Treatment of Type 2 Diabetes in Subjects with Obesity: What is the Best Approach?

The correlation between type 2 diabetes (T2DM) and obesity was remarkable by Sims and colleagues in the 1970s when they coined the term “diabesity” [1]. The prevalence of both T2DM and obesity has continuously increased worldwide. It has been predicted that in 2030 the prevalence of T2DM will reach more than 7.0% of the world’s population, paralleling the body mass index (BMI). The precise pathways leading to T2DM are not yet completely known, however, the current understanding of its pathophysiology recognizes, in most cases, obesity and physical inactivity as start-up processes [2]. The increased adipose tissue mass, mostly at visceral site, leads to elevated plasma nonesterified fatty acids (NEFA) concentrations, and these in turn leads to insulin resistance in insulin target tissues, such as muscle and liver [3]. The insulin resistance state represents a major stress on the pancreatic β-cells to increase their insulin secretion in order to offset the blunted insulin action. As long as the β-cells are able to increase their secretion of insulin sufficiently to overcome the insulin resistance, glucose tolerance is kept at normal levels. However, over time the β-cells begin to fail and initially the postprandial plasma glucose levels and subsequently the fasting plasma glucose concentration begin to rise, leading to the onset of overt type 2 diabetes [4]. Obesity, along with insulin resistance, predisposes individuals to low-grade chronic inflammation and metabolic complications. Further, the combination of insulin resistance and subsequent hyperinsulinaemia gives rise to a number of metabolic and cardiovascular changes that bring to metabolic syndrome, typically characterised by T2DM, obesity, dyslipidaemia, coronary artery disease and hypertension [5,6]. This picture is summarized in (Table 1). Moreover, obesity represents the major determinant of musculoskeletal and osteoarticular weight related diseases [7].

Table 1: Criteria of metabolic syndrome.

Obesity management can delay the progression of glucose intolerance to T2DM [8]. First line therapy for obesity is represented by lifestyle interventions such as low-calorie diet and aerobic exercise in order to reduce insulin resistance and increase GLUT-4 expression by skeletal muscles. About 300 minutes/week of endurance activity at moderate intensity, or even 150 minutes of more intense activity, can mobilize visceral fat that is correlated with the high cardiovascular risk. The general prescription for the population is at least of 150 minutes/week of moderate aerobic activity, equivalent to walking at 5-6km/h [9,10]. In obese patients with T2DM weight loss improves glycaemic control and can reduce antidiabetic drug administration, especially in the early phase of the disease [11]. Some older antidiabetic drugs, such as sulfonylureas, glinides, thiazolidinediones and insulin result in weight gain [12]. Conversely, glucagon-like peptide receptors agonists (GLP-1ra), as well as sodium-glucose co- transporter 2 inhibitors (SGLT2i), result in average weight loss. Although few clinical trials reported a small mean weight loss (0.5-1kg), metformin and dipeptidyl peptidase-4 inhibitors (DPP-IVi) are considered weight neutral medications. In any case, drugs for the treatment of obesity should only be offered in a multicomponent lifestyle programme [13].

Sodium-glucose cotransporter 2 inhibitors: SGLT2i, inhibiting renal glucose transporter, induce a loss of average 50-80g of glucose in urine per day and bring an osmotic diuresis associated with a loss of the body water. The most used SGLT2i are canaglifozin, dapaglifozin, empaglifozin. However, the weight loss observed is less than expected, probably due to a compensatory increase in food intake in patients treated with SGLT2i [22]. Indeed, several meta-analysis reported an average weight loss, observed in patients treated with SGLT2i, ranging from 0.591 to 2.1kg. The weight loss seems to occur rapidly in the early weeks of treatment, and then becomes more gradual. In the paper of Bolider et al., dapaglifozin causes a weight loss of -2.42kg vs. placebo at 102 weeks follow-up [23]. Long-term studies, verified by X-ray absorptiometry, support that dapaglifozin induces loss of fat mass (1.34kg) [23].

Other studies, including patients treated also with irpaglifozin, underline that there is a loss of visceral fat induced by SGLT2i of about -1.7kg from baseline [24]. The EMPAREG-OUTCAME trial with empaglifozin, at 10 or 25mg once daily, showed an average weight loss of about 2 or 3kg, respectively vs. 1kg in the placebo arm [25]. In the CANVAS study, canaglifozin displayed an average weight loss of about -1.6kg [26]. Finally, the DURATION 8 trial underlines how the combination metformin plus dapaglifozin once daily, combined with exenatide once weekly, resulted a 2% reduction of HbA1c and a weight loss of 3.4kg in 28 weeks of treatment. These beneficial changes are more sustained in combined therapy than in monotherapy [27]. Also the study SUSTAIN 9 [28], a double-bind trial, parallel-group, noticed that GLP-1ra plus SGLT2i combination is more powerful in the reduction of body weight and of glycated haemoglobin compared to the add one to metformin and sulphonylurea.

Metformin: Metformin is used as a first-line anti-diabetic drug. Metformin reduces hepatic gluconeogenesis, decreases intestinal absorption of glucose and improves peripheral glucose uptake. Since patients with obesity generally develop insulin resistance, metformin can correct this alteration, reducing circulating insulin and promoting weight loss. Indeed, initial study at time of FDA approval, evidenced a moderate effect of metformin on weight control [29], whereas the UKPS study reported a neutral effect on weight [30]. Although the statistical significance was not reached, some metanalysis have shown a reduction of weight in patients treated with metformin [31,32]. The DPP (Diabetes and Prevention Program) identified a weight loss (participants had reduced body weight and waist circumference compared with placebo) with metformin, closely related with therapeutic adherence [33]. Given to the paucity of evidence, the FDA did not approved metformin as weight loss treatment. However, the ADA guidelines suggest metformin therapy for prevention of T2DM in subjects with “prediabetes”, especially for those displaying a BMI ≥35kg/m² [34].

Most T2DM cases are related to over-weight or obesity, therefore, it is really important to promote weight loss with nutritional advices, as well as drugs. Significant interventions on patient's lifestyle are crucial to treat both diabetes and obesity that can be seen as the two faces of the same disease, the metabolic syndrome. Nowadays some drugs can help clinicians to treat both diseases; among these, the most effective are GLP-1ra, in terms of both reduction of glycated haemoglobin and weight loss, due to their mechanism of action. In particular, the most effective molecules are liraglutide and semaglutide. The combination therapy GLP-1ra and SGLT2i, considering their specific mechanistic synergy, can result in further reduction of glycated haemoglobin and weight, without any hypoglycaemic risks, as shown in the meta-analysis by Castellana et al. [35]. GLP-1ra and SGLT2i can bring cardiovascular advantage, strongly needed in this population with high cardiovascular risk. Metformin is always first-line therapy in T2DM for its tolerability, no hypoglycaemic risks and considerable action reducing haemoglobin glycated. Thanks to their different mechanism of action, metformin in association with GLP-1ra and/or SGLT2i probably represent the best choice for our patients with T2DM and obesity.

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