Weight Management in Type 2Diabetes: Current and EmergingApproaches to TreatmentDiabetes Care 2015;38:1161–1172 | DOI: 10.2337/dc14-1630

Diabetes is a growing global health concern, as is obesity. Diabetes and obesity areintrinsically linked: obesity increases the risk of diabetes and also contributes todisease progression and cardiovascular disease. Although the benefits of weightloss in the prevention of diabetes and as a critical component of managing thecondition are well established, weight reduction remains challenging forindividuals with type 2 diabetes due to a host of metabolic and psychologicalfactors. For many patients, lifestyle intervention is not enough to achieve weightloss, and alternative options, such as pharmacotherapy, need to be considered.However, many traditional glucose-loweringmedicationsmay lead toweight gain.This article focuses on the potential of currently available pharmacologicalstrategies and on emerging approaches in development to support the glycemicand weight-loss goals of individuals with type 2 diabetes. Two pharmacotherapytypes are considered: those developed primarily for blood glucose control thathave a favorable effect on body weight and those developed primarily to induceweight loss that have a favorable effect on blood glucose control. Finally, thepotential of combination therapies for the management of obese patients withtype 2 diabetes is discussed.

Obesity and diabetes are intimately linked (1). Obesitydin particular abdominalobesitydis a major driver in the development of diabetes and cardiovascular dis-ease (2), with the increasing prevalence of obesity mirrored by the rising prevalenceof diabetes (3). In addition, obesity and overweight are associated with multiplecomorbidities (4). Weight reduction, therefore, is a key therapeutic goal in both theprevention and management of type 2 diabetes (5).Weight reduction with intensive lifestyle intervention (ILI) has been shown to

reduce the incidence of diabetes by 58% (6). For individuals with diabetes, studies(Look AHEAD [Action for Health in Diabetes], N = 5,145) have shown that a loss of5–10% of body weight can improve fitness, reduce HbA1c levels, improve cardio-vascular disease (CVD) risk factors, and decrease use of diabetes, hypertension, andlipid-lowering medications (7,8). Additional benefits of weight loss include reductionof depression symptoms and remission or reduced severity of obstructive sleep apnea(9,10). Greater clinical improvements are observed with greater weight loss (8).Guidelines recommend lifestyle modifications as the foundation of weight loss.

Although ILI produces clinically beneficial weight loss for many patients, the reality isthat ILI is difficult to achieve andmaintain over the long-term for most patients. Even inan optimal clinical trial setting, such as Look AHEAD, one-third of all patients wereunable to achieve at least 5% weight loss after 1 year (11). Most individuals withdiabetes tend to lose weight over a period of 4–6 months, and lose 4–10% of theirbaseline weight before experiencing a plateau in weight loss, generally followed by a

1Department of Endocrinology, Diabetologyand Metabolism, Antwerp University Hospital,Antwerp, Belgium2Department of Diabetes, Nutrition and Meta-bolic Disorders and Clinical Pharmacology Unit,University of Liege, Liege, Belgium

Corresponding author: Luc Van Gaal, luc.van.gaal@uza.be.

Received 3 July 2014 and accepted 22 February2015.

© 2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Luc Van Gaal1 and Andre Scheen2

Diabetes Care Volume 38, June 2015 1161

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weight regain (12). In Look AHEAD, half ofall patients who lost 5% of their bodyweight after 1 year of ILI regained someor all of their initial weight loss by year 8(11). Long-term weight loss is still difficultto achieve for many patients, and alter-native options, such as pharmacotherapy,should be considered for patients whocannot lose weight with lifestyle modifi-cation alone.Many conventional glucose-lowering

agents commonly result in weight gain(13,14). In addition to antihyperglyce-mic agents, some antipsychotic medica-tions used to treat comorbid psychiatricdisorders and antiepileptic drug deriva-tives used to treat diabetic neuropathymay lead to weight gain (15,16). Meta-bolic, psychological, and behavioral fac-tors also affect the ability of people withdiabetes to lose weight (17,18). In addi-tion, homeostatic control of body weightis regulated by a complex neurohor-monal system that involves a feedbackloop between the brain and peripheraltissues, and perturbations to this systemaffect weight (19). Diet-induced weightloss increases the orexigenic hormonesghrelin and gastric inhibitory/glucose-dependent insulinotropic polypeptide(GIP) and decreases anorexigenic hor-mones leptin, peptide YY (PYY), cholecys-tokinin (CCK), amylin, and glucagon-likepeptide 1 (GLP-1) (20,21). Improvedglycemic control decreases glycosuria,which may impair weight loss. Functionalchanges within the brain also affect

the emotional and cognitive control re-lated to food intake (22). These factorsmean that sustained weight loss can beeven more difficult to achieve for over-weight and obese people with diabetes.

Although improvement of glucose con-trol remains the primary goal in pharma-cological treatment of type 2 diabetes,avoidance of pharmacologically inducedweight gain should also be consideredas a clinically important goal (23). Guide-lines recommend lowering HbA1c to#6.5% (48 mmol/mol) or #7.0% (53mmol/mol), which often necessitates in-sulin escalation or use of combinationtherapies to achieve this goal (5). Whenconsidering combination therapies, clini-cians should remain aware of the weightgain that is often associatedwith diabetesmedications.

The focusof this reviewarticle is to discussthe potential for pharmacotherapiesdthose currently available and those in ei-ther late- or early-stage developmentdtosupport the glycemic andweight loss goalsof people with diabetes. Although we rec-ognize that bariatric surgery may offer apotential treatment solution for some pa-tients (1), this topic will not be consideredin the present review.

WEIGHT GAIN WITHCONVENTIONAL THERAPIES

Many pharmacological agents usedin the treatment of diabetes directlycontribute to weight gain through theirglucose-lowering mechanisms (Table 1)

(13,14). The resultant decrease in bloodglucose levels corresponds with adecrease in glycosuria, a major con-tributing factor to the weight gainobserved in patients treated with con-ventional antihyperglycemic agents.Treatment with certain classes of ther-apies and several baseline patient char-acteristics are predictive of weight gain(Table 2) (24).

