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Antiobesity drugs in the management of type 2 diabetes: A shift in thinking?

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ABSTRACT

Antiobesity medications can improve metabolic control for patients with type 2 diabetes mellitus (DM) and obesity, but are underutilized. In this review, we describe the role of antiobesity drugs in the context of medically supervised and comprehensive weight-loss interventions and propose a pragmatic therapeutic algorithm for patients with type 2 DM and obesity that incorporates the use of antiobesity drugs early in the course of management.

KEY POINTS

  • Obesity contributes to type 2 DM and worsens its control. Yet insulin therapy and most first-line diabetes drugs cause weight gain as a side effect.
  • We believe that physicians should include body weight along with blood glucose levels as targets of therapy in patients with type 2 DM.
  • Several drugs are approved for weight loss, and although their effect on weight tends to be moderate, some have been shown to reduce the incidence of type 2 DM and improve diabetic control.
  • A stepwise approach to managing type 2 DM and obesity starts with lifestyle interventions and advances to adding (1) metformin, (2) a glucagon-like peptide-1 receptor agonist or a sodium-glucose cotransporter-2 inhibitor, and (3) one of the approved weight-loss drugs.


 

References

Obesity is a leading public health concern, affecting nearly 60 million adult Americans.1 It is a major risk factor for the development of insulin resistance and type 2 diabetes mellitus (DM).2 More than 90% of patients with type 2 DM have obesity, and obesity is a major obstacle to achieving long-term glycemic control.3

Clinical studies have demonstrated that a 6- to 7-kg increase in body weight increases the risk of developing type 2 DM by 50%, while a 5-kg loss reduces the risk by a similar amount.4 As a result, most patients who have a body mass index greater than 40 kg/m2 suffer from type 2 DM.5 Strong evidence exists that bariatric surgery and its resulting weight loss has positive effects on fasting blood sugar, hemoglobin A1c (HbA1c), lipid profiles, and other metabolic variables.6

When combined, obesity and type 2 DM carry a significant burden of micro- and macrovascular complications such as retinopathy, nephropathy, neuropathy, and cardiovascular disease. As a result, a high prevalence of morbidity and mortality is seen among patients with obesity and type 2 DM; those between the ages of 51 and 61 have a 7-times higher mortality rate compared with nonobese normoglycemic people, and patients with diabetes alone have a 2.6-times higher mortality rate.7

A DILEMMA IN THE CLINIC: FOCUS ON THE SUGAR OR THE WEIGHT?

Although type 2 DM and obesity go hand in hand, clinicians tend to focus on the sugar and neglect the weight, concentrating their efforts on improving blood glucose indices, and prescribing in many instances medications that cause weight gain. As a result, we are faced with a rising epidemic of obesity, perpetuating a preexisting epidemic of diabetes.

An optimal, comprehensive approach to managing patients with type 2 DM should encompass both the control of dysglycemia and its associated comorbidities, obesity being the key player.8 However, clinical practice is often misaligned with the evidence. For instance, many of our first-line oral treatments for type 2 DM (except for metformin) are associated with weight gain.9 With time, control of glycemia becomes more and more ineffective, at which point therapy is intensified with insulin, further exacerbating the weight gain.10

Therefore, it seems counterintuitive to treat a disease for which obesity is one of the main risk factors with medications that promote weight gain. Yet healthcare providers are faced with a therapeutic dilemma: should they focus their efforts on improving patients’ glycemic control, or should they invest in helping these patients lose weight? Although an ideal approach would incorporate both aspects, the reality is that it is far from practical.

A few issues impinge on integrating weight loss in the care of type 2 DM. Although the American Medical Association recognized obesity as a disease in 2013,11 some providers still perceive obesity as a self-inflicted condition that is due to bad lifestyle and behavior.11 Many clinicians may also have low expectations for patients’ success, and often lack the time and knowledge to intervene regarding nutrition, physical activity, and psychological issues pertinent to the management of obesity in type 2 DM. Therefore, in many cases, it seems less complicated and more rewarding for both patients and physicians to concentrate on improving the HbA1c value rather than investing efforts in weight loss. For diabetic patients with obesity, this could mean that clinicians may prescribe glucose-lowering therapies, such as insulin and sulfonylureas, at the expense of weight gain. Additionally, clinicians often experience the need to provide recommendations more aligned with metrics that dictate reimbursement (eg, HbA1c targets) within healthcare systems that still raise concerns regarding obesity visit reimbursements.

Lastly, the lack of trustworthy or pertinent evidence (lack of comparative effectiveness research) for antiobesity medications may limit their use in daily practice. Physicians have had little confidence in the efficacy of antiobesity drugs, and often raise significant safety concerns, especially after witnessing important fiascos in this field, eg, dexfenfluramine, rimonabant, and sibutramine.2,12,13

As a result, many of our patients with obesity and type 2 DM may not consider the need for weight loss, and may not even be aware that type 2 DM is caused by obesity and physical inactivity in the first place. Others have accumulated a significant degree of frustration, and have “thrown in the towel” already after unsuccessful weight-loss efforts, many of which were not medically supervised.

For all of the above reasons, both clinicians and patients often concentrate their efforts on treating blood glucose numbers rather than the “obesity-diabetes” as a whole.14 And as a result, our practices are slowly filling up with patients with obesity and type 2 DM who are treated primarily with insulin, resulting in a progressive (and untreated) obesity and diabetes epidemic.

DRUGS FOR TREATING OBESITY AND TYPE 2 DM

Drugs approved by the FDA for treatment of obesity
Because the body strongly defends its fat cells, the common advice to simply “eat less, move more” cannot be expected to bring about meaningful and lasting weight reduction or control of HbA1c. However, weight-loss drugs (Table 1),15 used in conjunction with an interdisciplinary lifestyle intervention program, may provide more success regarding both issues. Here we discuss a few pharmacologic therapies approved for the management of obesity in the context of type 2 DM, and vice versa. Taking into account that dosages of these medications should be individualized to achieve a weight-loss goal with the lowest effective dose possible.

Orlistat

Orlistat (Xenical) is the only weight-loss drug approved by the US Food and Drug Administration (FDA) that acts outside the brain. It inhibits pancreatic lipases, resulting in up to 30% less fat absorption in the gut. Orlistat has been approved for long-term use by the FDA.

Benefits. In the XENical in the Prevention of Diabetes in Obese Subjects study, treatment with orlistat resulted in a significant reduction in the cumulative incidence of type 2 DM after 4 years of treatment (9.0% with placebo vs 6.2% with orlistat), corresponding to a risk reduction of 37.3%.16 Mean weight loss after 4 years was significantly greater in the orlistat group (5.8 vs 3.0 kg with placebo; P < .001).16 Other benefits of orlistat included a reduction in low-density lipoprotein cholesterol independent of that expected from change in body weight.16

Adverse effects include flatulence with discharge and fecal urgency after high-fat dietary indiscretions. Serum levels of fat-soluble vitamins (A, D, E, and K) were lower with orlistat than with placebo,16 and a fat-soluble vitamin supplement should be taken 2 hours before or after taking orlistat. Serious but very uncommon adverse events such as kidney damage have been reported.17 Kidney and liver function should be monitored while taking orlistat.

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