Sudhakar Pemminati ^{1 *}, Richard Mark Millis ², Ashwin Kamath ³, Ashok Kudgi Shenoy ⁴, Vasavi Rakesh Gorantla ⁵

lifestyle, multimodal treatment, metabolic syndrome

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dear Editor, Type 2 diabetes mellitus (T2DM) is a world-wide public health problem [1]. As such, the Food and Drug Administration (FDA), pharmaceutical companies and medical researchers/practitioners should be discussing the costs vs. the benefits for economically-disadvantaged populations that are disproportionately affected by T2DM and, therefore, suffering the most [2]. The current debate about new antidiabetic drugs is focused mainly on pharmacological efficacy and does not take into account the multimodal mechanisms and treatments for this complex disease [3]. Whether the statistically- significant positive results demonstrated for these drugs translate into real benefits for patients in real-life clinical settings has yet to be established.

The multimodal principle of treatment, although welltaught in most medical schools, is often ignored in real- life, particularly when expensive drugs are readily available. For example, treatment of T2DM should start with the least costly, yet effective, nonpharmacological interventions, such as diet/exercise/lifestyle changes, thereafter progressing to first-line gluconeogenesis suppressors, such as metformin and later sulfonylureas. Only after such interventions have failed should the newer, very expensive GLP-1 agonists and SGLT2 inhibitors be introduced [3, 4].

Research should be carefully designed to determine whether the newer drugs benefit patients after diet/ lifestyle changes and standard treatments have failed. Such studies of multimodal treatment for T2DM should include not one, but several, intensities of diet/lifestyle modifications even before standard drug treatments are employed. Likewise, several intensities of standard drug treatments should be used in the presence and in the absence of different intensities of diet/exercise/ lifestyle modifications. The newer antidiabetics should be similarly added to the experimental regimens. Early introduction of SGLT2 inhibitors without trying the safer treatment options first may result in unnecessary harm [5], as well as increased cost to patients for whom diet/lifestyle and standard drugs may work in the correct combinations. Indeed, this approach is in accordance with the principles of personalized medicine, one of the most promising goals of 21^st century medical practice.

In the recent past, a rapid rise in the prevalence of metabolic syndrome has been observed globally, especially in developing countries like India. This increased prevalence of metabolic syndrome is thought to be an important predisposing factor for the current epidemic of T2DM [6, 7]. Complex environment-gene interactions give rise to most, if not all, human diseases, and metabolic syndrome is no exception. For example, two single-nucleotide polymorphisms (SNPs) of apolipoprotein C3 (APOC3), T > C 455 and C > T 482, alone or in combination with the fatty acid binding protein-2 (FABP2), Ala54Thr SNP, appear to be associated with a high risk for developing metabolic syndrome [8]. Even in populations such as those in India with low-fat diets, individuals with these genetic risk factors do not usually escape metabolic syndrome. This knowledge has evolved from basic research in medical science combined with genetic and clinical epidemiological research, an approach that must become more widely used if we are to effectively stem the tide of the current T2DM epidemic.

When properly added to a progressive, carefully-designed treatment regimen, the newer antidiabetic drugs may have limited value, with the cost to the patient being disproportionate to the benefit. What is needed is more information about the long-term safety and efficacy of these new antidiabetic drugs, which can only be gleaned from the right kind of multimodal clinical trial. This should be the subject of the current debate on T2DM.

The authors declare that there are no conflicts of interest.

1. Diabetes: facts and figures [internet]. Belgium: International Diabetes Federation; 2015 [cited 2016 Aug 14]. Available from: http://www.idf.org/about-diabetes/ facts-figures.
2. Kabadi UM. Sulfonylurea glimepiride: a proven cost effective, safe and reliable war horse in combating hyperglycemia in type 2 diabetes. J Diabetes Mellitus. 2015;5(4):211-26.
3. Pemminati S, Millis RM, Kamath A, Shenoy AK, Gangachannaiah S. Are the newer antidiabetic agents worth the cost?. J Clin Diagn Res. 2016;10(3):DOI: 10.7860/ JCDR/2016/17683.7384
4. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah ND, Denton BT. Second-line agents for glycemic control for type 2 diabetes: are newer agents better?. Diabetes Care. 2014;37(5):1338-45.
5. Chowdhary M, Kabbani AA, Chhabra A. Canagliflozin- induced pancreatitis: a rare side effect of a new drug. Ther Clin Risk Manag. 2015;11:991-4.
6. Pemminati S, Adhikari P, Pai MR, Pathak R. Metabolic syndrome among inmates of a ‘home for aged’ using IDF 2005 criteria. Nepal Med Coll J. 2009;11(1):31-3.
7. Pemminati S, Prabha Adhikari MR, Pathak R, Pai MR. Prevalence of metabolic syndrome (METS) using IDF 2005 guidelines in a semi urban south Indian (boloor diabetes study) population of Mangalore. J Assoc Physicians India. 2010;58:674-7.
8. Guettier JM, Georgopoulos A, Tsai MY, Radha V, Shanthirani S, Deepa R, et al. Polymorphisms in the fatty acid- binding protein 2 and apolipotrotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population. J Clin Endocrinol Metab. 2005;90(3):1705-11.