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Obesity Pharmacotherapy in Patients With Type 2 Scott Kahan1,2 and Ken Fujioka3

■ IN BRIEF Patients with obesity and are key targets for weight loss. Given the lack of behavioral weight loss in most patients, obesity pharmacotherapy options should be considered in this patient population. This article reviews key pharmacotherapy options for patients with coexisting obesity and type 2 diabetes. Diabetes that are associated with should be avoided in these patients if possible.

he U.S. Food and Admin- glycemic control (a 5% weight loss istration (FDA) defines the in- from baseline improves A1C by dication for obesity pharma- 0.5%; a 15% weight loss from base- T 2 cotherapy as a BMI >30 kg/m or line improves A1C by ~1.0%) and a BMI >27 kg/m2 with at least one reduces the need for diabetes med- obesity-associated comorbid condi- ications and yields numerous other tion. Under this definition, nearly health benefits, including reducing 50% of U.S. adults have an indica- pressure, improving LDL and tion for obesity pharmacotherapy. HDL cholesterol levels, and improv- Consideration of pharmacotherapy ing quality of life (2,3). and other treatment escalations be- Because behavioral treatment yond or in addition to behavioral alone will lead to sufficient weight counseling is especially important in loss and health improvements in only the subpopulation of patients with a minority of patients, obesity phar- obesity and type 2 diabetes given macotherapy is a valuable option for their increased risk of health condi- treatment escalation when indicated. tions such as Numerous studies have shown the and strong evidence of the benefits of benefit of combining behavioral ther- moderate weight loss in terms of di- apy and pharmacotherapy on weight abetes control and long-term health. and glycemic outcomes. 1Department of Health Policy, Johns This article focuses on the use of obe- In general, weight loss in patients Hopkins Bloomberg School of Public Health, Baltimore, MD sity pharmacotherapy in patients with with diabetes is challenging, and 2George Washington University School of coexisting obesity and type 2 diabetes. patients with diabetes consistently Medicine, Washington, DC Moderate weight loss yields sub- lose less weight with a given treat- 3Department of Nutrition and Metabolic stantial benefits in patients with ment than those who do not have Research, Scripps Clinic, La Jolla, CA obesity and type 2 diabetes. Weight diabetes. This is particularly notable Corresponding author: Scott Kahan, loss of as little as 2–3% from baseline in obesity pharmacotherapy trials, in [email protected] improves glycemic control (reduc- which weight losses are commonly https://doi.org/10.2337/ds17-0044 tions in A1C of 0.2–0.3% and in 25% lower in patients with obesity fasting glucose of >20 mg/dL) and and diabetes than in patients with ©2017 by the American Diabetes Association. Readers may use this article as long as the work and decreases the risk for obesity but without diabetes. is properly cited, the use is educational and not developing diabetes in those at high Why patients with diabetes con- for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 risk (1). Greater weight loss leads to sistently lose less weight than those for details. more significant improvements in without diabetes is not yet fully

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TABLE 1. Diabetes Medications That Tend to Increase Weight, Decrease Weight, or Are Weight Neutral Medications That Contribute to Medications That Contribute to Weight-Neutral Medications Weight Gain Weight Loss • (e.g., , • GLP-1 receptor agonists (e.g., • DPP-4 inhibitors (e.g., , glyburide, and ) and ) , , and ) • • 3.0 mg (a GLP-1 receptor agonist that is also • -Glucosidase inhibitors (e.g., • (e.g., α approved for weight loss) and ) ) • SGLT2 inhibitors (e.g., • Bile acid sequestrants (e.g., • (e.g., nataglinide , dapaglifozin, ) and ) and ) • Others (e.g., and

