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Optimizing diabetes treatment in the presence of obesity

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ABSTRACT

Evidence of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes has led to a search for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c, but also have weight loss as a potential side effect. The authors review medications approved for the treatment of type 2 diabetes mellitus (including pramlintide, also approved for type 1 diabetes) that also have weight loss as a side effect. Drugs discussed include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, the authors comment on the cardiovascular effects of these drugs.

KEY POINTS

  • The rationale for GLP-1 receptor agonists is that peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility. It also exerts an anorexic effect by acting on central pathways that mediate satiation.
  • SGLT-2 inhibitors have relatively weak glycemic efficacy. Inhibition of SGLT-2 alleviates hyperglycemia by decreasing glucose reabsorption in the kidneys and by increasing excretion in the urine, suggesting urinary loss of glucose (and hence caloric loss). This is thought to contribute to weight reduction in addition to initial weight loss from fluid loss due to osmotic diuresis.
  • Meta-analyses so far have shown that alpha-glucosidase inhibitors have either a neutral or a beneficial effect on body weight.


 

References

Diabesity was a term coined by Sims et al1 in the 1970s to describe diabetes occurring in the setting of obesity. Today, the link between type 2 diabetes mellitus (DM), obesity, and insulin resistance is well recognized, and 80% of people with type 2 DM are overweight or obese.2,3 Unfortunately, weight gain is a known side effect of most agents used to treat type 2 DM (eg, insulin, sulfonylureas, thiazolidinediones), and this often leads to nonadherence, poor glycemic control, and further weight gain.

During the past several years, evidence has emerged of a neurophysiologic mechanism that involves hormones from adipocytes, pancreatic islet cells, and the gastrointestinal tract implicated in both obesity and diabetes.2 This has led to research for drugs that not only either target obesity and diabetes or reduce hemoglobin A1c (HbA1c), but also have weight loss as a potential side effect.

In this paper, we review medications approved for the treatment of type 2 DM (including pramlintide, also approved for type 1 DM) that also have weight loss as a side effect. Drugs we will discuss include glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, neuroendocrine peptide hormones, alpha-glucosidase inhibitors, and metformin. Where appropriate, we also comment on the effects of the drugs on cardiovascular outcomes.

GLP-1 RECEPTOR AGONISTS

Mechanism of action

GLP-1 is a hormone produced from the proglucagon gene in the alpha cells of the pancreas, in the L cells of intestinal mucosa (predominantly in the ileum and distal colon), and in structures of the nervous system including the brainstem, hypothalamus, and vagal afferent nerves.4 Food in the gastrointestinal tract, especially if high in fats and carbohydrates, stimulates secretion of GLP-1 in the L cells, which in turn amplifies insulin secretion in a glucose-dependent manner (the incretin effect).4 Glucagon secretion is inhibited by GLP-1 during times of hyperglycemia but not hypoglycemia, thereby preventing inappropriately high levels of the hormone.5 Peripheral GLP-1 activates a cascade of centrally mediated signals that ultimately result in secretion of insulin by the pancreas and slowing of gastrointestinal motility.5 Lastly, GLP-1 exerts an anorexic effect by acting on central pathways that mediate satiation.6

Sites of action and physiologic effects of glucagon-like peptide-1
Recent studies suggest that GLP-1 receptor agonist drugs have proliferative, anti-apoptotic, and differentiation effects on pancreatic beta cells, thereby leading to improved glycemic control.7Table 1 summarizes the sites of action and physiologic effects of GLP-1.7

Bioactive forms of GLP-1 are rapidly degraded in the circulation by the dipeptidyl peptidase-4 enzyme. GLP-1 receptor agonists have slightly altered molecular structure and longer duration of action than native GLP-1. Short-acting GLP-1 agonists (eg, exenatide, lixisenatide) have more effect on gastric emptying and lower postprandial blood glucose levels, whereas long-acting GLP-1 agonists (eg, liraglutide, albiglutide, dulaglutide, semaglutide, exenatide) have a greater effect on fasting glucose levels.4

Effects on HbA1c and weight loss

Currently approved glucagon-like peptide-1 receptor agonists for diabetes mellitus
As a class, GLP-1 receptor agonists have been proven to cause significant reduction in HbA1c levels. In a meta-analysis of 17 randomized controlled trials involving patients with type 2 DM with suboptimal control on 1 or 2 oral agents, GLP-1 agonists decreased HbA1c levels by 1% (treatment difference 0.5% to 1.6%) compared with placebo.8 HbA1c reductions from each GLP-1 agonist along with dosing, administration, and weight loss benefit are shown in Table 2.9–14

Of the current GLP-1 agonists, exenatide and liraglutide have been on the market the longest, thus studied more in terms of weight reduction.

