Weight Beneficial Treatments for Type 2 Diabetes

S P E C I A L

F E A T U R E R e v i e w

Weight Beneficial Treatments for Type 2 Diabetes L. F. Meneghini, D. Orozco-Beltran, K. Khunti, S. Caputo, T. Damçi, A. Liebl, and S. A. Ross Diabetes Research Institute (L.F.M.), University of Miami Miller School of Medicine, Miami, Florida 33136; Cathedra of Family Medicine (D.O.-B.), Clinical Medicine Department, University Miguel Hernandez, 03550 San Juan de Alicante, Spain; Department of Health Sciences (K.K.), University of Leicester, Leicester LE1 7RH, United Kingdom; Servizio di Diabetologia (S.C.), Policlinico Gemelli, Universita` Cattolica, 00168 Rome, Italy; Istanbul University (T.D.), Cerrahpasa Medical Faculty, Department of Endocrinology, Diabetes and Metabolism, 34378 Istanbul, Turkey; Center for Diabetes and Metabolism (A.L.), 83670 Fachklinik Bad Heilbrunn, Germany; and University of Calgary (S.R.), Alberta, Canada AB T2N 1N4

Context: The close link between type 2 diabetes and excess body weight highlights the need to consider the weight effects of different treatment regimens. We examine the impact of “weight-friendly” type 2 diabetes pharmacotherapies and suggest treatment strategies that mitigate weight gain. Evidence Acquisition: Evidence was identified via PubMed search by class and agent and in bibliographies of review articles, with final articles for inclusion selected by author consensus. Evidence Synthesis: Substantial evidence confirms the weight benefits of metformin and shows that, of the newer available agents, glucagon-like peptide-1 (GLP-1) agonists and amylin analogs promote weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors and bile acid sequestrants are weight-neutral. Liraglutide and exenatide appear to have similar effects on weight; however, recent research suggests a potentially greater effect of liraglutide on glycemic control compared to exenatide, when used as a second-line therapy. Mounting evidence suggests that insulin detemir may provide the most favorable weight benefits of available insulins. Conclusions: Weight-beneficial agents should be considered in patients, particularly obese patients, who fail to reach glycemic targets on metformin therapy. We propose the following treatment choices based on potential weight benefit and blood glucose increment: long-acting GLP-1 agonists (liraglutide), DPP-4 inhibitors, bile acid sequestrants, amylin analogs, and basal insulin for patients with elevated fasting plasma glucose; and short-acting (exenatide) or long-acting GLP-1 agonists, amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants for patients with elevated postprandial glucose. The weight-sparing effects of insulin detemir, notably in patients with high body mass index, should also be considered when initiating insulin therapy. (J Clin Endocrinol Metab 96: 3337–3353, 2011)

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ntil recently, only two drugs available for type 2 diabetes (T2D) treatment could be considered weight-neutral: metformin and acarbose (1). Although weight is a modifiable risk factor and an integral part of T2D management, weight control is particularly challenging when treatments such as sulfonylureas (SU), thiazolidinediones (TZD), and/or insulin are introduced to achieve glycemic targets. In addition, both

weight gain and weight loss can be self-perpetuating. Beyond the psychological implications, weight gain increases insulin resistance, which in turn leads to escalating insulin requirements and eventual intensification of therapy (2). Because these effects could be reversible with adequate weight reduction (3), treatment decisions should ideally incorporate weight-friendly strategies in the management plan.

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-1074 Received March 23, 2011. Accepted August 10, 2011. First Published Online September 7, 2011

Abbreviations: BMI, Body mass index; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; OAD, oral antidiabetic agent; PPG, postprandial glucose; RCT, randomized control trial; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione.

