Glucocentricity or adipocentricity: The unceasing quest for El Dorado

I have read with great interest the reflections of Gorgojo Martínez¹ about the best therapeutic approach to patients with type 2 diabetes mellitus (T2DM) and his decision to place his bet on focusing attention on excess weight management to the detriment of treatment focused on blood glucose control. I must admit that this is an attractive idea that will undoubtedly have many supporters, of which I may become one, after an appropriate discussion. There are however some aspects in his approach that I would like to qualify.

First of all, when defining the adipocentric approach, the author states that the main parameters in T2DM should be body mass index (BMI) and waist circumference (WC). It is obvious that for a variable associated with a disease to be considered as a main parameter, i.e. the therapeutic target, it should be altered in all individuals with the disease. While the relationship between and T2DM is true and evident, it is not less true that a substantial number of patients withT2DM have normal weight. As an example, in the UKPDS² study, initial BMI in the study population was 27.5 kg/m² with a standard deviation of 5.2 kg/m², which, assuming a normal distribution of the population, means that approximately 16% of patients had an initial BMI less than 22 kg/m². The author tries to explain this circumstantial oblivion regarding a not negligible number of patients by stating that patients with “T2DM and normal weight probably have other forms of DM such as LADA or monogenic or secondary DM”. However, this statement is far from true. Even assuming that other forms of DM are more common in patients with normal weight, no sufficient data are available in the literature to state that all, or even a majority, of adult patients with DM and normal weight have a disease pathogenetically different from type 2 diabetes.³ Thus, if we use BMI or WC as a main parameter, we run the risk of not including in the therapeutic algorithm of T2DM a substantial number of patients who actually suffer the disease.

Second, we should not forget that the true objective in treatment of T2DM is to improve the quality and life expectancy of patients. It is clear that glucocentric approaches have shown great limitations regarding the achievement of this goal. However, the same is similarly or even more true of the adipocentric approach, as is shown by the lack of data on morbidity and mortality variables from randomized clinical trials and the questionable relations between weight and complications in patients with T2DM.^4,5 In my opinion, it is clear that the most robust current strategy is a multifactorial approach.⁶ In this regard, prioritization of excess weight management over treatment of hypertension and dyslipidemia (“… but we may probably avoid the use of multiple drugs if the patient achieves weight goals”) is worrying.

The author's statement about the beneficial effect of metformin treatment on microvascular complications in the UKPDS study deserves a separate comment. Although this was not the main study endpoint, the truth is that neither in the initial study⁷ nor in the follow-up study⁸ did the group randomized to metformin show any significant differences from the conventional group regarding the microvascular complication rate.

The author's approach contains other debatable aspects which I will only indicate briefly for reasons of space, such as advocating the use of novel drugs as a second line treatment before their significant effects on robust variables and clearly proven long-term safety have been shown, or the uncertainty about the long-term persistence of the benefits of metabolic surgery in the absence of morbid obesity.

To sum up, this is a daring and welcome approach, but one that runs the risks of leaving behind a substantial number of patients with T2DM, of playing down the achievement of blood pressure and lipid goals by focusing too much on weight goals, and of prioritizing a subordinate variable without having adequate evidence of the benefits of such a strategy. For the time being, I myself will not be searching for El Dorado and will continue to make do with a prudent but safer approach.

Funding

G. Giménez-Pérez states that he has received fees for lectures and training actions from the pharmaceutical companies Esteve, Lilly, Novo Nordisk, MSD, Almirall, Ferrer, and Sanofi-Aventis.