Treating the Obese Diabetic

Julia Kenkre; Tricia Tan; Stephen Bloom


Expert Rev Clin Pharmacol. 2013;6(2):171-183. 

In This Article

Pharmacological Treatments

In Europe, at the time of writing, there is only one pharmacological agent approved for antiobesity treatment: orlistat. In the USA, while there are several available drugs for use as short-term adjuncts to weight loss including diethylpropion, benzphetamine, phentermine and phendimetrazine, here the authors will focus on those agents intended for longer term treatment: orlistat, phentermine/topiramate modified release, lorcaserin and, as yet unapproved, naltrexone/bupropion.


Orlistat, available both over the counter and on prescription, works to block dietary fat absorption by approximately 30% via reversible inhibition of gastric and pancreatic lipases in the gut lumen.[203] Orlistat has been shown to be effective at producing modest weight loss in diabetics, can prevent progression to diabetes in the 'at risk' population and can lead to some improvement in CV risk factors, including cholesterol, systolic and diastolic blood pressure.[83] A meta-analysis found the mean weight loss for orlistat-treated patients was 2.89 kg (95% CI: 2.27–3.51 kg) at 12 months.[84]

It has been evaluated for use in concert with oral antidiabetic medications; a multicenter RCT was conducted in Type 2 diabetics, who were clinically stable on a SU, to compare the effect of a hypocaloric diet plus either orlistat or placebo. At 1 year mean weight loss from baseline was 6.2% (±0.5%) in those on orlistat versus 4.3% (±0.5%) in the placebo group. Improved glycemic control, as evidenced by a significant reduction of 0.28% (±0.09%) in HbA1c versus an increase of 0.18% (±0.11%) in the placebo group and reduced fasting glucose and a better lipid profile, were also noted in the orlistat group.[85] A later 1-year, multicenter RCT to assess the effect of orlistat and hypocaloric diet in Type 2 diabetics on metformin showed that orlistat-treated patients lost significantly more weight at 1 year compared with placebo (4.7 ± 0.3 kg vs 1.8 ± 0.3 kg, respectively).[86] With regards to prevention of diabetes in an at risk population, the XENDOS study, a 4-year RCT, found that orlistat plus lifestyle measures resulted in a lower incidence of diabetes over the 4-year study and a greater weight loss compared with lifestyle changes alone.[87]

Side effects of orlistat include oily stools, fecal urgency and oily spotting, and it can also reduce the absorption of fat-soluble vitamins. More recently, cases of serious liver injury have been reported, although this adverse event is very rare.[88]

Lorcaserin (Belviq®)

Lorcaserin (Belviq; Arena Pharmaceuticals, CA, USA), approved in June 2012 by the FDA but still under review by the EMA, is a selective agonist at the G-protein coupled 5HT2c receptor. Activation of this receptor has previously been shown to decrease hunger and increase satiety,[89] the mechanism of which has been proposed to be by increasing pro-opiomelanocortin (POMC) expression with subsequent increased release of α-melanocyte stimulating hormone, which stimulates the anorexigenic melanocortin 4 receptor.[90]

Lorcaserin has been shown to have a moderate effect on weight loss and glycemic control in the diabetic population, although questions remain regarding its long-term safety profile. The BLOOM-DM study was a 1-year RCT in Type 2 diabetics taking metformin or SU, or both, comparing placebo with 10 mg lorcaserin daily (q.d.) versus lorcaserin 10 mg twice daily (b.i.d.). There were statistically significant differences in mean weight reduction of 4.5% (4.7 kg) in the lorcaserin b.i.d. group, 5% (5 kg) in the lorcaserin q.d. group and 1.5% (1.6 kg) in those taking placebo; HbA1c reduction was 0.9, 1 and 0.4%, respectively.[91] There was noted to be an increased incidence of hypoglycemia among those on lorcaserin, especially in those concomitantly taking a SU.

The consistent adverse effects of lorcaserin in the above trials included nausea, dizziness and headache.[92] Additional serious adverse events, seen at higher rates in those taking lorcaserin, included serotonin syndrome, psychiatric and cognitive effects such as memory impairment and disturbance in attention.