Substantial increases in weight havebeen observed in patients treated withinsulin (24). The mechanisms responsi-ble for insulin-induced weight gain arevaried, complex, and partially unknown.Subcutaneous administration bypasseshepatic insulin sensors and leads tophysiologically abnormal levels of insu-lin exposure at peripheral tissues, whichmay disrupt the homeostatic regulationof body weight (25). A comparativestudy showed that subcutaneous deliv-ery of insulin leads to more weight gainthan intraperitoneal delivery (26). Pre-clinical research has shown that insulinhas a role in the central nervous system,where it regulates satiety signals andsuppresses appetite, and it is suggestedthat these functions may be impairedin type 2 diabetes (27). Insulin-inducedhypoglycemia is a further factor; mildhypoglycemia in rats stimulates appe-tite and leads to the increased consump-tion of calories (28). Some patientsparticipate in compensatory overeatingbecause of their fear of hypoglycemia(29). Preclinical data indicate that

Table 1—Antidiabetes therapies associated with weight gain

Drug class Mechanism of action How mechanism of action leads to weight gain

Insulin* (25,27,28,30,32) c Regulates glucose metabolism c Causes hypoglycemia, a potent stimulus to feedc Lowers blood glucose by facilitating peripheral

glucose uptake, primarily by skeletalmuscle and fat

c Perceived risk of hypoglycemia may lead tocompensatory overeating

c Inhibits hepatic glucose productionc Glycemic control reverses the negative energy balance

from glycosuriac Inhibits lipolysisc Inhibits proteolysis

c Insulin is an anabolic hormone and may lead to changesin metabolism that encourage weight gain

c Enhances protein synthesis

Sulfonylurea (24,32) c Stimulates release of insulin from pancreaticb-cells

c Glycemic control reverses the negative energy balancefrom glycosuria

c May also have mild extrapancreatic effectssuch as increasing the sensitivity of peripheraltissues to insulin

c Causes hypoglycemia, a potent stimulus to feed

TZD (32–35) c Decreases insulin resistance in the periphery andin the liver

c Increases adipocyte differentiationc Improves glycemic control

c Redistributes fat (less visceral, more subcutaneous) c Increases plasma volume

*Most insulins are associated with weight gain; however, insulin detemir has been shown to have a reduced weight-gain effect comparedwith otherinsulins (111).

1162 Weight Management in Type 2 Diabetes Diabetes Care Volume 38, June 2015

insulin inhibits lipolysis and promoteslipogenesis (30). Generally, insulin haslimited effects on resting metabolic rate,and it is unlikely that insulin-inducedglucose improvement affects weightthrough changes in basal energy expen-diture (31).Sulfonylureas are insulin secretagogs

that lead to minimal weight gain, com-pared with insulin, through many of thesame mechanisms that occur with insulinuse (24). The insulin secretion after sulfo-nylurea administration lasts for several

hours (32), which increases the risk of hy-poglycemia and can then cause patients toparticipate in compensatory overeating.Reduction of glycosuria is another poten-tial mechanism for weight gain with sulfo-nylureas. Less significant weight-gaineffects have been demonstrated withmeglitinidesdanother class of insulinsecretagogsdpresumably due to theirshorter duration of action and associatedlower risk of hypoglycemia.

Thiazolidinediones (TZDs) enhanceglucose uptake by peripheral tissues

through the activation of peroxisomeproliferator–activated receptor-g (PPAR-g)(33). Activation of PPAR-g promotes pre-adipocyte differentiation into smaller,mature adipocytes. Although thesesmaller adipocytes are more insulin sen-sitive, PPAR-g activation triggers an in-crease in adiponectin secretion fromthese cells, which may also contributeto the insulin-sensitizing effects of TZDs.Increases in appetite andwater retentionmay also be factors that contribute toTZD-associated weight gain (34). Al-though TZDs may lead to an increase infat mass, there is a shift of fat distribu-tion from visceral to subcutaneous adi-pose depots, which may contribute tothe improved hepatic and peripheraltissue sensitivity to insulin observedwith TZD treatment (35).

Among traditional glucose-loweringagents, metformin is the only agentthat can be considered weight neutral(Table 3) and may even give rise to min-imal weight loss (24). The favorable ef-fect onweight observed withmetforminuse may be due to its ability to reduceenergy intake (31).

Table 2—Predictors of weight gain*

Baseline patient characteristicpredictive of weight gain Result

Age c Patients #65 years are more likely to gain weightc Patients .65 years are more likely to lose weight

Ethnicity c Caucasians are more likely to gain weight

Smoking status c Current smokers are more likely to gain weight

Baseline HbA1c c Patients with HbA1c .7.2% (55 mmol/mol) are morelikely to gain weight

c Patients with HbA1c #7.2% (55 mmol/mol) are morelikely to lose weight

*Based on results from van Dieren et al. (24).

Table 3—Antidiabetes therapies that are weight neutral or have weight-loss potential

Drug class Mechanism of actionHow mechanism of action leads to weight

loss/weight neutrality

a-Glucosidase inhibitors (32) c Reversibly inhibits membrane-bound intestinala-glucoside hydrolase enzymes

c Weight loss due to inhibition of carbohydratedigestion and delayed gastric emptying via GLP-1

c Delays glucose absorptionc Increases GLP-1 secretion

Amylin mimetics (32,68) c Induces satiety c Weight loss due to increased satiety and decreasedcaloric intakec Slows gastric emptying

c Decreases hepatic glucose output bysuppressing postprandial secretion of glucagon