) FROM RESEARCH TO PRACTICE understood, although there are likely TABLE 2. Common Medications for Weight Loss in Patients several relevant factors, including With Diabetes genetic, metabolic, and environmen- FDA-Approved Medications for Medications Not Explicitly tal contributors. Notably, as patients Weight Loss Approved for Weight Loss with diabetes improve glycemic • Liraglutide 3.0 mg • Metformin control, decreased glycosuria, and possibly decreased energy expendi- • Naltrexone-bupropion SR • Pramlintide ture, occur (4). • Lorcaserin • SGLT2 inhibitors Perhaps the most relevant con- • Phentermine • SGLT2 inhibitors + phentermine tributor, and one that is readily • Phentermine-topiramate ER within the control of health care • Orlistat providers to address, is the use of diabetes medications that are known ER, extended release; SR, sustained release. to contribute to weight gain—espe- cially and sulfonylureas. As diabetes (3.0 mg)—achieves sufficient betes or , even if counsel- diabetes progresses, there is often weight loss outcomes to be formally ing alone has not previously occurred, a vicious circle of increasing β-cell approved for obesity treatment. because of the high risk in this patient dysfunction and Obesity Pharmacotherapy population (6). requiring more intensive diabetes Options for Patients With Liraglutide 3.0 mg treatment, which then Diabetes Liraglutide is a -like peptide contributes to further weight gain Several medications have been ap- 1 (GLP-1) receptor agonist that was and worsening of diabetes. In con- proved for the treatment of obesity, approved in 2010 under the brand trast, when diabetes medications all of which lead to clinically mean- name Victoza (liraglutide 1.8 mg) for with weight loss or weight-neutral ingful weight loss of ~5–15% of base- the treatment of type 2 diabetes. It properties are used instead of those line weight and A1C reductions of has since been studied and approved known to cause weight gain, patients 0.5–1.6% in patients completing at by the FDA in 2015 for the treatment have better glycemic control and least 1 year of medication treatment of obesity, under the brand name lose more weight. The percentage (Table 2). Obesity pharmacotherapy Saxenda, albeit at the higher dose of of patients attaining a goal A1C can also counter the weight gain asso- 3.0 mg daily. Liraglutide is the only of ≤7.0% is significantly higher in ciated with diabetes medications that to be explicitly patients receiving diabetes medica- tend to cause weight gain. Weight loss approved for weight management. tions that are weight neutral or have and glycemic control are significantly The medication is administered sub- weight loss side effects (5). Table 1 improved when pharmacotherapy is cutaneously via a pen injection device. lists several diabetes medications and combined with behavioral therapy. Liraglutide, like other GLP-1 their tendency to increase, decrease, Behavioral counseling, discussed else- receptor agonists, has a number of or have no effect on body weight. where in this issue (p. 237), generally mechanisms of action, including Of note, although there are several precedes pharmacotherapy, although stimulation of insulin secretion, diabetes medications that contribute recent guidelines suggest consider- improved insulin sensitivity, sup- to weight loss, only liraglutide—at a ation of primary pharmacotherapy in pression of glucagon, and decreased higher dose than that approved for patients with obesity and either dia- gastric emptying. However, the

VOLUME 30, NUMBER 4, FALL 2017 251 FROM RESEARCH TO PRACTICE / OBESITY TREATMENT IN DIABETES PATIENTS mechanism of action that is believed Liraglutide should be prescribed at what distinguishes responders from to be most relevant with respect to an initial dose of 0.6 mg daily during nonresponders, although genetic weight loss is a centrally acting, the first week of treatment and grad- underpinnings are believed to be satiety-inducing effect on neurons ually titrated up by 0.6 mg weekly important, and it is anticipated that in the arcuate nucleus of the hypo- until the dose of 3.0 mg is achieved, future pharmacogenetic research will thalamus. When humans consume which usually occurs by the fifth lead to opportunities to identify likely food, numerous hormones, includ- week of treatment. This slow titra- responders before starting treatment. ing GLP-1 are released from the tion minimizes the likelihood of side Overall, the most common side small intestine and feed back to the effects, especially and gastro- effects of liraglutide 3.0 mg are hypothalamus to signal satiety, essen- intestinal (GI) disturbances. Nausea GI-related, and especially nausea. tially signaling that food has been is the most common side effect of Risks exist for thyroid C-cell tumors consumed and the relentless drive liraglutide. When it occurs, it tends (in rodents) and acute ; for food seeking can be temporarily to increase during the first few weeks