J Clin Endocrinol Metab, November 2011, 96(11):3337–3353

jcem.endojournals.org

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Weight Beneficial Treatments for Type 2 Diabetes

An increasing number of antidiabetic agents that are not associated with weight gain have become available in recent years. Some agents, such as the glucagon-like peptide-1 (GLP-1) agonists (exenatide, liraglutide), metformin, and amylin analogs (pramlintide), are associated with weight loss. Other agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, saxagliptin, vildagliptin), bile acid sequestrants (colesevelam), and ␣-glucosidase (carbohydrate) inhibitors (acarbose, miglitol, voglibose), are weight-neutral. In addition, basal insulin analogs, such as insulin detemir and glargine, appear to have differential effects on weight gain relative to human insulin preparations, biphasic, and prandial insulin regimens. In this focused review article, we examine the effects of “weight-friendly” pharmacotherapies in the treatment cascade of T2D and suggest glucose-lowering strategies that mitigate weight gain and its potential negative impact on glycemic control, cardiovascular disease, and other health outcomes.

Methods This review includes a comprehensive selection of representative clinical trials covering all agents with data available to report weight change in T2D. The literature search for articles to include in this review started with the bibliographies of several relevant review articles (4 – 6) for reports of T2D clinical trials reporting weight as an outcome. Articles deemed appropriate were included, and additional references were identified using the “related citations” search option on PubMed. This was judged by the authors to be a preferable approach to starting the literature review with a term search on PubMed. In particular, the authors were concerned that using the search term “weight” might produce results only for agents showing consistent weight benefits, which could lead to biased results. Alternatively, excluding the search term “weight” would have likely produced an unworkably large number of articles, with only a minor proportion of relevant trials for inclusion in this paper. Additional PubMed searches were performed by class or agent using the following search terms (‘All fields’): “incretin,” “DPP4 inhibitor,” “biguanide,” “amylin analog,” “bile acid sequestrant,” “␣ glucosidase inhibitors,” “colesevelam,” “acarbose,” or “insulin,” limited to clinical trials in type 2 diabetes [MeSH term]. At each stage of the search, each author provided expert opinion on which articles to include or exclude; this was done to prevent bias. Generally, articles summarizing nonrandomized studies were excluded in cases where insulin was evaluated in combination with regimens no longer commonly prescribed; these decisions were made based on author expert opinion regarding clinical relevance. The final selection of studies considered suitable for inclusion was based on author consensus.

Results Pharmacological treatments in T2D providing weight benefit: clinical trials Metformin monotherapy and combination therapy The biguanide insulin-sensitizing agent, metformin, is thought to decrease hepatic glucose production and en-


hance peripheral tissue sensitivity to insulin. Metformin, along with lifestyle intervention, typically achieves reduction in hemoglobin A1c (HbA1c) of approximately 1.0% (7) and is the recommended first-line treatment of T2D in all current management guidelines (8 –10). Metformin is weight-neutral, or associated with modest weight loss, particularly in obese patients (11). The weight benefits of metformin monotherapy have been demonstrated in several trials reporting a 0.6- to 2.9-kg weight reduction in treatment-naive patients followed for 6 months to 5 yr; most of this weight loss occurred within the first year (12–15). Often, this outcome was compared with weight increases in the comparator groups in these trials: rosiglitazone (⫹4.8 kg), glyburide (⫹1.6 kg) (13), and pioglitazone (⫹1.9 kg) (14). In addition, switching previously diet- and glyburide-treated patients to metformin resulted in a 3.8-kg weight loss, whereas patients continuing glyburide monotherapy did not experience any significant weight change (12). Research also indicates that combination treatment with metformin appears to mitigate, to some degree, the weight gain associated with SU and TZD therapy (12, 15). A meta-analysis was recently published that comprises randomized controlled trials (RCT) of noninsulin antidiabetic therapies added to metformin in T2D patients with inadequate response to maximized metformin therapy (16). The meta-analysis reports statistically significant weight gain in patients adding SU (⫹2.1 kg), glinides (⫹1.8 kg), and TZD (⫹2.1 kg) to metformin. Only the addition of GLP-1 analogs resulted in further significant weight loss (⫺1.7 kg), whereas DPP-4 and ␣-glucosidase inhibitors were weight-neutral. GLP-1 analogs were associated with the largest simultaneous reductions in HbA1c (⫺0.97%), compared with ␣-glucosidase inhibitors (⫺0.64%), glinides (⫺0.65%), DPP-4 inhibitors (⫺0.78%), SU (⫺0.79%), and TZD (⫺0.85%). Thus, although a number of trials investigating the effects of combination therapy with metformin report weight benefits (17–21), the only second-line agents associated with additional weight loss in patients already receiving maximally tolerated metformin doses were the GLP-1 analogs. Weight reduction with GLP-1 analogs has also been shown to be sustainable in the long term. In an 82-wk extension trial, exenatide addition to metformin resulted in a final HbA1c reduction of 1.3% and mean weight loss of 5.3 kg in the 92 of 150 (61%) completers (18). In an open-label single-arm extension study of exenatide, glycemic control and weight benefits were sustained for up to 3.5 yr (22). Weight reduction has also been demonstrated for patients adding GLP-1 analogs as third-line agents, both for patients previously treated with metformin/SU combina-