Finally, there are potential concerns with lorcaserin with regards to both carcinogenicity and valvulopathy. In rodent studies mammary and brain tumors developed after lorcaserin treatment. However, the number of mammary tumors first reported was subsequently reduced following independent review.[93] Regarding brain tumor risk, it has been argued that astrocytomas were seen only in higher dose exposure in rodent studies with an estimated safety margin of 70-fold.[204] In contrast to previously developed nonselective serotonin agonists, such as fenfluramine and dexfenfluramine, lorcaserin is less potent at the 5HT2B receptor, which is thought to be involved in the pathogenesis of valvulopathy.[94] In the BLOOM-DM study, unlike the other larger Phase III studies, higher rates of valvulopathy were seen in the lorcaserin (2.9%) versus placebo (<1%) group; the authors felt this was due to an unusually low rate of valvulopathy in the placebo group. On the basis of 5200 patient echocardiograms from the Phase III trials, no significant relative risk for valvulopathy was found with lorcaserin treatment versus placebo (mean relative risk: 1.16; 95% CI: 0.81–1.67).[93]

Phentermine/Topiramate Controlled Release (Qysmia™)

Phentermine is a centrally acting medication that leads to hypothalamic noradrenaline release and was approved by the FDA in 1959 for the short-term treatment of obesity.[95] Prolonged use was found to be associated with increased tolerance and dependency.[88] It is an effective weight loss agent that works via suppression of appetite but is associated with several adverse effects including anxiety, insomnia, increased blood pressure and palpitations.[96,97] Topiramate, a sulphamate-substituted monosaccharide, is used as an anticonvulsant and for migraine prophylaxis. Clinical trials have shown that topiramate therapy can both lead to and maintain weight loss, although its mechanism of action is not clear.[98,99] Its use as a monotherapy, however, has been precluded by dose-dependent CNS-related adverse events. Theoretically, a lower dose combination of these two drugs may lead to fewer side effects while still producing significant weight loss. Qysmia (Vivus Inc., CA, USA), a controlled release version of this combination, was approved by the FDA in July 2012.

The CONQUER trial was a 56-week RCT where obese/overweight adults with at least two or more comorbidities were given lifestyle counseling and also randomized to placebo or controlled release phentermine/topiramate (PHEN/TPM CR) 7.5 mg/46 mg or 15 mg/92 mg. In total, 16% percent of participants had Type 2 diabetes. At 1 year placebo-subtracted weight loss among Type 2 diabetics was 4.9% in the 7.5 mg/46 mg group and 6.9% in the 15 mg/92 mg group. In those taking high-dose PHEN/TPM CR there were significant improvements in blood pressure, lipids and waist circumference, although a small increase in heart rate of 1.7 bpm occurred. In the diabetic population, a statistically significant reduction of 0.4% in HbA1c was seen in both treatment groups compared with a 0.1% reduction in the placebo group.[100]

SEQUEL extended CONQUER by 1-year and found the beneficial effects of PHEN/TPM CR appear to be maintained, suggesting the combination is able to produce sustained weight loss with a weight reduction of 9% in the diabetic population versus 2% in the placebo group.[101]

Safety concerns with this combination of medications center on its potential for teratogenicity. Additionally, elevations in resting heart rate were seen in the trials above, probably caused by the sympathomimetic effects of phentermine. Despite this, however, there was a decrease in blood pressure. Other concerns include risk of metabolic acidosis due to the ability of topiramate to inhibit carbonic anhydrase, glaucoma, as well as psychiatric and cognitive adverse effects.[93]

Naltrexone Plus Bupropion (Contrave®)

Bupropion is a dopamine and noradrenaline reuptake inhibitor. It is thought to induce weight loss via activation of hypothalamic POMC neurons, which then subsequently stimulate the melanocortin 4 receptor via release of α-melanocyte stimulating hormone, resulting in reduced food intake and increased energy expenditure. Naltrexone, a current treatment for opiate addiction and alcoholism, works synergistically with bupriopion, possibly by blocking auto-inhibitory feedback on POMC neurons, thus leading to sustained enhanced neuronal firing.

The Contrave (Orexigen Therapeutics, CA, USA) Obesity Research (COR) trials were four RCTs undertaken to assess the efficacy of naltrexone/buproprion in both the diabetic and nondiabetic population. COR-Diabetes was a 56-week RCT undertaken in 505 obese/overweight Type 2 diabetic patients. In those taking naltrexone SR 32 mg plus bupriopion SR 360 mg, mean placebo-subtracted weight change from baseline was 3.3%. A reduction in the HbA1c of 0.6% was seen versus a 0.1% reduction in the placebo group. Additional improvements in waist circumference, triglyceride and HDL cholesterol levels were also noted.[102]

Among the COR trials the main adverse events seen were nausea, vomiting, headache, dizziness, constipation and dryness of the mouth. The naltrexone/bupropion combination has yet to gain FDA or EMA approval as concern remains regarding CV safety. The combination is seen to eliminate or attenuate the decreases in blood pressure and heart rate normally seen with weight loss, suggesting that this drug may well attenuate the expected CV benefits of weight loss. Additional safety concerns center on neuropsychiatric side effects. Both psychiatric effects, such as sleep-related disorders and anxiety, and cognitive side effects, such as memory and attention impairments, were seen at higher rates in those taking bupropion plus naltrexone compared with placebo. Although an increased risk of suicide has been noted with bupriopion, this has not been seen thus far with naltrexone/bupropion.[103]