Biguanides/metformin (31,32) c Decreases hepatic glucose production c May have an anorectic effectc Decreases glucose productionc Decreases intestinal absorption of glucosec Improves insulin sensitivity by increasing

peripheral glucose uptake and utilization

GLP-1R agonists (98) c Binds and activates the human GLP-1R c Weight loss due to inhibition of gastric emptyingc Enhances glucose-dependent insulin secretion

by the pancreatic b-cellc Decreased calorie ingestion through central

nervous systemc Increases intracellular cAMP leading to insulin

release in the presence of elevated glucoseconcentrations

c Reduced acid secretion

c Increases satiety

DPP-4 inhibitors (98) c Increases and prolongs active incretin levels c Slight reduction in caloric intake compensatingfor reduction in glycosuriac Increases insulin release and decreases

glucagon levels in the circulation in aglucose-dependent manner

SGLT2 inhibitors (55) c Binds to SGLT2 receptors and preventsreabsorption of filtered glucose

c Calorie loss due to increased renal glucoseexcretion

c Lowers renal threshold for glucosec Increases renal glucose excretion

care.diabetesjournals.org Van Gaal and Scheen 1163

ANTIDIABETES THERAPIES WITHWEIGHT-LOSS POTENTIAL

The ability to target poor glycemic controland overweight/obesity simultaneouslyrepresents the ideal approach tomanage-ment of type 2 diabetes (23). Severaltherapies show promise in this area (Ta-ble 3), the most promising of which areconsidered below.

GLP-1 Receptor AgonistsGLP-1 is an endogenous peptide hor-mone produced in the gut in responseto nutrient absorption. The insulino-tropic action of GLP-1 is dependent onglucose (36), which means its activityshould not be associated with hypogly-cemia. GLP-1 exerts its effects throughbinding to the GLP-1 receptor (GLP-1R),which is expressed on pancreatic b-cells(37). GLP-1/GLP-1R signaling increasesb-cell sensitivity to glucose and sup-presses glucagon secretion frompancre-atic a-cells (38,39). In addition, GLP-1exerts extra pancreatic effects, such asreducing hepatic glucose productionand inhibiting gastric emptying (39).GLP-1 action at the hypothalamus pro-motes satiety (40). Because native GLP-1is rapidly inactivated in vivo, GLP-1Ragonists were developed that mimicthe actions of GLP-1 in vivo but are re-sistant to enzymatic degradation and in-activation by dipeptidyl peptidase-4(DPP-4) (41). GLP-1R agonists exert di-verse actions on multiple-target tissuesand lead to a reduction in blood glucoseand in body weight (42,43).Exenatide and liraglutide were the

first two GLP-1R agonists available forthe treatment of type 2 diabetes. In ameta-analysis of randomized controlledtrials (RCTs) with exenatide twice-dailyand once-weekly (trial durations of 12–52 weeks), the overall reduction inHbA1c from baseline was –1.1% (43).However, clinicians should consider theresults from studies of intention-to-treat populations wherever possible,because the weight-loss responses totreatment may differ compared withcompleter populations (44). The once-weekly extended-release formulationof exenatide has consistently demon-strated weight-loss properties acrossmultiple clinical trials (45,46), showinga mean weight loss of –2.67 kg versuscomparator drugs (i.e., exenatide twice-daily, insulin, liraglutide, pioglitazone)(43). Gastrointestinal side effects, such

as nausea and vomiting, although rare,occurred as the most commonly re-ported adverse events (AEs), and mostAEs were of mild-to-moderate severityand transient (46). The weight loss ob-served with exenatide once-weekly wasindependent of these gastrointestinalAEs. Because exenatide stimulates insu-lin secretion in a glucose-dependentmanner, there was a limited occurrenceofmajor andminor hypoglycemia acrossclinical trials (46). Liraglutide (1.8 mgq.d.) has similarly been shown to reduceHbA1c (–1.18%) and weight (–3.24 kg)from baseline at 26 weeks (47,48). Lira-glutide (1.8 mg q.d.) is generally welltolerated, and the most frequently re-ported AEs were gastrointestinal (48).In a 26-week study of liraglutide (1.8mg q.d.) compared with exenatide (10mg b.i.d.), gastrointestinal AEs resolvedmore quickly, and fewer cases of minorhypoglycemia were seen in the liraglu-tide treatment arm (25.5%) than in theexenatide arm (33.6%) (48). Episodes ofminor hypoglycemia were thought to bemainly due to the concomitant medica-tions used (sulfonylureas).

Liraglutide (1.2 mg and 1.8 mg) hasbeen investigated in combinationwith in-sulin, metformin, sulfonylurea, metfor-min plus rosiglitazone, or metforminplus glimepiride (49). Significant reduc-tions in HbA1c over baseline were ob-served within 8 weeks of treatment withliraglutide combination therapy (plusmetformin, glimepiride, or metforminplus rosiglitazone; P, 0.0001 for all com-binations) and were maintained untilweek 26 (50). The addition of liraglutidetometformin or metformin plus rosiglita-zone led toweight reductions, but liraglu-tide plus sulfonylurea treatment wasweight neutral. As with monotherapy,most AEs with liraglutide combinationtherapy were gastrointestinal in nature(51). Major hypoglycemia was reportedonly when liraglutide was used in combi-nation with a sulfonylurea. Similarly, ex-enatide once-weekly has been studied incombination with other antihyperglyce-mic agents with study durations of 24–30 weeks (52). In combination with met-formin, metformin plus sulfonylurea,sulfonylurea with or without TZD, ormetformin plus TZD, treatment with ex-enatide once-weekly led to significantimprovements from baseline in HbA1clevels and body weight with all combina-tions. The most common AEs were

hypoglycemia, nausea, diarrhea, and na-sopharyngitis; however, hypoglycemiawas much lower in patients not on con-comitant sulfonylurea therapy.

Although GLP-1R agonists are gener-ally safe and tolerable, postmarketingreports of acute pancreatitis with GLP-1R agonist use have led to pancreatitisbeing listed under the warnings and pre-cautions in exenatide (twice-daily andonce-weekly) and liraglutide U.S. pre-scribing information (53), and the U.S.Food and Drug Administration (FDA)and the European Medicines Agency(EMA), despite a reassuring positionstatement, continue to investigate thissafety signal (54). The current evidenceregarding a potential link between pan-creatitis and GLP-1R agonist therapieshas been conflicting, and large-scale, on-going, prospective studies will hopefullyaddress questions surrounding a possi-ble association.