tion therapy (22–26) and those treated with metformin/ TZD combination therapy (27). A single trial comparing the addition of the two available GLP-1 analogs, liraglutide or exenatide, to existing treatment with metformin and/or SU showed that liraglutide achieved greater HbA1c reduction (HbA1c, ⫺1.12 vs. ⫺0.79%, respectively) with similar weight benefits (⫺3.2 vs. ⫺2.9 kg) relative to exenatide (23). When compared with insulin glargine, liraglutide in combination with metformin and SU achieved improved glycemic control (HbA1c, ⫺1.33 vs. ⫺1.09%) and weight benefit (⫺1.8 vs. ⫹1.6 kg) (28). Waist circumference also decreased with liraglutide (⫺1.50 cm) compared with an increase with insulin glargine (⫹0.89 cm). Other studies comparing exenatide with insulin support the aforementioned GLP-1 weight benefits and report comparable HbA1c reductions, although it is important to note that insulin dosing in most studies comparing GLP-1 agonists to insulin replacement might have been suboptimal (25, 28 –30). The study by Barnett et al. (29) compared insulin glargine with exenatide in patients with T2D receiving a single additional oral antidiabetic agent. After 16 wk, both groups achieved similar HbA1c reductions (⫺1.36%), but patients receiving exenatide lost weight (mean, ⫺4.2 kg), whereas patients receiving insulin glargine gained weight (mean, 3.3 kg). In a 26-wk study comparing exenatide and glargine in patients (n ⫽ 551) with inadequately controlled T2D, Heine et al. (30) observed body weight increases of 1.8 kg in the insulin glargine group compared with a 2.3-kg decrease in the exenatide group (a difference of 4.1 kg), in association with similar reductions in HbA1c (⫺1.11%). Lastly, Nauck et al. (25) compared exenatide vs. biphasic insulin aspart in a 52-wk, open-label study. Again, both treatments were associated with similar HbA1c reductions (exenatide, ⫺1.04%; biphasic insulin aspart, ⫺0.89%), and patients taking exenatide experienced weight loss compared with weight gain in the insulin group (between-group difference, ⫺5.1 kg). Of note is that, in all of these studies comparing a GLP-1 agonist to insulin therapy, the final insulin doses were approximately 0.25 U/kg 䡠 d, which is an amount that is substantially lower than what has been observed in prior insulin treatto-target studies. This was likely due to concerns about hypoglycemia and weight gain often associated with insulin use. If patients receiving insulin in these studies had been given higher doses, HbA1c outcomes in the insulin group may have been improved. However, higher doses of insulin, for example, in the Veteran Affairs Diabetes Trial, have been associated with increased weight gain as well as hypoglycemia, a predictor of cardiovascular mortality and macrovascular outcomes (31, 32). A slightly higher, but


