance with the chronic care model[3]. Arguably, the closer collaboration between patient and physician may be expected to achieve optimal results in a fashion similar to that shown for type 1 diabetes[4].

Secondly, in close relationship with individualised healthcare, comes the choice of glycaemic targets[1]. Indeed, it has now been realised that caution is needed to avoid too precipitous glycaemic control in subjects with established cardiovascular disease[5]. Likewise, prudence is needed in patients with long diabetes duration, poor life expectancy and/or a heavy burden of comorbidities[1]. In this context, the new position statement provides clear suggestions as to which patients should be more intensively and which less stringently treated. Specifically, stricter glycaemic control is advised, among others, for patients with short diabetes duration, longer life expectancy, as well as absence of unrelated comorbidities and/or vascular complications, whereas less stringent control is advocated for those with the opposite profile[1]. More importantly, the clinician is encouraged to assess every patient on an individualised basis and, dependent on his characteristics as outlined above, place him on a scale between the strictest and least stringent therapeutic targets[1]. At the end of the day, this new approach emerges as the most clinically wise, because it pays tribute to patient uniqueness, and guides patient and physician alike towards treatment flexibility.

Impressively, the new consensus acknowledges that very little is known in terms of which oral agent is the best add-on treatment to metformin[1]. Likewise, in the event of metformin intolerance, it is unknown which agent had best be used as monotherapy[1]. This recognition has duly replaced the older distinction between better and less well studied therapeutic alternatives[6] and provides freedom of choice to the clinician. Certainly, in everyday clinical practice it is not always easy to predict which antidiabetic drug will be the most efficacious in the individual patient, and randomised trials are no safe guide in this endeavour, because they provide general truths that do not necessarily apply to the patient in question[7].

Moreover, the new statement suggests that triple oral combination therapy may be attempted in some patients[1]. This is important because it corresponds to therapeutic choices commonly used in clinical routine, especially in patients reluctant to embark on insulin. The treatment alternative based on three oral agents had hitherto not been approved by existing guidelines, and so its suggestion can be viewed with relief.

A fifth change is that pre-mixed insulin is mentioned as an acceptable, more convenient but less flexible, treatment modality[1]. The premixed insulin regimen may suit patients who eat regularly and cannot easily cope with a more complex regimen[1]. Again, such treatment scheme had not been proposed at all by the prior version[6], and this represents important progress in our understanding of the complexity and suppleness inherent in insulin therapy. As stated in the consensus, any insulin is efficacious in reducing plasma glucose and HbA_1c and may, to a variable degree depending on insulin type, be related with some weight gain and/or hypoglycemia[1]. Initiation of basal insulin analogues with subsequent addition of rapid-acting insulin analogues at mealtimes is by far the safest and the most precise and flexible regimen[1] to be widely used, but there is some evidence that one may, in selected patients, start and intensify treatment with premixed insulins as well[8], which should not be entirely ignored.

In addition, the new combination therapy including injectable GLP-1 agonists and basal insulin is now described as a meaningful option[1]. This regime has the advantages of adequate basal coverage by insulin with simultaneous post-prandial effect by the GLP-1 agonist, as well as the potential for some weight loss[9], and it merits further clinical exploration.

Finally, this document clearly emphasises the increasing complexity of antidiabetic treatment options with the ever-rising role of thoughtful clinicians in their implementation[1]. The authors acknowledge that the new position statement is less prescriptive and algorithmic than the previous one. Current evidence must be thoroughly evaluated, and its limitations should not be overlooked. Clinicians are given freedom to judge on their own what is best in every single patient, and their expertise is called upon as an aid in this enterprise[1]. This is a clinical message of vast importance. Indeed, some medications may be withdrawn and others come to the market, but expert clinical judgement will triumphantly survive such changes. What should by all means prevail is the inspiration to combine the best available evidence with clinical judgement suited to every situation, so that patients benefit, or, as the poet Dylan Thomas wrote, “Though lovers be lost, love shall not”[10].

Given these inspiring changes, it now remains to see how they will translate into practice. Will the diabetes community respond to this challenge and seize the opportunity to improve treatment It is likely that some uncertainty may arise, granted that no absolute therapeutic suggestion is offered. This uncertainty needs to be overcome by carefully examining the potential of therapeutic alternatives in everyday clinical situations. Every experienced clinician should be encouraged to pursue the new approach in order to find out its strengths and limitations. Of further concern, the new position statement may not be very helpful in primary healthcare. At this healthcare level, a more concrete guide to antidiabetic treatment might be appropriate. Nonetheless, primary care physicians should also comprehend the fundamental principles of the new approach and realise that treatment should, ideally, be tailored to patients’ attributes and needs. If a more explanatory algorithm based on the new principles is needed, there will be time to write it.

In conclusion, the new position statement of the American Diabetes Association and the European Association for the Study of Diabetes on the management of T2DM reflects important progress in our understanding. Therefore, the authors expect that it will encourage more flexible and efficacious patient healthcare, thereby contributing to improved treatment satisfaction. The beneficial effect of these promising improvements remains to be seen in the near future.