Although exenatide and liraglutideare the established GLP-1R agonists inthe U.S. and Europe, lixisenatide and albi-glutide have been approved in Europe,and albiglutide and dulaglutide in theU.S. Other GLP-1R agonists, such assemaglutide and additional exenatideextended-release formulations (i.e., once-monthly and once-yearly formulations)are under clinical development (53).Clinical trial data show that these ther-apies provide reductions in HbA1c levelsand body weight in people with type 2diabetes.

Sodium-Glucose Cotransporter 2InhibitorsAnother new class of antidiabetes ther-apies that show potential for weight loss(although they are not indicated forweight loss per se) are the sodium-glucose cotransporter 2 (SGLT2) in-hibitors (55). In individuals with type 2diabetes, SGLT2 expression is increasedin the renal proximal tubular cells, lead-ing to increased renal glucose reab-sorption, which ultimately aggravateshyperglycemia. SGLT2 inhibitors reduceblood glucose mainly through increasedglycosuria, although indirect mechanismshave also been reported (23,55).

A meta-analysis of 10 RCTs showedthat dapagliflozin (1–50 mg per day) wasassociated with a reduction in baselineHbA1c of –0.53% in patients with type 2diabetes (56). In all studies, dapagliflozinmonotherapy significantly lowered HbA1c

1164 Weight Management in Type 2 Diabetes Diabetes Care Volume 38, June 2015

compared with placebo (P , 0.01). Da-pagliflozin therapy was associatedwith a –1.63-kg reduction in bodyweight and had a favorableweight profilecompared with placebo and metformin.Dapagliflozin-induced body weight hasbeen shown to occur through reductionsin fatmass, visceral fat, and subcutaneousfat (57,58). Although dapagliflozin mono-therapy did not lead to hypoglycemia, theincidence of hypoglycemic events in-creased when dapagliflozin was com-bined with sulfonylureas and insulin(56). Dapagliflozin was also associatedwith an increased risk of mild urinaryand genital tract infections comparedwith placebo.Multiple studies have demonstrated

that canagliflozin (100 and 300 mg q.d.)treatment resulted in significant HbA1creductions compared with placebo or ac-tive comparator (55). After 26weeks, can-agliflozin (100 and 300 mg q.d.) reducedHbA1c levels from baseline by –0.77% and–1.03%, respectively (59). Canagliflozinhas demonstrated dose-related reduc-tions in baseline body weight: –2.2%and –3.3% after 26 weeks and –3.3%and –4.4% after 52 weeks for 100 and300 mg, respectively, in individuals withdiabetes (59,60). Canagliflozin (50–300mg) has also been reported to have bene-ficial weight effects in overweight or obeseindividuals without diabetes (61). Overall,the reported incidence of hypoglycemiaafter 26 weeks with canagliflozin (100and 300 mg) was low (;3%) and similarto the incidence reported with placebo(59), except in patients on background sul-fonylurea (62). The incidence of mild gen-ital mycotic infections and urinary tractinfections (UTIs) was higher with canagli-flozin treatment than with placebo (59).In addition to their effect of reducing

HbA1c and body weight, dapagliflozin andcanagliflozin showed beneficial effects onblood pressure in individuals with type 2diabetes (55). These effects may be due toincreased glucose and sodium excretion inthe urine with SGLT2 inhibitors (23). Al-though increased glucose excretion con-tributes to the weight loss observed withSGLT2 inhibitor treatment, weight reduc-tion is often limited to ,4 kg after even52 weeks of treatment (55). This attenua-tion of weight loss may occur becauseSGLT2 inhibitor–induced glycosuria is ac-companied by compensatory hyperphagia,as demonstrated in animal studies (63) andsuggested by human studies (64,65).

As with monotherapy, SGLT2 inhibi-tors combined with other antihypergly-cemic agents (i.e., metformin, insulin,sulfonylurea, TZD) have been found toreduce HbA1c (dapagliflozin [1–50 mg]:–0.73%; canagliflozin [50–300 mg]:–0.97%) and body weight (overall:–0.59 kg) (55,66). When used in combi-nation therapy, dapagliflozin and cana-gliflozin were associated with anincreased risk of genital tract infections,whereas dapagliflozin was also associ-ated with a modest increased risk ofUTI. However, the number of hypogly-cemic episodes experienced by patientstreated with SGLT2 inhibitors did notdiffer from placebo.

Empagliflozin was approved in 2014by the FDA and EMA to improve glyce-mic control in adults with type 2 diabe-tes, and beneficial effects on HbA1c andweight have been observed with empa-gliflozin asmonotherapy or combinationtherapy (55). A meta-analysis of 10 RCTsfound that mean changes in HbA1c were–0.62% for empagliflozin (10 mg) and–0.66% for empagliflozin (25 mg) com-pared with placebo (67). The incidenceof hypoglycemia with empagliflozintreatment was similar to placebo. Meanweight change from baseline was –1.85and –1.84 kg, with 10- and 25-mg empa-gliflozin doses, respectively, comparedwith placebo. Although an increase inthe incidence of UTIs was not ob-served, the risk of genital tract infec-tion was increased with empagliflozinversus placebo.

Additional SGLT2 inhibitors, such asipragliflozin (approved in Japan) and to-fogliflozin, are in clinical development(55). Initial study data have also shownreductions in HbA1c levels and in bodyweight in people with diabetes.