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not intensive, dose of insulin may result in improved HbA1c with fewer complications; however, the expected accompanying increase in weight gain or cardiovascular risk is unknown. Combination therapy with metformin has also been employed to reduce the degree of weight gain associated with insulin. A meta-analysis (33) assessing three clinical trials using NPH insulin (34, 35) or insulin glargine (36) indicated that addition of metformin to basal or basal/ bolus insulin resulted in statistically significantly less weight gain compared with insulin monotherapy. Similar results have been reported elsewhere (37). Individual RCT have demonstrated that, in combination with metformin, both insulin glargine and insulin detemir are associated with less weight gain relative to NPH insulin (⫹2.6 vs. ⫹3.5 kg, and ⫹0.4 vs. ⫹1.9 kg, respectively) (38, 39) Furthermore, initiation with basal insulin is generally associated with less weight gain relative to insulin regimens comprising prandial insulin coverage (40 – 43). However, combining metformin with a rapid-acting insulin preparation can still provide significant weight benefit. Lund et al. (44) demonstrated that metformin combined with biphasic insulin aspart resulted in significantly less weight gain compared with repaglinide plus the same insulin regimen (2.2 vs. 4.7 kg, respectively). Other non-insulin monotherapy and combination therapy GLP-1 receptor agonists. Exenatide, based on the reptilian GLP-1 homolog exendin-4, is administered sc, twice daily, 0 to 60 min before meals (45). Administered as monotherapy, exenatide is associated with weight loss of approximately 3 kg over 24 wk of treatment, with Hb1Ac reductions of 0.7 to 0.9% (46). When added to SU, exenatide achieved dose-dependent weight loss (up to ⫺1.6 kg) and HbA1c reductions (up to ⫺0.86%) (47). In addition, a recent meta-analysis by Fakhoury et al. (48) confirmed a positive association between exenatide and weight loss. Liraglutide is a human GLP-1 analog with high homology to native human GLP-1 (97 vs. 53% for exenatide), a long half-life (up to 13 h vs. 2 to 4 h for exenatide) (49), and low immunogenicity (23, 27, 28, 50, 51). In recent T2D trials, liraglutide monotherapy showed weight loss, compared with weight gain seen with the SU glimepiride (50) and glibenclamide (52). Liraglutide monotherapy (1.2- and 1.8-mg doses) was associated with dose-dependent reductions in mean body weight (⫺1.9 and ⫺2.3 kg, respectively) compared with a mean weight gain of approximately ⫹1.0 kg in patients treated with glimepiride (50). Similarly, liraglutide (0.9-mg dose) achieved weight loss of ⫺0.9 kg compared with weight gain of ⫹1.0 kg

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with glibenclamide (P ⬍ 0.0001) in Japanese subjects (52). Additionally, a meta-analysis of 38 RCT comparing incretin therapies for T2D to placebo found that liraglutide had the greatest HbA1c-reducing effect (⫺1.03%), compared with exenatide (⫺0.75%), sitagliptin (⫺0.79%), and vildagliptin (⫺0.67%) (48). In combination with SU, liraglutide has demonstrated greater improvements in HbA1c and weight control than add-on rosiglitazone or placebo (51). In addition, liraglutide in combination with metformin and SU has demonstrated superior HbA1c reductions (estimated treatment difference, ⫺0.33%) and greater weight reductions (⫺3.24 vs. ⫺2.87 kg) relative to exenatide (23) (Table 1). Interestingly, although overall improvement in HbA1c was greater in the group receiving liraglutide, there were significant differences in fasting plasma glucose (FPG) and postprandial glucose (PPG) in the two groups. Whereas patients receiving liraglutide achieved significantly reduced FPG levels compared with those receiving exenatide (⫺29 vs. ⫺11 mg/dl; P ⬍ 0.0001), patients receiving exenatide achieved significantly reduced breakfast and dinner PPG increments compared with those receiving liraglutide (estimated treatment difference of 24 mg/dl after breakfast, P ⬍ 0.0001; and 18 mg/dl after dinner, P ⫽ 0.0005) (23). DPP-4 inhibitors. Saxagliptin and sitagliptin monotherapy have demonstrated reductions in HbA1c of 0.4 – 0.9%, respectively, and weight changes not significantly different from placebo (20, 53, 54). In combination with pioglitazone, sitagliptin significantly reduced HbA1c compared with placebo (⫺0.9 vs. ⫺0.2%, respectively), without significant weight gain (55). In combination with a TZD (either pioglitazone or rosiglitazone), saxagliptin (2.5 and 5 mg) significantly reduced HbA1c compared with TZD alone (⫺0.66, ⫺0.94 vs. ⫺0.3%, respectively), with small weight increases in all study groups (56). In combination with glimepiride or glimepiride plus metformin, sitagliptin produced significant reductions in HbA1c vs. either treatment alone (⫺0.45 vs. 0.28%, respectively), although weight gain, while moderate, was significantly higher with sitagliptin (⫹0.8 kg for sitagliptin vs. ⫺0.4 kg for placebo; P ⬍ 0.001) (57). In combination with glyburide, saxagliptin (2.5 and 5 mg) significantly reduced HbA1c vs. glyburide up-titration alone (⫺0.54, ⫺0.64, vs. 0.08%, respectively). In this study, mean body weight increased in all groups but was highest in patients receiving saxagliptin (0.7 to 0.8 kg for saxagliptin vs. 0.3 kg for up-titrated glyburide alone) (58). Study investigators speculated that the modest weight gain observed with DPP-4 inhibitors in combination therapy