Exenatide. Exenatide BID was the first GLP-1 agonist, approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of type 2 DM. In a 30-week triple-blind, placebo-controlled study of 336 patients already on background therapy with metformin, progressive weight loss was noted with exenatide 5 μg (−1.6 ± 0.4 kg) and exenatide 10 μg (−2.8 ± 0.5 kg) compared with placebo (−0.3 ± 0.3 kg; P < .001).15 A meta-analysis of 14 trials with 2,583 patients showed significant weight reduction with both exenatide 5 μg twice daily (a difference of −0.56 kg, 95% confidence interval [CI] −1.07 to −0.06, P = .0002) in 8 trials and exenatide 10 μg twice daily (a difference of −1.24 kg, 95% CI −1.69 to −0.78, P < .001) in 12 trials, after treatment for more than 16 weeks.16

Liraglutide. Liraglutide has a longer half-life than exenatide and is administered once daily. It is not a first-line therapy for type 2 DM and is recommended as an add-on. Approved daily doses for type 2 DM are 1.2 mg and 1.8 mg.

Multiple studies of glycemic control and weight loss with liraglutide have been conducted since its introduction to the US market in 2010. In the Liraglutide Effect and Action in Diabetes (LEAD) series of trials, liraglutide use as monotherapy or in combination with oral agents was associated with significant dose-dependent weight loss.17 Liraglutide monotherapy (at 1.2 mg and 1.8 mg) compared with glimepiride in the LEAD-3 trial led to significant weight reduction (2.1 kg and 2.5 kg, respectively, P < .001) after 16 weeks, and was sustained up to 52 weeks.18 Addition of liraglutide (at 1.2 mg and 1.8 mg) to metformin plus rosiglitazone resulted in significant weight loss (1.02 kg and 2.02 kg, respectively) whereas the addition of placebo caused a 0.6-kg weight gain (P < .001).19 The SCALE study randomized 846 adults with type 2 DM who were overweight to obese (body mass index [BMI] ≥ 27 kg/m2), were taking 0 to 3 oral antihyperglycemic agents (metformin, thiazolidinedione, and a sulfonylurea), and had stable body weight and an HbA1c of 7% to 10% to liraglutide 1.8 mg, liraglutide 3.0 mg, or placebo. Mean weight loss after 56 weeks was 6.0% (6.4 kg) with liraglutide 1.8 mg, 4.7% (5.0 kg) with liraglutide 3.0 mg, and 2.0% (2.2 kg) with placebo.20

In 2016, high-dose once-daily liraglutide 3.0 mg (Saxenda) was approved by the FDA for weight loss. In a double-blind randomized trial of liraglutide 3.0 mg vs placebo in patients who had a BMI of at least 30 or who had a BMI of at least 27 plus treated or untreated dyslipidemia or hypertension, Pi-Sunyer et al21 reported a mean weight reduction of 8.4 ± 7.3 kg with liraglutide vs 2.8 ± 6.5 kg with placebo (a difference of −5.6 kg, 95% CI −6.0 to −5.1, P < .001) after 56 weeks. Furthermore, 63.2% of patients in the liraglutide group lost at least 5% of body weight vs 27.1% with placebo, and 33.1% in the liraglutide group lost 10% or more of body weight vs 10.6% in the placebo group (P < .001).21 Of note, liraglutide 3.0 mg is not indicated for type 2 DM per se.

In a 2012 meta-analysis of randomized controlled trials of adults with and without type 2 DM, with a BMI of 25 or greater, and who received GLP-1 receptor agonists at clinically rele­vant doses (exenatide ≥ 10 μg/day, exenatide ≥ 2 mg/week, or liraglutide ≥ 1.2 mg/day), those taking GLP-1 receptor agonists had more weight loss than those on a control intervention (oral antihyperglycemic, insulin, or placebo) at a minimum of 20 weeks, with a weighted mean difference −2.9 kg (95% CI −3.6 to −2.2) in 21 trials and 6,411 participants.22

GLP-1 agonists currently being investigated for obesity treatment are lixisenatide, albiglutide, taspoglutide, and oxyntomodulin.23

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

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