PramlintidePramlintide acetate is a synthetic analogof human amylin that has been shown toreduce HbA1c and bodyweight in patientswith diabetes (68). It is indicated for themanagement of type 2 diabetes in theU.S. but is not available in Europe. A meta-analysis showed that in patients with type2 diabetes, pramlintide is associatedwith a small but significant reduction inHbA1c (–0.33%, P = 0.0004) that is consis-tent over time (–0.3 to –0.42%; weeks12–52) (69). Pramlintide was associatedwith a significant reduction in weightfrom baseline compared with control

(–2.57 kg, P , 0.00001), although therewas some heterogeneity in the weight-loss data across studies. Pramlintide wasassociated with a higher incidence ofmild-to-moderate, mainly transient, nau-sea than control. Some studies have re-ported the incidence of hypoglycemia(mild to moderate) to be higher withpramlintide versus placebo, whereasothers have reported the converse (69).

ANTIOBESITYPHARMACOTHERAPIES

Although several antiobesity agents havebeenwithdrawn fromthemarket becauseof safety concerns, five are now avail-able in the U.S.dorlistat, lorcaserin,phentermine plus topiramate, naltrexoneplus bupropion (NB), and liraglutide (3.0mg) (Table 4) for chronic weight manage-mentdand one (orlistat) is currentlyavailable in Europe, with liraglutide (3.0mg) and NB having recently received fa-vorable opinions from the Committee forMedicinal Products for HumanUse. Thesepharmacotherapies have been demon-strated to help people with type 2 diabe-tes achieve their weight-loss goals andprovide them with an HbA1c-reducingbenefit (70–73).

OrlistatOrlistat is indicated for obesity manage-ment, including weight loss and weightmaintenance, when used in conjunctionwith a reduced-calorie diet, and reductionof the risk of weight regain after priorweight loss (74). Orlistat functions as anantiobesity agent by inhibiting gastroin-testinal lipases, thereby reducing absorp-tion of dietary fat (75). In a 4-year studyofobese patients without diabetes, orlistat(120 mg t.i.d.) plus lifestyle changes pro-duced moderate weight loss (–5.8 kgfrom baseline vs. –3.0 kg from baselinewith lifestyle changes alone) and resultedin a greater reduction in the incidence oftype 2 diabetes over lifestyle changesalone (6.2% vs. 9.0%, a –37.3% reduction;P = 0.0032) (76).

Orlistat also provided weight-loss ben-efits for patients with diabetes. After 52weeks of orlistat treatment (120mg t.i.d.)combined with a reduced-calorie dietand a weight-management program,obese patients with type 2 diabetesachieved –5.0% reduction in weightfrom baseline versus –1.8% with placebo(P , 0.0001) and –1.1% HbA1c reductionversus –0.2% with placebo (P , 0.0001)

care.diabetesjournals.org Van Gaal and Scheen 1165

(70). Retrospective analysis of sevenstudies of orlistat (120 mg t.i.d.) con-firmed that orlistat-treated patientshad significantly greater decreases inbody weight than the placebo group(–3.77 vs. –1.42 kg, P , 0.0001) andlarger mean decreases in HbA1c than pla-cebo (–0.74% vs. –0.31%, P , 0.0001)(77). For patients with minimal weightloss (,1% of baseline body weight), orli-stat still provided a significantly greaterdecrease in HbA1c than placebo (–0.29%vs. –0.14%, P = 0.008). Potential mecha-nisms to explain the better glycemic con-trol independent of weight loss may bethe improvement of insulin sensitivity,slower/incomplete digestion of dietaryfat, reduction of postprandial plasmanonesterified fatty acids, decreased vis-ceral adipose tissue, and stimulation ofGLP-1 secretion. Orlistat was generallywell tolerated, and gastrointestinal ef-fects were the most commonly reportedAEs, but all events were considered mildor moderate (75,76).

LorcaserinLorcaserin is indicated as an adjunct to areduced-calorie diet and increasedphysical activity for chronic weightmanagement in adults with an initialBMI of$30 kg/m2 (obese) or $27 kg/m2

(overweight) in thepresenceof at least oneweight-related comorbid condition such

as hypertension, dyslipidemia, or type 2diabetes (78). In overweight or obesepatients without diabetes, lorcaserintreatment provided a25.81% reductionfrom baseline body weight after 1 yearversus22.16% with placebo (P, 0.001)(79). Lorcaserin is a selective small-moleculeagonist of the 5-hydroxytryptamine 2Cserotonin receptor (5HT2C), which regu-lates mechanisms related to satiety, in-gestive behavior, glucose tolerance, andhepatic insulin sensitivity (71). Unlikepreviously available antiobesity agents,lorcaserin has a low affinity for the5HT2B receptor subtype, whose activa-tion has been linked to the developmentof valvular heart disease (78).

In a phase 3 study of subjects withtype 2 diabetes treated with metforminor a sulfonylurea, lorcaserin treatmentresulted in mean weight changes of24.5% (twice daily) and 25.0% (oncedaily) compared with 21.5% with pla-cebo at week 52 (71). Participants alsoshowed a significant improvement inglycemic control: HbA1c decreased20.9% and 21.0% from baseline withlorcaserin twice daily and once daily, re-spectively, versus 20.4% with placebo(P , 0.001 for each lorcaserin dose). Itis interesting to note that the reductionsin HbA1c observed with lorcaserin areequal to or higher than those observedwith other antiobesity agents, such as

phentermine plus topiramate and NB,despite a smaller amount of weightloss (71,73,80). This suggests that theantihyperglycemic effect of lorcaserinmay be due to more than weight lossalone. Although hypoglycemia wasslightly more frequent in the lorcaserintreatment groups than in the placebogroup, no severe hypoglycemia wasreported (71). No evidence of in-creased depression, suicidal thoughts,or echocardiogram-detected valvular re-gurgitations were found in the lorcaserintreatment arms. Overall, the most com-mon AEs with lorcaserin were headache,back pain, nasopharyngitis, and nausea.

Phentermine Plus TopiramatePhentermine is a norepinephrine- anddopamine-releasing agent (with a lowereffect with dopamine vs. norepineph-rine) approved for the short-term treat-ment of obesity (80). Topiramate hasseveral pharmacological mechanismsof action and has been assessed as a sin-gle agent for weight reduction in obesepatients with and without type 2 diabe-tes and hypertension (81–83).

