Conclusions
Treatment of overweight or obese individuals with type 2 diabetes with NB resulted in a 5.0% reduction in body weight, compared with a reduction of 1.8% with placebo. Patients treated with NB were more than twice as likely to lose ≥5% of their initial body weight as patients treated with lifestyle intervention alone. The weight loss in the NB-treated group was evident as early as the first visit (week 4), and was maintained for the 56-week period, with no evidence of weight regain. This weight loss was accompanied by a significant reduction in HbA1c (placebo-corrected difference −0.5%) along with other favorable glycemic effects. Modest improvements in waist circumference, HDL-C, and triglycerides were also observed. The most frequently reported adverse event with NB was nausea.
Adipose tissue is an active endocrine and immune organ whose dysfunction contributes to metabolic diseases (e.g., diabetes) and increases cardiovascular disease. Thus, the objective of weight loss in overweight patients with metabolic disease is not solely cosmetic but also to improve the health of patients. In terms of clinically meaningful weight loss, human studies suggest that 5% weight loss significantly improves glucose control and other cardiovascular parameters and results in reduced mortality in patients with diabetes. This magnitude of weight loss has also been associated with a delay in the progression to type 2 diabetes in patients with prediabetes.
The magnitude of weight loss (both absolute and placebo corrected) in the current study of overweight and obese individuals with type 2 diabetes was lower than that observed in NB trials in patients without type 2 diabetes. In the COR-I and COR-II studies, which used a lifestyle intervention similar to the current study, mean body weight changes (mITT) were −6.1 and −6.4% with NB vs. −1.3 and −1.2% with placebo. In the COR-BMOD study, which included a more intensive, group-based lifestyle intervention, mean mITT body weight changes were −9.3% (NB) and −5.1% (placebo). The somewhat more modest weight loss in the current study is not surprising, as it is typical that less weight loss is observed in patients with diabetes taking OADs compared with patients without diabetes. While the reason for the attenuated magnitude of weight loss in patients with diabetes is not well understood, it may relate to differences in insulin resistance, adipose cell metabolism, concomitant medications for the treatment of diabetes, and glucose metabolism. Nevertheless, of study participants who completed 1 year of treatment, more than one-half of NB patients lost ≥5% of body weight and more than one-quarter achieved ≥10% weight loss.
Consistent with the observed improvement in body weight, NB-treated patients exhibited clinically and statistically significant improvement in HbA1c and generally beneficial changes in other markers related to glycemic control. The extent of reduction in HbA1c (−0.5% [−5.5 mmol/mol] vs. lifestyle intervention alone) compares well with the reported efficacy of several drugs currently used for treating diabetes. The magnitude of reduction was even greater in patients with higher baseline HbA1c values. This degree of improvement is meaningful in relation to long-term risk for microvascular complications and may contribute to a favorable environment with regard to macrovascular complications. The clinical impact of the HbA1c reduction with NB was demonstrated by the fact that patients on placebo were more likely to require an increased dose or number of OADs to maintain glycemic control (which lessened the apparent treatment difference with NB on both HbA1c and fasting glucose) (Supplementary Table 2).
NB treatment was also accompanied by improvements in a number of additional markers of cardiovascular risk, such as waist circumference, triglycerides, and HDL-C. In normoglycemic obese patients, weight loss with NB treatment has been demonstrated to be largely due to reductions in subcutaneous and visceral adipose tissue, the latter of which is associated with improvements in glycemia and lipidemia. Thus, treatment with NB in overweight/obese patients with (and without) diabetes was associated with an improvement in the cardiovascular risk profile. However, bupropion has a documented pressor effect that was associated with a numerically, but not statistically, greater reduction in blood pressure in the placebo group compared with NB. Although the hemodynamic effects of NB were demonstrated to be small and transient, the overall cardiovascular effects of NB could not be adequately assessed in the NB phase 3 clinical program because the patient population had an extremely low CV event rate (~0.2/100 patient-years). In order to assess the clinical effect of the NB-related improvements in weight and other cardiovascular risk factors, along with the documented pressor effect of buproprion (a transient elevation in pulse rate and blood pressure), a cardiovascular outcomes trial of NB is currently ongoing (clinical trial reg. no. NCT01601704, clinicaltrials.gov). This outcomes trial is designed to assess the incidence of major cardiovascular events in patients receiving NB compared with placebo.
The safety profile of NB in this population was generally consistent with the phase 3 trials conducted in patients without type 2 diabetes. Importantly, NB was not associated with an increase in hypoglycemia. The safety profile of the two agents used in combination is also similar to the postmarketing surveillance data available for the two agents used individually. The most common adverse event reported with NB was nausea, which led to withdrawal in ~10% of NB patients. Much of the patient withdrawal occurred within the first 4 weeks of treatment, during which patients started treatment at a lower initial dose and were required to escalate weekly. Patients unable to tolerate the study medication were discontinued from study drug treatment. The rate of nausea in NB-treated patients in the current study (42%) tended to be higher than previous phase 3 studies (29–34%). This may be related to interaction with the background medications used by patients with diabetes in the current study, as NB-treated patients taking metformin (~75% of the population) reported a higher incidence of nausea than those not on metformin. This result was not unexpected, as gastrointestinal side effects are commonly associated with metformin treatment.
Limitations of this study include the exclusion of patients with type 2 diabetes who were receiving insulin therapy (which can promote weight gain) or glucagon-like peptide-1 receptor agonist therapy (which is associated with mild weight loss). Thus, these results may not be applicable to all patients with type 2 diabetes. Furthermore, a relatively high dropout rate was observed in this study. Although the dropout rate was similar to the other NB phase 3 trials. and does not differ from other reported studies in obesity drug development, it should be considered when evaluating the treatment effect. Finally, the 1-year study duration, while common, is not adequate to fully assess the consequences of improved body weight on long-term outcomes.
The current epidemic of obesity and obesity-related diabetes continues to be of increasing concern. Unfortunately, a number of the drugs used to treat diabetes are associated with weight gain, and new approaches to prevention and treatment are needed. In this study of overweight/obese patients with type 2 diabetes, NB treatment, in conjunction with a standardized lifestyle intervention, resulted in a clinically meaningful improvement in body weight, which was associated with improvement in HbA1c and other cardiovascular risk factors. Thus, a combination drug such as NB has the potential to become a useful agent for the treatment of overweight/obese patients diagnosed with prediabetes or type 2 diabetes.