both are known risks of the broad turned off (7–9). of titration and generally diminishes GLP-1 receptor agonist class of med- Liraglutide administration leads over the course of several weeks to ications. This medication should to a dose-dependent weight loss months. In the authors’ experience, be avoided in patients with history response. In a 20-week (phase 2) clin- when nausea or other side effects are of medullary thyroid carcinoma or ical trial, liraglutide 1.8 mg led to a limiting, this titration can be further pancreatitis. The most notable risk in 5.5-kg weight loss, which plateaued slowed for as long as necessary, and, patients with diabetes is hypoglyce- by 20 weeks, whereas liraglutide 3.0 in some cases, lower doses can be mia. Asymptomatic hypoglycemic is mg led to a 7.2-kg weight loss, which used indefinitely, as long as patients common in patients with and with- continued to trend toward further are experiencing benefit. out diabetes, although symptomatic weight loss as the short trial ended A second recommendation is to is far more common (10). Phase 3 trials with 1-year dura- evaluate patients’ responsiveness to in patients with diabetes, and severe tion confirmed this, showing that treatment. The FDA recommends hypoglycemia has only been reported weight loss with liraglutide 3.0 mg evaluating weight loss after 16 weeks in patients taking concomitant sulfo- continued through at least 1 year, of treatment. Patients who lose ≥4% nylurea medications (15). with average weight loss at 56 weeks of their baseline weight during this approaching 10 kg (11). time will likely continue to lose Naltrexone-Bupropion In patients with diabetes and weight, whereas those who lose <4% Sustained-Release obesity, liraglutide 3.0 mg leads to of baseline weight are unlikely to lose Naltrexone-bupropion sustained- impressive improvements in weight significantly more weight with con- release (SR), which is FDA-approved and diabetes control. In the SCALE tinued treatment. Thus, it is advised under the brand name Contrave, is Diabetes trial, which randomized to stop medication for those in the a combination of naltrexone and 846 patients with diabetes to either latter group. bupropion in a sustained-release for- liraglutide or placebo, those assigned During the pivotal trials, 77.2% of mulation that works in multiple ways to liraglutide 3.0 mg lost 6.0% of patients were responders (≥4% weight to decrease food intake and weight. their baseline body weight, com- loss during the initial 16 weeks), and Bupropion is a norepinephrine and pared to 4.7 and 2.0% weight losses this group lost 10.8% of their base- dopamine reuptake inhibitor, and in patients randomized to liraglutide line body weight at the end of 1 year naltrexone is an opioid receptor an- 1.8 mg or placebo, respectively (12). of treatment, compared with just 3% tagonist. Animal studies suggest that, Approximately three times as many weight loss for nonresponders. In when used together, bupropion and patients taking liraglutide 3.0 mg patients with diabetes being treated naltrexone increase the firing rate of lost at least 5 and 10% of their base- with liraglutide 3.0 mg, responders pro-opiomelancortin neurons in the line body weight compared to those lost 8.5% of their weight at the end hypothalamus, in part as a result of assigned to placebo. Those random- of 1 year, compared to a 3.1% weight naltrexone-induced reduction in an ized to liraglutide 3.0 mg had an A1C loss in nonresponders (13). A 3-year autoinhibitory effect of β-endorphins, improvement of 1.3%, compared study following responders who ini- leading to diminished appetite and to improvements of 1.1 and 0.3% tially had prediabetes showed the food intake (16). Additionally, this with liraglutide 1.8 mg and placebo, weight loss experienced at 1 year was combination medication also affects respectively. mostly maintained through 3 years reward-driven eating and decreases There are two key prescribing of treatment, and progression to dia- cravings for high-calorie, pleasurable recommendations that improve tol- betes was reduced by nearly 80% foods (17,18). This effect occurs as erability and outcomes: slow titration compared with those who received a result of action in the mesolimbic and attention to responsiveness. placebo (14). It is not yet known system of the brain, which controls