A phase 3 study examined the efficacyof the combination of phentermine 7.5mg/topiramate 46.0 mg (PHEN 7.5/TPM46.0) or phentermine 15.0 mg/topiramate92.0 mg (PHEN 15.0/TPM 92.0) onweight loss after 56 weeks (80). Patients

Table 4—Antiobesity therapies currently approved for chronic weight management

Drug Mechanism of action How mechanism of action leads to weight loss

Orlistat (75–77) c Inhibits gastrointestinal and pancreaticlipases

c Prevents absorption of dietary fat

Lorcaserin (71) c Selectively stimulates 5HT2C c Promotes feelings of satiety and regulatesappetite

Phentermine plus topiramate (80,84) c Phentermine acts on hypothalamus tostimulate norepinephrine release fromadrenal glands

c Promotes feelings of satiety and regulatesappetite

c Topiramate acts on multiple cellulartargets as an antiepileptic agent

c The precise mechanisms by whichphentermine plus topiramate produceweight loss is unknown

Naltrexone sustained release plus bupropionsustained release (73,86)

c Increases levels of dopamine and POMCneuronal activity

c Suppresses appetite

c Blocks opioid receptors on POMCneurons, preventing feedback inhibitionof these neurons and further increasingPOMC activity

c Increases secretion of melanocortins, whichmediate anorectic effects and regulateenergy balance

Liraglutide (3.0 mg) (98) c Binds and activates the humanGLP-1R

c Weight loss due to inhibition of gastricemptying

c Enhances glucose-dependent insulinsecretion by the pancreatic b-cell

c Decreases calorie ingestion through centralnervous system

c Increases intracellular cAMP leading toinsulin release in the presence ofelevated glucose concentrations

c Reduces acid secretion

c Increases satiety

1166 Weight Management in Type 2 Diabetes Diabetes Care Volume 38, June 2015

with type 2 diabetes (a subgroup of 388subjects in this study [N = 2,487])achieved weight reductions of 26.8%with PHEN 7.5/TPM 46.0 and 28.8%with PHEN 15.0/TPM 92.0 versus21.9% with placebo (80). For patientswith diabetes, significantly greater re-ductions in HbA1c (–0.4 mmol/L) wereseen with both doses of PHEN/TPMthan with placebo (–0.1 mmol/L). In the108-week extension study, both doses ofPHEN/TPM were associated with signifi-cant and sustained weight loss (–9.0%,P , 0.0001; placebo, –2.0%) (84). PHEN7.5/TPM 46.0 and PHEN 15.0/TPM 92.0led to reductions in HbA1c of –0.4% and–0.2%, respectively, in contrast to theplacebo group (0%) (84). Furthermore,in patients without diabetes, the twodoses of PHEN/TPM led to 54% and76% reductions, respectively, in the pro-gression of subjects to type 2 diabetes,compared with placebo (84).Phentermine plus topiramate was

well tolerated; constipation, paresthe-sia, and dry mouth were the most com-monly reported treatment-emergentAEs (84). However, the FDA has re-quired a Risk Evaluation and MitigationStrategy for phentermine plus topira-mate to educate prescribers and pa-tients on the increased risk of orofacialclefts in infants exposed to phenter-mine plus topiramate during the firsttrimester of pregnancy (85).

Naltrexone Sustained Release PlusBupropion Sustained ReleaseNaltrexone is an opioid receptor antag-onist,whereas bupropion is a norepineph-rine and dopamine reuptake inhibitor(86). The combination increases pro-opiomelanocortin (POMC) neuronal firing,which may have anorectic effects. Thecombination provides greater weightloss thanmonotherapy with either agentor placebo (86), which is an effect con-firmed in overweight/obese patientswith type 2 diabetes, hypertension, orhyperlipidemia (23). In patients withtype 2 diabetes, NB therapy significantlydecreased HbA1c from baseline (–0.6%vs. –0.1% with placebo, P , 0.001)(73). NB-treated patients experiencedsignificantly greater weight reductionfrom baseline than patients in the pla-cebo group (–5.0% vs. –1.8%, P, 0.001).Compared with placebo, treatment withNB was associated with a higherincidence of nausea, constipation, and

vomiting but was not associated with in-creased depression, suicidal thoughts, orhypoglycemia. NB may represent a novelpharmacological approach for the treat-ment of obesity, but further studies arerequired to assess its effects on cardio-vascular outcomes, because systolicblood pressure and pulse rate havebeen found to be higher with NB thanwith placebo (78).

LiraglutideLiraglutide (3.0 mg q.d.) has beenshown to provide weight-reductionbenefits for obese patients; after 20weeks, the placebo-subtracted reduc-tion in weight from baseline with liraglu-tide (3.0 mg) treatment was –4.4 kg (P =0.003) (87). A further study showed thatafter 1 year, subjects who received lira-glutide (3.0 mg) lost –5.8 kg more thanthe placebo group, and after 2 years,pooled participants who completed thestudy on liraglutide (2.4/3.0 mg)maintained a weight loss of –7.8 kg(88). The weight reductions observedwith liraglutide (3.0 mg q.d.) primarilyresult from reductions in fat mass andbody fat percentage (including visceralfat) rather than in lean tissue mass(88,89). Similar to liraglutide (1.8 mg)treatment in patients with diabetes,the most common AEs with liraglutide(3.0 mg) treatment in obese patientswere gastrointestinal and consistentwith the known physiological effectsof GLP-1R agonists (88). Liraglutide(3.0 mg) was approved by the FDA inDecember 2014 for chronic weightmanagement in addition to a reduced-calorie diet and physical activity and isnow undergoing EMA regulatory reviewfor the treatment of obesity.