scenarios might have been due to decreased glucosuria (58) or background treatment with an SU or TZD (56, 57).

␣-Glucosidase inhibitors. Systematic review and metaanalyses have shown that acarbose is weight-neutral (1, 59). Results from 16 RCT showed a weighted mean absolute difference in body weight between acarbose and placebo of ⫺0.1 kg (1). Similarly, a meta-analysis of 41 RCT of ␣-glucosidase inhibitors (acarbose, 30; miglitol, seven; voglibose, one; and various, three) confirmed that these agents had no statistically significant effect on body weight. Both acarbose and miglitol were associated with significant reductions in HbA1c of between 0.7 and 0.8% relative to placebo (59). Several clinical trials have demonstrated an additive effect of acarbose in patients treated with a SU, resulting in significant reductions in HbA1c of between 0.5 and 1.3% (60). Bile acid sequestrants. The bile acid sequestrant colesevelam has demonstrated significant placebo-corrected reductions in HbA1c (range, 0.32 to 0.41%) in combination with metformin (61), SU (62), or insulin (63) in 1018 subjects with baseline HbA1c of 7.5 to 9.5% (64). In a 26-wk trial in subjects already receiving metformin with or without other oral antidiabetic agents (OAD), the addition of colesevelam achieved weight loss similar to placebo (⫺0.5 vs. ⫺0.3 kg) (61). In combination with SU, body weight was unchanged with colesevelam, compared with a reduction of 0.4 kg with placebo (62). In patients already treated with insulin with or without OAD, body weight increased by 0.6 kg with colesevelam and 0.2 kg with placebo (63). Amylin analogs. Most published trials of amylin analogs have investigated the addition of pramlintide to existing insulin treatment. A dose-finding study with pramlintide added to a variety of insulin regimens showed weight loss (⫺1.4 kg) across the active treatment groups (65), with HbA1c reductions of 0.62 to 0.68% in the 120-␮g dose group. No weight gain was seen when pramlintide was added to the basal insulins glargine or detemir. Additionally, pramlintide lowered FPG similarly to rapid-acting insulin analogs, without the weight gain associated with insulin (66). A single phase 2 study investigating the use of pramlintide in obese subjects reported a placebo-corrected mean weight reduction of ⫺3.6 kg (67). Pramlintide is currently approved only for use in patients already taking prandial insulin. Insulin Insulin remains the most effective agent to control serum glucose, especially in the setting of decreased endog-



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TABLE 1. Weight change in clinical trials in patients with T2D: antidiabetic agents associated with weight loss or neutrality