252 SPECTRUM.DIABETESJOURNALS.ORG k a h a n a n d f u j i o k a reward-driven behavior to pleasur- schedule, which may take several age, in patients completing 1 year of able activities and is responsible for months to achieve the therapeutic treatment (25). Patients with type 2 cravings for highly palatable foods in dose (22). diabetes treated with lorcaserin lost response to various food cues (19). As with liraglutide, it has been 4.5–5% of baseline body weight, Of note, this medication may have shown that early weight loss predicts depending on the dose administered, particular benefits in patients with long-term success with this medica- and achieved an improvement in depression or tobacco use because tion. In a pooled analysis of phase 3 A1C of 0.9–1.0% compared to 1.5% bupropion has been approved for trials, weight loss of ≥5% at 16 weeks weight loss and 0.4% A1C improve- both indications; of note, however, of treatment predicted average weight ment in those taking placebo (26,27). the combination of naltrexone and loss of 11.7% at the end of 1 year (23). In one study, patients with predia- bupropion has not been explicitly Thus, it is recommended that patients betes and obesity who were treated approved for these purposes. who achieve ≥5% weight loss by week with lorcaserin had a 38% lower risk Several phase 3 randomized, 16 continue the medication, whereas of developing type 2 diabetes than

controlled clinical trials have been those who do not achieve this thresh- patients treated with placebo (28). FROM RESEARCH TO PRACTICE completed showing impressive weight old should consider discontinuation Patients who respond to lorcase- loss and improvement in obesity- because they may not be getting suf- rin usually do so relatively quickly. related comorbid conditions. In a ficient benefit. Therefore, response to treatment trial of naltrexone-bupropion SR in This medication is contraindi- should be evaluated 12 weeks after patients with obesity and type 2 dia- cated in patients with uncontrolled initiation. If patients lose ≥5% of betes, those who were treated with hypertension, those being treated their weight from baseline, they the medication for 1 year lost 5.9% with chronic opioid medications or will likely continue losing weight, of initial body weight and had an monoamine oxidase inhibitor med- with weight loss at the end of 1 year A1C reduction of 0.6% compared ications, and those at high risk for exceeding 10%, so the medication to a 2.2% weight loss and 0.1% A1C seizures. There is a warning that should generally be continued. For reduction in the placebo group (20). young adults and adolescents may patients who do not lose ≥5% of ini- As described above with respect to experience suicidal thoughts when tial body weight after 12 weeks, the liraglutide, there are two key prescrib- treated with bupropion. Finally, medication is generally discontinued ing recommendations that improve asymptomatic hypoglycemia is com- because there is a low likelihood of tolerability and outcomes. mon, although symptomatic or severe further weight loss (29). The most common adverse events hypoglycemia has been found to Lorcaserin is classified as a sched- (AEs) in the clinical trials were nau- occur only in patients with diabetes ule IV substance. Dosing is 10 sea and vomiting, which occur in taking concomitant medications such mg twice daily or 20 mg XR once 30–40 and 15–20% of individuals, as sulfonylureas that increase the risk daily and does not require titration. respectively, depending on the pop- of hypoglycemia. The most common AEs are head- ulation studied (21). Slow titration ache, dizziness, fatigue, nausea, dry is recommended, whereby the dose Lorcaserin mouth, and constipation, although is slowly increased from 1 tab (8 mg Lorcaserin is a selective serotonin-2c these are relatively uncommon and naltrexone/90 mg bupropion) daily (5HT-2c) receptor agonist, which rarely lead to treatment discontinua- to the therapeutic dose of two tabs specifically stimulates the 5HT-2c tion. In some patients, hypoglycemia twice daily (32 mg naltrexone/360 receptors in the hypothalamus, lead- may occur when lorcaserin is taken mg bupropion) over the course of 4 ing to increased satiety and weight concomitantly with blood glucose– weeks. This phased titration greatly loss. As opposed to earlier serotonin lowering agents for diabetes, and it improves tolerability, especially with agonists that were used off label is recommended that medications respect to nausea and vomiting, for weight loss, lorcaserin primar- such as sulfonylureas be discontin- although some patients may benefit