Safety ConcernsRecent safety concerns about an in-creased risk of major cardiac AEs haveled to market withdrawal of existing an-tiobesity medications or a lack of newtreatments being approved (90). Assess-ment of cardiovascular safety has nowemerged as a major consideration for allnew antiobesity and glucose-loweringagents under current review by theFDA (91). Given the significant need foreffective and safe weight-loss medica-tion, it is perhaps not surprising thatmany more antiobesity therapies are indevelopment, as detailed in the the re-cent article by Rodgers et al. (74); these

newer therapies are also overviewedbelow. The potential of these therapiesin patients with type 2 diabetes, as wellas their cardiovascular safety, will needto be established.

FUTURE PROSPECTS IN CLINICALDEVELOPMENT

As our knowledge of the physiology ofappetite and energy homeostasis im-proves, so too will our ability to under-stand how therapies might be combinedto provide effective weight manage-ment in patients with type 2 diabetes,while also minimizing AEs. Therapiesthat are currently under clinical investi-gation are included in Table 5.

GLP-1R AgonistsSimilar to liraglutide (3.0 mg), exena-tide (10 mg b.i.d.) has been shown toprovide weight-reduction benefits inobese people with or without prediabe-tes (92). After 24 weeks, the placebo-subtracted difference in percentageweight reduction was –3.3% (P ,0.001); exenatide-treated subjects lost–5.1 kg from baseline versus –1.6 kgwith placebo (92). GLP-1R agonists fororal delivery are also currently underinvestigation in preclinical and clinicalstudies (93).

GLP-1R Agonist CombinationTherapiesBecause GLP-1R agonists and basal insu-lins offer complementary pharmaco-logic effects on prandial and fastingglycemia (94), there is growing clinicalinterest in combinations of these twoagents. The combination of exenatide(10 mg b.i.d.) with insulin glargine (ap-proved in the U.S. and Europe) led togreater reductions in HbA1c levels, com-pared with insulin glargine alone(–1.74% vs. –1.04%). Treatment with ex-enatide and insulin glargine led to aweight decrease of –1.8 kg, whereasinsulin glargine alone led to a weightincrease of 1.0 kg. The number of hypo-glycemic events between groups didnot differ significantly.

Liraglutide with insulin degludec(IDegLira)dnow approved in Europedis another combination currently beinginvestigated for the treatment of type2 diabetes. Initial clinical data showthat IDegLira led to greater reductionsin HbA1c (–1.9%) versus insulin deglu-dec (–1.4%) or liraglutide (–1.3%) alone

care.diabetesjournals.org Van Gaal and Scheen 1167

(95). IDegLira also provided a modestweight loss of –0.5 kg from baselineto week 26, a –2.2-kg reduction, com-pared with insulin degludec. IDegLiraalso resulted in significantly fewerhypoglycemic episodes than insulindegludec.A combination of insulin glargine

with lixisenatide has also been investi-gated (96). The addition of lixisenatideto insulin glargine produced greater re-ductions in HbA1c (–0.32%; P, 0.0001)and postprandial hyperglycemia (differ-ence vs. placebo, –3.2 mmol/L; P ,0.0001) compared with insulin glarginealone. The addition of lixisenatide alsohad a favorable effect on body weight(difference vs. placebo –0.89 kg;P = 0.0012). Nausea, vomiting, andsymptomatic hypoglycemia were morecommonly reported with lixisenatidethan with insulin glargine alone.Another potential future option is a

SGLT2 inhibitor/GLP-1R agonist combi-nation (55). The effect of GLP-1R ago-nists on satiety may weaken thecompensatory “overeating” mecha-nism observed with SGLT2 inhibitionand enhance weight loss by SGLT2inhibitors (63).

FUTURE PROSPECTS INPRECLINICAL DEVELOPMENT

Given the role of leptin and amylin incontrolling food intake and energy ex-penditure and the role of incretins(GLP-1) in glucose and weight control(97,98), that many of the therapies inpreclinical development involve thesedifferent hormones is no surprise. Ther-apies that are currently being studied areincluded in Table 5.

Peptide Hormone CombinationTherapiesBecause results with recombinant hu-man leptin ormetreleptin (human leptinanalog) have been disappointing in re-ducing HbA1c levels and weight forobese patients with type 2 diabetes(97), approaches are now focused onleptin-related synthetic peptides, suchas leptin receptor antagonists or leptin-related synthetic peptide analogs ormimetics, and leptin combinationtherapies (99). Initial preclinical andclinical data suggest that leptin andamylindtwo hormones involved in thecontrol of satietydhave additive effects(99). A proof-of-concept RCT in over-weight/obese subjects showed that

combination treatment with pramlintide/metreleptin led to a significant earlier, sus-tained, and greater weight loss than treat-ment with pramlintide or metreleptinalone (100). However, a subsequent trialwas recently halted due to safety con-cerns (101).

Polyethylene glycolated (PEG)-leptin,along with PEG-GLP-1/glucagon, may beanother potential combination therapyoption (102). This combination is an in-triguing potential antihyperglycemic op-tion, because preclinical data indicatethat PEG-leptin and PEG–GLP-1/glucagoncoagonism can restore leptin responsive-ness, which is often reduced when leptinis used alone. Responsiveness to leptin isassociated with decreased food intake,improved glucose tolerance and insulinsensitivity, and with decreased trigly-cerides and lower plasma cholesterolconcentrations. These may be the con-tributing factors that lead to the weightloss observedwith leptin/GLP-1/glucagoncoagonism. These results suggest thatthe pharmacology of leptin in combina-tion with other agents, such as GLP-1Ragonists and amylin analogs, warrants ad-ditional study as a potential antihypergly-cemic therapy that is associated withweight loss.

Another potential therapy is the com-bination of amylin analogs and GLP-1Ragonists. Because both agents can slowgastric emptying, it is possible that thesetwo agents combined may have synergis-tic effects, but the gastrointestinal toler-ance should be evaluated.

