Treatment of diabetes in obese patients



by J. E. N. Salles, Brazil





Of an estimated 347 million adults living with type 2 diabetes worldwide, nearly 80% are obese. While the development of type 2 diabetes is multifactorial, this high prevalence of obesity strongly suggests that it plays a crucial role in the progression from normal glucose tolerance to overt type 2 diabetes. Moreover, the major causes of morbidity and mortality in patients with type 2 diabetes are cardiometabolic complications, which are, in themselves, associated with obesity. Several studies have shown that isolated weight loss plays a key role in improving glycemic control, with even modest weight loss (approximately 5% of body weight) improving glycemic control in overweight or obese individuals. Although weight loss is essential for better control of the disease, not all glucose-lowering treatments for diabetes promote weight loss or are weight neutral. Therefore, the effect of glucose-lowering medications on weight should be taken into consideration when prescribing for overweight or obese patients with type 2 diabetes, and, whenever possible, medications for comorbid conditions that are associated with weight gain should be minimized.


It is present in all algorithms for the treatment of type 2 diabetes and is also an approach that is compatible with all the latest developments in diabetes research, while remaining the most effective treatment of the disease. What is it?

While it may seem that I am talking about metformin, I am actually referring to weight loss in type 2 diabetes, an approach that should be achieved with dietary reeducation and exercise according to the guidelines for the treatment of type 2 diabetes. Although we often discuss this approach with our patients, sometimes we fail to emphasize to them the importance of a correct diet in the treatment of diabetes. We should make it clear that an approach that encompasses not only diet, but also the practice of physical activity leading to weight loss may be able to improve glycemic control.

Of an estimated 347 million adults living with type 2 diabetes worldwide, nearly 80% are obese. Although the development of type 2 diabetes is multifactorial, this high prevalence of obesity strongly suggests that it plays a central role in the progression from normal glucose tolerance to overt type 2 diabetes.1 In addition, the major causes of morbidity and mortality in patients with type 2 diabetes are cardiometabolic complications, which are, in themselves, associated with obesity.2,3

Treatment of type 2 diabetes and weight reduction

Several studies have shown that isolated weight loss plays a key role in improving glycemic control, with even modest weight loss (approximately 5% of body weight) improving glycemic control in overweight or obese individuals.4 One of the most recent of these studies, Look AHEAD (Action for HEAlth in Diabetes),5 was designed to show whether a specific weight intervention with dietary reeducation and regular physical activity, while the patients maintained their respective treatments, would be effective in improving metabolic control and reducing cardiovascular outcomes. In its first year, Look AHEAD showed a reduction in glycated hemoglobin of 0.7 percentage points, a value comparable to that seen with oral antidiabetic dipeptidyl peptidase-4 (DPP-4) inhibitors.5 These results were directly linked to weight reduction, and this was associated with several factors that we will discuss below. The greater the patient’s attendance at consultations, the greater was the weight loss, showing that commitment and the patient-physician relationship are fundamental in the treatment of patients with diabetes and in obese patients.5

Another pillar in the treatment of patients with diabetes is physical activity, which in this study was divided between aerobic and anaerobic, and was performed under the guidance of professionals. Again, the patients who did physical exercise more frequently achieved a greater weight reduction.5

Obesity is known to lead to insulin resistance, which is generated by the interaction between genetic predisposition, obesity, and inflammatory processes. When there is obesity, insulin resistance originates in principle from disharmony in the distribution and function of the body’s adipose tissue. Visceral adipose tissue (intra-abdominal) and peripheral adipose tissue (subcutaneous) make up the total fat mass. The increase in total fat mass leads to a rise in the production of inflammatory cytokines and release of free fatty acids. Cytokines, via post-receptor mechanisms, prevent the anti-inflammatory action of insulin, while fatty acids tend to be more present in the circulation and may accumulate in other tissues. This increase in circulatory triglycerides is proportional to the decrease in triglyceride uptake in adipose tissue. Once fatty acids accumulate between muscle or liver cells, they can accumulate either as triglycerides, which are benign, or as inflammatory compounds. They generate local inflammation—just as cytokines do in adipose tissue—which contributes to the formation of local insulin resistance.6 In the Look AHEAD study,5 the reduction in glycated hemoglobin in the first year was significantly greater in the intensive lifestyle intervention group (despite not persisting throughout the study) than in the control group (diabetes support and education).