Study design Metformin-based therapy Monotherapy 29-wk R, PG, DB, MC, controlled (12)

32-wk R, DB, MC, PG (15)

4-yr (median) R, DB, MC, controlled (13) 1-yr R, DB, PG (14) GLP-agonists ⫹ MET 30-wk triple-blind, PC, MC (17) 82-wk MC, extension study (18) to DeFronzo, 2005 (17) 24-wk R, OL, PG, MC; n ⫽ 372 (26)

30-wk PC, DB, MC (24)

52-wk OL, MC, noninferiority trial (25) 30-wk R, MC, noninferiority study (104)

22-wk comparator-controlled, OL, MC, extension (105) to Drucker et al., 2008 (104) (52 wk total)

26-wk R, DB, double-dummy, active-control, PG, MC, subset analysis (106) 26-wk R, OL, DB, activecontrol, PG, MC (107) DPP-4 inhibitors ⫹ MET 24-wk R, DB, PC, PG, MC (20) 24-wk R, DB, PC, MC (21)

% HbA1c, decrease from baseline

Mean ⌬ weight (kg)

⌬ Weight P

Regimen by arm

n

Mean BMI (kg/m2)

MET (850 –2550 mg/d) initial pharmacotherapy vs. PLA MET (500 –2500 mg/d) after GLY vs. MET ⫹ GLY vs. GLY MET (500-3000 mg/d) as initial pharmacotherapy or after OAD vs. MET ⫹ ROS MET (500 mg/d to 1000 mg BID) initial pharmacotherapy vs. ROS vs. GLY MET (850 mg up to TID) initial pharmacotherapy vs. PIO

143

29.9

1.4

⫺0.6

NS

210

29.4

0.4

⫺3.8

c

272

30.6

0.38

⫺1.9

b

1454

32.1

Increase 0.14/yr

⫺2.9 over 5 yr

597

31.4

1.50

⫺2.5

b

110

34

0.4

⫺1.6

a

113 150 (92)

34 34

0.78 1.3

⫺2.8 ⫺5.3

a

124

34.2

1.75

⫺1.96

245

33

0.6

⫺1.6

a

241 (199)

34

0.8

⫺1.6

a

253

30.6

1.04

⫺2.5

b

148

35

1.9

⫺3.7

NS, BID vs. QD

147

35

1.5

⫺3.6

128

35

2.0

⫺4.1

130

35

2.0

⫺4.5

83

31.5

1.3

63

30.9

1.4

221 (218) 225 (221) 219 (219)

33.1 32.6 32.6

1.5 1.24 0.90

361 564

32.1–32.4 31.1–31.7

1.4 –1.9 0.59 – 0.69

In patients failing MET, exenatide 5 ␮g BID ⫹ MET Exenatide 10 ␮g BID ⫹ MET In patients failing MET, exenatide 5 ␮g BID ⫹ MET for 4 wk, then 10 ␮g BID ⫹ MET Exenatide, 5 ␮g BID for 4 wk and 10 ␮g BID thereafter in patients failing MET/SU vs. BIAsp 30 QD ⫹ SU/MET vs. BIAsp 30 BID ⫹ SU/MET In patients failing MET/SU, exenatide (5 ␮g BID) ⫹ MET/SU Exenatide (5 ␮g, then 10 ␮g BID) ⫹ MET/SU Exenatide (5 ␮g BID for 4 wk, then 10 ␮g BID) ⫹ MET/ SU, vs. BIAsp Exenatide (long-acting release formulation, 2 mg QW) Exenatide, 10 ␮g BID, in drug-naive or patients on one or more MET, SU, TZD Exenatide (long-acting release formulation, 2 mg QW) Patients continuing on exenatide 2 mg QW Patients switching from exenatide BID to 2 mg QW Liraglutide 1.8 mg QD ⫹ MET Liraglutide 1.8 mg QD ⫹ GLI Liraglutide 1.8 mg QD ⫹ MET Liraglutide 1.2 mg QD ⫹ MET Sitagliptin 100 mg QD ⫹ MET Sitagliptin (50 mg) ⫹ MET Saxagliptin (2.5, 5, and 10 mg) ⫹ MET

