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Choice of Glucose-lowering Therapy— A Metabolic Fulcrum-based Approach

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Published Online: Oct 29th 2015 US Endocrinology, 2015;11(2):79–80 DOI:
Authors: Sanjay Kalra, Yashdeep Gupta
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Choosing the appropriate glucose-lowering therapy for the optimal management of type 2 diabetes is always challenging. Existing guidelines either do not offer any recommendations as to which particular drug to use as second- or third-line therapy, or make the issue too confusing for a primary care physician to follow. We suggest a simple, metabolic fulcrum-based approach, which classifies persons with type 2 diabetes as being eubolic, as being predominantly catabolic, or as having “maladaptive anabolism.” This metabolic triage, performed using phenotypic features, with or without supporting investigations, allows the rational choice of therapy, which helps achieve glycemic targets in a more efficient manner.


AGIs, DPP4i, GLP1RA, metabolic phenotype, metabolic triage, metformin, phenotypic approach, SGLT2 inhibitors, sulfonylureas


With multiple classes of glucose-lowering drugs now available, the opportunity to achieve effective diabetes control has never been brighter. The American Diabetes Association (ADA) and European Association for Study of Diabetes (EASD) list seven classes of drugs in their recommendation.1 Metformin, pioglitazone, sulfonylureas, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 receptors agonists (GLP1RA), sodium glucose cotransporter-2 inhibitor (SGLT2i), and basal insulin are included in their treatment plan. The International Diabetes Federation (IDF) also includes alpha-glucosidase inhibitors (AGIs) and premixed insulin in its therapeutic algorithm,2 while bromocriptine and colesevelam find a place in the management strategy of American Association of Clinical Endocrinologists (AACE).3

Challenge of Choice
At the same time, however, this opportunity creates a challenge for physicians, who shoulder the responsibility of making rational, evidencebased prescription, which is safe, well-tolerated, and effective. Current treatment guidelines offer a choice of second- and third-line therapies, leaving the physician to take a “patient-centered” decision. No clear-cut guidance is available to help inform this decision, and the physician often relies upon a strategy of trial and error. In many resource-limited settings, reference investigations are not available, and the physician bases his decision upon experience, rather than evidence.

We propose a simple, metabolic fulcrum-based approach to the choice of glucose-lowering therapy, which can be practiced not only by primary care physicians but also by specialists. This metabolism-based analysis allows delineation of people with diabetes into various groups, each suited to a particular therapeutic approach.

Phenotypic Approach
Phenotype, defined as the sum of external attributes, includes a number of variables, which include anthropometric variables, such as age, gender, and weight. Weight is an important aspect of health, which influences the choice of glucose-lowering therapy. Specific life stages, such as preconception, pregnancy, and lactation, are also included in phenotype variables. Other biologic variables include cardiovascular health, hepatic function, renal function, and bone health (see Table 1).

Based on available evidence, a phenotypic framework can be crafted to allow the rational choice of glucose-lowering therapy. The multiple variables listed in modern, comprehensive guidelines, however, make it challenging for the primary care physician to understand and implement the recommendations in practice.

Metabolic Fulcrum
We propose simpler, metabolic fulcrum-based systematics, based upon a basic classification of metabolic status, to help inform the choice of glucose-lowering therapy (see Figure 1). The term “metabolism,” derived from the Greek word for change, “metabole,” refers to all life-sustaining chemical reactions that occur in a living organism. Healthy metabolism, or eubolism, can be visualized as a balance between the opposing processes of catabolism (breakdown of organic matter) and anabolism (building up of tissues).

Metabolic Triage
If so, all individuals can easily be classified as belonging to one of three metabolic categories: a eubolic, a predominantly catabolic, or a predominantly anabolic. A healthy person, with signs of neither catabolism nor excessive anabolism, may be termed a eubolic. Evidences of catabolism, including asthenia, weight loss, cachexia, and malnutrition, qualify a person with diabetes as having severe insulin deficiency. Presence of weight gain and stigmata of metabolic syndrome justifies the label “maladaptive anabolism” and represents an insulin-resistant condition.

This systematic arrangement allows a “metabolic triage” of diabetes and lends itself well to the choice of glucose-lowering therapy. While this

Strengths and Limitations
Such an approach, though not yet evidence-based, follows the precepts of logical empiricism. It poses many challenges, which must be met if its full potential is to be realized. The definitions of “maladaptive anabolism” and “catabolism” need uniformity. Similarly, consensus is required regarding the exact placement of various drugs. Our model, however, is characterized by its dynamism and flexibility. All descriptors are relative and subject to change: these characteristics mirror the meaning of “metabole” itself.

This malleability allows the application of this metabolic fulcrum-based approach to the choice of glucose-lowering therapy in diabetes. Such usage strengthens, rather than detracts from, existing treatment guidelines.1–3 It helps the patient and physician choose a rational therapy and facilitate faster achievement of glycemic targets in a more-efficient manner.

Article Information:

Sanjay Kalra, MD, DM, and Yashdeep Gupta, MD, DM, have no conflicts of interest to declare. No funding was received for the publication of this article


Sanjay Kalra, MD, DM, Department of Endocrinology, Bharti Hospital, Karnal, India. E:


This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and
reproduction provided the original author(s) and source are given appropriate credit.




1. Inzucchi S, Bergenstal R, Buse J, et al., Management of hyperglycemia in type 2 diabetes, 2015: a patient centered approach update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes, Diabetes Care, 2015;38:140–9.
2. Ceriello A, Colagiuri S, International Diabetes Federation guideline for management of post meal glucose: a review of recommendations, Diabet Med, 2008;25:1151–6.
3. Handelsman Y, Mechanick J, Blonde L, et al., American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan, Endocr Pract, 2011;17:1–53.

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