In order for us to approach the patient in a more practical and effective way, endocrinologists and diabetologists should focus their efforts on metabolic control and also on weight loss. This is supported by the standards of medical care in diabetes recently published by the American Diabetes Association (ADA). Physicians are advised to consider the effect of glucose-lowering medications on weight when prescribing for overweight or obese patients with type 2 diabetes, and to minimize, whenever possible, medications for comorbid conditions that are associated with weight gain.7

Approach to the treatment of diabetes with obesity

Not all glucose-lowering treatments for diabetes have been shown to promote weight loss or to be weight neutral. Exogenous insulin, thiazolidinediones, and certain insulin secretagogues have often been associated with weight gain. Unlike these drugs, metformin, α-glucosidase inhibitors, sodium– glucose cotransporter 2 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and amylin mimetics are associated with weight loss, and dipeptidyl peptidase-4 inhibitors appear to be weight neutral.7

With the arrival of GLP-1 receptor agonists, the treatment of type 2 diabetes has gained a great ally for the patient with diabetes and obesity, where weight loss becomes essential for better control of the disease. A phase 3 study with one such GLP-1 receptor agonist, liraglutide, named the LEAD trial, showed significant weight reduction in patients with type 2 diabetes, compared with other treatments, as well as reduction of glycated hemoglobin. The LEAD-3 Mono trial (Liraglutide Effect and Action in Diabetes [LEAD-3]: effect on glycemic control of liraglutide versus glimepiride in type 2 diabetes), which compared liraglutide monotherapy with glimepiride monotherapy, showed an average reduction of 2.5 kg in favor of liraglutide.8 The LIRA-DPP-4 Study Group compared liraglutide with the DPP-4 inhibitor sitagliptin, in patients also receiving metformin, and the patients randomized to liraglutide presented greater weight loss, ranging from 2.9 kg with 1.2 mg of liraglutide per day to 3.5 kg with 1.8 mg per day, in addition to better metabolic control.9 These studies very nicely show that reduction of glycated hemoglobin, in combination with weight reduction, can afford extra benefit to the patient with type 2 diabetes. But the great challenge while using GLP-1 receptor agonists is adherence to treatment. On average, only 34% of patients initiating daily GLP-1 receptor agonist therapy maintain their use after the first year.10 A GLP-1 receptor agonist administered by a continuous delivery system would, therefore, be very useful in improving adherence and metabolic control of type 2 diabetes patients.





The FREEDOM trial program, a group of phase 3 studies, showed that continuous subcutaneous delivery of the GLPS 1 receptor agonist exenatide by ITCA 650, a miniature osmotic pump system, improved glycated hemoglobin control and also weight reduction. In the FREEDOM 1 trial (phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of exenatide in patients with type 2 diabetes),11,12 patients on a stable dose of a sulfonylurea, metformin, or pioglitazone, in single- drug therapy or combination, were randomized to receive exenatide (40 or 60 μg) administered by ITCA 650, or a placebo, in addition to their current treatment. The patients randomized to exenatide presented a 1.4-percentage-point drop from the initial glycated hemoglobin at both doses, with significantly greater weight loss of 3.1 kg at the 60 g dose and a weight loss of 2.3 kg at the 40 μg dose, against a weight loss of 0.6 kg in the placebo group.

GLP-1 receptor agonists and DPP-4 inhibitors, which are incretin- based therapies, differ in two major ways. GLP-1 receptor agonists guarantee greater weight reduction and greater lowering of glycated hemoglobin. In the FREEDOM 2 study (an open-label multicenter sub-study to evaluate the efficacy, safety, and tolerability of exenatide in patients with type 2 diabetes with high baseline HbA1c),13 patients on monotherapy with metformin were randomized to receive 60 μg exenatide or 100 mg sitagliptin daily. Patients in the exenatide group showed a significant 1.5-percentage-point drop from the initial glycated hemoglobin versus a drop of only 0.8 percentage points in the sitagliptin group. The difference was even more evident when considering weight reduction. Patients who received exenatide lost 4.0 kg, while those who received sitagliptin lost only 1.3 kg. In response to these and other studies, type 2 diabetes treatment algorithms prefer GLP-1 receptor agonists as a strategy for reducing blood glucose and weight. As an example, since 2013 the American Association of Clinical Endocrinologists (AACE) has listed the drugs to be combined with metformin.14 In 2013, GLP-1 receptor agonists were the first choice, followed by DPP-4 inhibitors. In 2016, after the publication of the cardiovascular safety studies of empagliflozin, sodium/ glucose cotransporter 2 (SGLT2) inhibitors started to appear ahead of DPP-4 inhibitors, but GLP-1 receptor agonists remained the first option in combination with metformin.15 This shows that therapies that consistently achieve weight loss in type 2 diabetes patients are always welcome options. SGLT2 inhibitors are undoubtedly a safe option, but their effect on weight is less pronounced than that of GLP-1 receptor agonists and not as long-lasting, so GLP-1 receptor agonists remain the main choice after metformin in patients with type 2 diabetes and obesity.

Final considerations

The choice of the best antidiabetic drug is based not only on the control of glycated hemoglobin, but also on the comorbidities of type 2 diabetes, ie, obesity and hypertension. Drugs that act on these comorbidities are recommended in the treatment of type 2 diabetes, with preference given to GLP-1 receptor agonists.■


References
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Keywords: diabetes; obesity; treatment; weight reduction Keywords: diabetes; obesity; treatment; weight reduction