ily stimulates the 2c subtype rather ued or doses lowered when starting from even slower titration. Although than other serotonin receptors in treatment with lorcaserin. As with the weekly escalation schedule was the brain and body, thereby leading all obesity medications, lorcaserin “forced” in the clinical trials (i.e., to fewer AEs and risks of treatment is contraindicated during pregnancy doses had to increase according to (24). Lorcaserin was approved by the and lactation. Caution is necessary this schedule regardless of whether FDA in 2012 under the brand name if patients are being treated with the medication was well tolerated), Belviq, initially at a dose of 10 mg serotonergic or antidopaminer- to further improve tolerability in twice daily, and has since also been gic medications, which can, rarely, clinical practice, we recommend for approved as Belviq XR (20 mg). precipitate serotonin syndrome or patients who continue to experience Treatment with lorcaserin leads neuroleptic malignant syndrome. side effects an even slower titration to a 7–8% body weight loss, on aver- Other warnings include caution in

VOLUME 30, NUMBER 4, FALL 2017 253 FROM RESEARCH TO PRACTICE / OBESITY TREATMENT IN DIABETES PATIENTS patients with valvular heart disease, group (31). Patients treated with ications, and hyperthyroidism. If congestive , or psychi- the medication also had improved discontinuation is necessary, patients atric disorders and those at risk for cardiometabolic markers, including treated with the highest dose (15/92 priapism (30). reduced and lipids, mg) require tapering by taking the and many were able to decrease or Phentermine-Topiramate dose every other day for 1 week before discontinue blood pressure and dia- Extended-Release discontinuing; patients taking other betes medications. In patients with doses can discontinue the medication The combination of phentermine prediabetes, progression to type 2 dia- without weaning (35). and topiramate, approved by the betes was reduced by 76% compared Orlistat FDA in 2012 and sold as Qsymia, to placebo in patients treated with the takes advantage of the additive higher dose (15/92 mg) of the medica- Orlistat is the only noncentrally act- weight loss effects of these medica- tion. In a of 130 patients ing medication for obesity treatment. tions. Phentermine, a sympathomi- with type 2 diabetes, those random- It is a pancreatic lipase inhibitor that metic amine, has been approved for ized to phentermine-topiramate decreases absorption of ingested fat. short-term weight loss since 1959; by ER lost 9.4% of baseline weight, com- The medication is dosed thrice daily itself, it decreases appetite and leads pared to 2.7% weight loss in those with meals. It was initially approved to moderate weight loss. Topiramate, assigned to placebo. A1C was reduced by by the FDA in 1999 as Xenical and which has multiple mechanisms of 1.6% in the treatment group, compared has since been approved for over-the- action, is approved as monotherapy to 1.2% in the placebo group (34). counter use at half-dose (60 mg), for migraine and seizure prevention. Treatment is initiated at 3.75 branded as Alli. On average, topiramate alone leads to mg phentermine/23 mg topiramate Several studies have shown that relatively little weight loss. However, ER and escalated to 7.5/46 mg after orlistat leads to moderate weight loss. together, these medications lead to 2 weeks. Patients’ response should Most notably, the XENDOS (Xenical impressive weight loss at quite low be evaluated after 12 weeks at this in the Prevention of Diabetes in doses. dose; those who achieve a weight Obese Subjects) trial showed that In the SEQUEL trial (31), a 2-year loss ≥3% should continue the med- orlistat plus behavioral counsel- evaluation of phentermine-topiramate ication, whereas those not achieving ing led to meaningful weight loss extended-release (ER) versus placebo, this degree of weight loss should through 4 years of therapy, yielding patients treated with the medication increase their dose (to 11.25/69 mg, approximately twice the weight loss lost ~10% of their body weight on followed by 15/92 mg) or discontinue of counseling plus placebo. Among average, compared to <2% in the pla- the medication. The most common 3,305 patients randomized to orlistat cebo group. In the EQUIP trial (32), AEs are paresthesias, dizziness, dys- or placebo, those in the orlistat group patients with severe obesity (BMI geusia, insomnia, constipation, and lost 