Unimolecular Dual- or Triple-IncretinReceptor AgonistsAnother incretin pathway compound inearly-stage development is a peptidethat acts as an agonist at both the GLP-1andGIP receptors (103). A preclinical studyindicates that this dual agonist has the po-tential to enhance the antihyperglycemicand antiobesity effects observed withmonoagonism because it affects adiposity-induced insulin resistance and pancre-atic insulin deficiency. A recent study inrodents found that a newmonomeric pep-tide triagonist, simultaneously acting atthree key metabolically related peptidehormone receptors (GLP-1, GIP, glucagon),provided additional glucose control andweight-reducing benefits over dual coa-gonism (104). Extensive clinical investiga-tion into the efficacy and safety ofcoagonist therapy for the treatment of

Table 5—Future prospects

Drug class/combinationMechanism of action and/or potential for

weight loss

Long-acting basal insulin/GLP-1analog (94,95)

c Acts on receptors for GLP-1c GLP-1 action suppresses appetite, compensating

for a potential insulin-induced weight increase

Pramlintide/metreleptin (100) c Leptin has a pivotal role in energy metabolism byinhibiting food intake and increasing energyexpenditure

c Amylin analogs slow gastric emptying

PEG–leptin/GLP-1/glucagon (102) c Leptin has a pivotal role in energy metabolism byinhibiting food intake and increasing energyexpenditure

c GLP-1/glucagon coagonism restores leptinresponsiveness

c Improves glucose and lipid metabolism

Unimolecular dual-incretinagonist (103)

c Acts on receptors for both GLP-1 and GIPc Lowers postprandial glucose through pancreatic

b-cell insulin secretionc GLP-1 action suppresses appetitec Increases satietyc Decreases food intakec Decreases fat mass

Unimolecular triple-incretinagonist (104)

c Acts on receptors for GLP-1, GIP, and glucagonc Lowers postprandial glucose through pancreatic

b-cell insulin secretionc GLP-1 action suppresses appetitec Decreases food intakec Decreases fat massc Increases energy expenditure

1168 Weight Management in Type 2 Diabetes Diabetes Care Volume 38, June 2015

patientswithobesity and type2diabetes isnow required.

POTENTIAL THERAPEUTICTARGETS

Owing to the complex pathophysiologyof diabetes, additional therapeutic tar-gets are under investigation as potentialagents for glycemic control, many incombination with GLP-1R agonists (105).These possible agentsdsuch as GLP-1R ag-onist/PYY, fibroblast growth factor 21 withor without GLP-1R agonist, and GLP-1R/glucagon coagonistsdmay offer the po-tential to normalize glucose levels but arestill in early development (105,106). PYY isan incretin hormone that also has a role insatiety (106). The associated hypothesisis that PYY may further enhance the glu-cose-lowering and weight-reducing ef-fects of GLP-1R agonists. Fibroblastgrowth factor 21 has broad metaboliceffects, including enhancing insulin sen-sitivity, decreasing triglyceride concen-trations, and inducing weight loss, andthis activity acts additively with GLP-1(107,108). By combining two peptideswith different effects, GLP-1R/glucagoncoagonism may normalize adiposity andglucose tolerance through fat loss, de-creased food intake, and increased en-ergy expenditure, while minimizinghypoglycemic risk (109).Another agent under clinical in-

vestigation as an antiobesity agent isbeloranib, a fumagillin-class methionineaminopeptidase-2 inhibitor that has re-cently completed phase 2 trials (110).Because beloranib treatment is associ-ated with rapid weight loss and improve-ments in lipids (110), beloranib couldlikely also have a beneficial effect in thetreatment of overweight/obese patientswith type 2 diabetes.Further research with all of these tar-

gets is required to determine their suit-ability as antihyperglycemic agents.

CONCLUSIONS

Although lifestyle interventions aimedat prompting weight loss are importantin the management of type 2 diabetesand the benefits of weight reduction areirrefutable, most patients remain over-weight or obese. A shift in the approachto weight management in people withtype 2 diabetes is clearly needed. Healthcare practitioners should consider theweight effects of pharmacotherapy inthe management of patients with

diabetes and consider weight-neutralor weight-reducing medications thatcan complement the patient’s desirefor a healthier lifestyle.

For patients struggling to achieve ormaintain their weight-managementobjectives, concomitant antiobesitymedications can be considered, withthe aim of reducing patients’ bodyweight and glycemic targets. Recent ap-provals of therapies that provide bothglycemic control and weight reduction,and the healthy pipeline of antiobesitymedications, bode well for a widerchoice in the future, with some agentstargeting the central nervous system toreduce food intake and others targetingthe hormonal pathways involved inweight regulation and glucose homeo-stasis. The emergence of a range of phar-macotherapies with varying modes ofaction, coupled with ongoing improve-ments in our knowledge of the physiologyof appetite and energy homeostasis,provides the prospect of a rational com-bination therapy that is both effectiveand tolerable.

Acknowledgments. The authors are gratefulto Dr. Jennifer Chang of AXON Communica-tions for writing assistance in the developmentof the manuscript.Funding. L.V.G. received grant support fromNational Research Funds, Belgium, and alsoreceived grant support for hepatic researchfrom the European Union consortium (Hepadipand Resolve consortia).Duality of Interest. Writing assistance for themanuscript was funded by Novo Nordisk. NovoNordisk was also provided with the opportunityto perform a medical accuracy review. L.V.G. is,or has been, a member of the advisory boardsand speakers bureaus of AstraZeneca/Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly,Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, and Sanofi (in the period 2010–2013). A.S. has received lecture or adviserfees from AstraZeneca/Bristol-Myers Squibb,Boehringer Ingelheim, Eli Lilly, Janssen, MerckSharp & Dohme, Novartis, Novo Nordisk, Sanofi,and Takeda (in the period 2010–2013). A.S. alsoreceived an unrestricted research grant fromNovo Nordisk and Novartis. No other potentialconflicts of interest relevant to this article werereported.AuthorContributions. L.V.G. andA.S. conceivedand designed the manuscript, analyzed and inter-preted the data, drafted and revised the paper,and approved the final version for publication.

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