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

Prevalence of both obesity and type 2 diabetes (T2DM) is increasing worldwide. Obesity, along with insulin resistance, predisposes individuals to low-grade chronic inflammation. Moreover, the combination of insulin resistance and hyperinsulinemia gives rise to the metabolic syndrome. The management of obesity can delay the progression to diabetes and first line treatment is represented by interventions on lifestyle (low-calorie diet and aerobic exercise). In obese patients with T2DM, weight loss improves glycaemic control and, therefore, reduces the antidiabetic drug need. While some older medications, including insulin, result in weight gain, the new molecules (glucagon-like peptide receptors agonists [GLP-1ra] and sodium-glucose co-transporter 2 inhibitors [SGLT2i]) result in weight loss. GLP-1ra has an anorexic action because it slows emptying gastric, whereas SGLT2i induce glycosuria by an osmotic diuresis associated with a loss of water. To date, metformin is used as a first-line anti-diabetic drug. This molecule is known to reduce hepatic gluconeogenesis, to decrease intestinal absorption of glucose and to improve peripheral glucose uptake. In obese patients with insulin resistance metformin can correct this alteration and promote weight loss. the same disease, the metabolic syndrome. Metformin is the first-line therapy in T2DM for its tolerability and efficacy in reducing glycated hemoglobin. Thanks to their different mechanism of action, metformin in association with GLP-1ra and/or SGLT2i probably represent the best choice for obese patients with T2DM.


IOD.000579. 4(1).2020
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]. Waist circumference >94cm in men and >80cm in women Triglycerides levels ≥1.7mmol/L or specific treatment for this lipid abnormality HDL cholesterol <1.03mmol/L in males and <1.29mmol/L in females Systolic blood pressure: systolic ≥130 or diastolic ≥85mmHg or treatment of previously diagnosed hypertension Glucose levels ≥5.6mmol/L or previously diagnosed type 2 diabetes Therapy 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]. respectively when compared to baseline in a diabetic population with 6-12 months follow-up [14,15]. Currently, FDA, and also the European Medicines Agency (EMA), approved liraglutide 3mg/ day for treatment of obesity, because it produced an -8.4kg weight reduction also in a non-diabetic population [16]. Common side effects are nausea and vomiting which may occur at the beginning of the treatment. Semaglutide (1mg/weekly) is nowadays approved for T2DM therapy and is similar to liraglutide, displaying, however, a longer half time and inducing a significant weight loss from baseline (-8.5kg) as liraglutide [17]. Semaglutide is the only oral GLP-1 agonist and at the dose of 14mg once daily produces a greater weight loss than the maximum dose of liraglutide approved for the treatment of type 2 diabetes. Semaglutide at 1.0mg once weekly seems more efficient in weight loss than dulaglutide 1.5mg once weekly. In fact, they caused a weight loss of -6.5kg and -3.0kg from baseline, respectively [18]. Exenatide carries lower weight loss activity by -4.5kg, as underlined by the DURATION 1 Trial [19], compared with albiglutide (-1.7kg from baseline), as described by the study of Rosenstock et al. [20]. Also lixisenatide once daily caused weight loss of -2.96kg from baseline [21].

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].

IOD.000579. 4(1).2020
Other studies, including patients treated also with ipraglifozin, 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 glycated haemoglobin and a weight loss of 3.5kg 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-blind 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 UKPDS study reported a neutral effect on weight [30]. Although the statistical significance was not reached, some meta-analyses 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/m 2 [34].

Discussion and Conclusion
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 glycated haemoglobin. 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.