10.6 kg at 1 year and maintained 2 ≥35 kg/m ) who completed 1 year dry mouth, which are usually mild a loss of 5.8 kg at 4 years, compared of treatment with phentermine-topi- and transient. Approximately 3% of to 6.2 and 3.0 kg, respectively, at 1 ramate ER 15/92 mg lost 14.4% of patients on the lower doses and 9% and 4 years in the placebo group. body weight compared with 2.1% on the highest dose discontinue the Among patients with impaired glu- in the placebo group; 83.5% lost at medication due to an AE (35). cose tolerance at baseline, the risk least 5% of body weight, compared Phentermine-topiramate ER is of progression to type 2 diabetes with 25.5% in the placebo group, classified as a schedule IV controlled was reduced by 45% compared to and 67.7% lost at least 10% of body substance. It is contraindicated the placebo group (37). In patients weight compared with 13.0% of during pregnancy and lactation. with type 2 diabetes, orlistat reduces those completing placebo treatment. However, because topiramate is a A1C by ~0.3–0.5% when used in Sub-analysis in patients with extreme known teratogen (that can cause combination with oral antidiabetes obesity (BMI >45 kg/m2), a popu- cleft lip/palate), pregnancy should be medications or insulin (38–40). lation rarely studied for nonsurgical ruled out before starting the medica- Patients using orlistat should be weight loss interventions, showed that tion, and women of childbearing age counseled on the risk of GI AEs such >50% of patients who completed the should be advised to use contracep- as diarrhea, flatulence, or other GI trial lost >15% of their initial body tion and to have monthly pregnancy complaints, when consuming large weight, and 28% of patients lost testing during use. It is notable, how- amounts of fat while taking the med- >20% of their initial body weight (33). ever, that a large study of >800,000 ication. Although these and other GI Patients with type 2 diabetes in subjects did not find an increased risk AEs are common, it is notable that, the SEQUEL trial maintained a 9% of birth defects (36). Other contra- in the XENDOS trial, far more weight loss over 2 years, compared indications include glaucoma, use of patients in the orlistat group than in to a 2% weight loss in the placebo monoamine oxidase inhibitor med- the placebo group completed the trial

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(52 vs. 34%), suggesting that the side creased food intake of ~250–300 kcal discontinued before completion of effects are reasonably tolerated when per day and moderate weight loss in enrollment because of the identi- the medication is taken as prescribed. the range of 2–4 kg (26,44–46). fication of potentially neutralizing Because orlistat binds to fat-soluble anti-drug antibodies to leptin in pre- Pramlintide , patients are at risk for viously exposed patients (52). is a pancreatic hormone that deficiencies. Thus, they should be As with many GI hormones that is co-secreted by β-cells in a one-to- advised about the need for a nutri- slow gastric emptying and have tionally balanced, reduced-fat, and one ratio with insulin in response to a known receptors in the brain, nausea reduced-calorie diet, and they should meal. Amylin has been shown to slow is a common side effect of pramlin- take a multivitamin that contains gastric emptying, suppress glucagon tide, affecting 28–48% of patients. fat-soluble vitamins separately from secretion, and lower food intake. Slower and longer titration after the medication (at bedtime). Orlistat Importantly, amylin increases energy treatment initiation may minimize should not be used in patients with disposal by preventing compensato- nausea and improve tolerability, and ry decreases of energy expenditure

cholestasis or chronic malabsorp- many patients may not tolerate the FROM RESEARCH TO PRACTICE tion syndromes. Further warnings in weight-reduced individuals (47). full dose but still experience a bene- include coadministration with cyc- Pramlintide is an analog of human ficial response at lower doses. amylin that is approved for patients losporine, which leads to a decrease in the absorption of cyclosporine and with type 1 or type 2 diabetes who Semaglutide is a human GLP-1 an- an increased level of urinary oxalate, have not achieved desired glucose alogue with a similar structure to which may predispose patients to kid- control despite the use of mealtime liraglutide that is currently in de- ney stones (41). insulin. In human