Approximately ⫺2.2 Approximately ⫺0.1 ⫺3.38 ⫺2.86 ⫺0.96 ⫺0.6 to ⫺1.3 ⫺1.43 to ⫺0.53

b

c

NR

NS vs. switch

b

b b b

c

NR (Continued)

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TABLE 1. Continued

Study design Insulin ⫹ MET 9-month R, OL, PG, MC trial (38) 24-wk R, OL, PG, MC; n ⫽ 315 (41) 24-wk R, OL, PG, MC; n ⫽ 315 (41) 14-wk MC, R, 2 ⫻ 2 factorial trial of OL insulin glargine and PC MET; n ⫽ 500 (37) 32-wk MC, R, OL, prospective, crossover (108) 32-wk MC, OL, crossover study (40) 26-wk R, MC, active-control trial (39) 24-wk R, MC, OL, PG (109) 12-month R, DB, doubledummy, PG, single center; n ⫽ 101 (44) 34-wk R, PG; n ⫽ 200 (110) GLP-1 agonists Exenatide 24-wk R, DB, PC, PG, MC (46) 26-wk R, OL, PG, MC (23)

30-wk triple-blind, PC, MC (47) ⱖ3-yr MC extension study (22) to 3 PC trials (17, 24, 47) Liraglutide 14-wk R, DB, PC, PG, MC (111)

52-wk R, DB, double-dummy, active-control, PG, MC trial (50) 26-wk R, DB, double-dummy, active-control, PG, MC trial (51) 26-wk R, PG, PC, OL, MC (28)

26-wk DB, PC, PG trial (27) 26-wk R, OL, PG, active-control, MC (23)



n

Mean BMI (kg/m2)

MET ⫹ glargine MET ⫹ NPH MET ⫹ glargine

61 49 158

31.3 32.0 32.0

1.99 2.1 0.4

⫹2.6 ⫹3.5 ⫺0.5

MET ⫹ prandial lispro, TID

157

32.1

0.7

⫹1.2

MET ⫹ glargine

124

35.6

53

31.7

0.93

⫹1.6

52

30.1

1.32

⫹2.3

47 50

29.6 29.4

0.42 1.00

⫹0.06 ⫹0.82

b

125 146 187 177 52

31.6 32.0 29.6 29.5 24.5

1.1 1.0 1.31 164 1.42

⫹0.4 ⫹1.9 ⫹2.1 ⫹1.4 ⫹2.22

b

93

33.4

1.5

⫹4.6

b

77 78 231

32 31 32.9

0.7 0.9 0.79

⫺2.8 ⫺3.1 ⫺2.87

a

NS vs. comparator

125

33

0.46

⫺0.9

NS vs. placebo

129

33

0.86

⫺1.6

a

217

33.5

1.0

⫺5.3

c

226 45 46 45 44

24.26 23.93 23.74 23.59

0.72 1.07 1.50 1.67

⫺0.05 ⫹0.13 ⫺0.10 ⫺0.48

251 247 (246) 695

33.2 32.8 29.8 –30.0

232 (230)