studies, pram- lintide, acting as an amylin analog, velopment for the treatment of type Additional Pharmacotherapy slowed gastric emptying, reduced 2 diabetes and obesity and not yet Considerations the postprandial rise in glucagon, approved by the FDA. In a 12-week The medications described above are and increased satiety leading to de- trial in which patients with obesity FDA-approved for obesity treatment creased caloric intake (48). Among received a 1-mg once-weekly subcu- and have been studied explicitly in pa- patients with obesity but without taneous dose of semaglutide, weight tients with type 2 diabetes. We brief- diabetes, a 16-week trial showed im- decreased by 5 kg, energy from ad ly describe below several additional proved appetite control and weight libitum meals was reduced by 24%, options that may be considered for loss 3.7% greater than with placebo. and patients experienced less hun- weight loss in patients with diabetes A 12-month trial found weight loss ger and cravings, better control of but have either not been formally ap- of 6.3–8.0 kg with higher doses of eating, and a lower preference for proved for this purpose or do not have pramlintide (49,50). high-fat, energy-dense foods (53). In sufficient data in patients with type In a meta-analysis of four clinical patients with diabetes randomized to 2 diabetes. We also briefly mention trials with 930 patients with type 2 either semaglutide or insulin, weight several medications in the pipeline diabetes who were being treated with decreased 5.2 kg with semaglutide that may soon be evaluated for obesity insulin, pramlintide treatment led to compared to weight gain with insu- pharmacotherapy approval by FDA. a mean weight loss of 2.6 kg and A1C lin. A1C decreased 1.6%, which was Metformin reduction of 0.3–0.4% compared to twice the A1C reduction of patients treated with insulin (54). Moreover, Metformin has a long history of use in placebo (51). a cardiovascular outcomes trial in patients with diabetes and prediabetes Combination therapy with pram- high-risk patients with type 2 dia- and was one of the first antidiabetes lintide and recombinant leptin has betes showed impressive weight loss, medications that did not increase the been proposed and studied as a novel improvements in glycemic control, risk for weight gain. It is widely con- obesity treatment. In one study, and significantly lower rates of cardio- sidered a first-line medication for type patients were started on pramlint- vascular death and nonfatal myocar- 2 diabetes and for diabetes prevention ide to obtain a target weight loss of dial infarction and stroke in patients (42). Metformin has several mecha- 2–8%, and then recombinant leptin treated with semaglutide compared to nisms of action that are believed to was added. Patients who completed placebo (55). be related to weight loss, including treatment with pramlintide and stimulating pro-opiomelanocortinin leptin had a mean weight loss of Combined Phentermine and neurons in the hypothalamus, im- 12.7% from baseline and were still Sodium–Glucose Cotransporter proving leptin and insulin sensitivity, losing weight at the completion of 2 Inhibitor increasing GLP-1 levels, and modu- the study. Unfortunately, a confir- Phentermine, as described above, lating gut flora (43). Numerous stud- matory clinical trial (clinicaltrials. has been used for decades for short- ies show that metformin leads to de- gov identifier NCT01235741) was term weight loss treatment. Aside

VOLUME 30, NUMBER 4, FALL 2017 255 FROM RESEARCH TO PRACTICE / OBESITY TREATMENT IN DIABETES PATIENTS from two very small studies con- and Orexigen and has received research with improvements in clinical markers. funding from Eisai. Obesity 2016;24:2278–2288 ducted in the 1970s, phentermine 14. Le Roux CW, Astrup A, Fujioka K, et al. as monotherapy has not been ex- References 3 years of liraglutide versus placebo for type plicitly studied in patients with 1. Jensen MD, Ryan DH, Apovian CM, et 2 diabetes risk reduction and weight man- type 2 diabetes (56,57). Sodium– al. 2013 AHA/ACC/TOS guideline for the agement in individuals with prediabetes: glucose cotransporter 2 (SGLT2) management of overweight and obesity a randomised, double-blind trial. Lancet in adults. Circulation 2014;129(Suppl. 2017;389:1399–1409 inhibitors are a newer class of medi- 2):S102–S138 15. Saxenda (liraglutide 3.0 mg) prescrib- cations approved for type 2 diabetes 2. 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