30.4

1.33

356

33.2–33.5

1.5

⫺1.0 to ⫺2.0

233

32.9

1.12

⫺3.24

Regimen by arm

MET ⫹ glargine , then biphasic insulin lispro MET ⫹ biphasic insulin lispro then glargine MET ⫹ glargine then NPH/lispro MET ⫹ NPH/lispro 75/2, twice daily, then glargine MET ⫹ detemir ⫹ aspart MET ⫹ NPH ⫹ aspart MET ⫹ SU ⫹ lispro 70/30, BID MET ⫹ SU ⫹ glargine MET ⫹ biphasic insulin aspart, BID MET ⫹ PIO ⫹ biphasic insulin aspart, BID As initial pharmacotherapy: Exenatide 5 ␮g BID Exenatide 10 ␮g BID In patients failing MET, SU, or both, exenatide 10 ␮g BID ⫹ MET or SU or both, vs. liraglutide In patients failing SU, exenatide 5 ␮g BID ⫹ SU vs. SU/PLA Exenatide 5, then 10 ␮g BID ⫹ SU vs. SU/PLA In patients failing MET and/or SU, exenatide 5 ␮g BID for 4 wk, then 10 ␮g BID ⫹ MET and/or SU Liraglutide after diet or OAD: 0.1 mg/d 0.3 mg/d Maximum, 0.6 mg/d Maximum, 0.9 mg/d Liraglutide as initial pharmacotherapy vs. GLI: 1.2 mg QD 1.8 mg QD Liraglutide (0.6, 1.2, or 1.8 mg QD) ⫹ GLI vs. rosiglitazone Liraglutide (1.8 mg QD) ⫹ MET/ GLI vs. insulin glargine ⫹ MET/GLI vs. placebo Liraglutide (1.2 or 1.8 mg QD) ⫹ MET/TZD In patients failing MET, SU, or both, liraglutide 1.8 mg QD ⫹ MET or SU or both vs. exenatide

HbA1c near normalized

0.84 1.14 0.6 –1.1 (dose dependent)

⫺0.73

⫺1.85,e ⫺3.24f ⫺2.26,e ⫺3.39f ⫺0.2 to ⫹0.7 (weight gain seen at lower doses) ⫺1.8

⌬ Weight P NS vs. comparator b

b

a,b

b

NS vs. comparator b

a

NS

b

a,b

a,b

a

NS vs. comparator

(Continued)



3343

TABLE 1. Continued

Study design DPP-4 inhibitors Sitagliptin 24-wk DB, PC, R, MC (53)

Saxagliptin 24-wk DB, PC, R, PG, MC (54)

Bile acid sequestrants Colesevelam 26-wk R, DB, PC, PG, MC (61) 26-wk R, DB, PC, PG, MC (62) 16-wk R, DB, PC, PG, MC (63)

Amylin analogs 24-wk R, OL, PG, MC study; n ⫽ 113 (66)

52-wk R, DB, PC, PG, MC; n ⫽ 656 (65)

n

Mean BMI (kg/m2)



Sitagliptin 100 mg QD 200 mg QD

238 250

NR NR

0.61d 0.76d

⫺0.2 ⫺0.1

a

Saxagliptin 2.5 mg QD 5 mg QD 10 mg QD

102 106 98

31.9 32.2 31.7

0.43 0.46 0.54

⫺1.2 ⫺0.1 ⫺0.1

a

Colesevelam (3.75 g/d) ⫹ MET or MET/OAD Colesevelam (3.75 g/d) ⫹ SU Colesevelam (3.75 g/d) ⫹ insulin (various) with or without OAD

159

33.9

0.4

⫺0.5

NR

230 147

33.1 34.9

0.32 0.41

⫺0.01 ⫹0.6

NR NS vs. baseline

Glargine or detemir, once or twice daily, with or without OAD ⫹ mealtime pramlintide Pramlintide (90 ␮g BID) ⫹ insulin regimen (any) Pramlintide (120 ␮g BID) ⫹ insulin regimen (any)

57

36

1.1d

0.0

171

33.8

0.35

⫺0.5

a

166

34.1

0.62

⫺1.4

a

Regimen by arm

⌬ Weight P

a a

Endpoint analysis was carried out on intent to treat (ITT) population unless otherwise indicated. Where two n values are presented, ITT values are followed by the analysis set (numbers exposed or numbers completed). BID, Twice daily; DB, double blind; GLI, glimepiride; MC, multicenter; MET, metformin; NS, not significant; OL, open label; PG, parallel group; PLA, placebo; PIO, pioglitazone; QD, once daily; R, randomized; TID, three times daily; PC, placebo controlled; QW, once weekly; GLY, glyburide; BIAsp, biphasic insulin aspart; NR, not reported. a

P ⬍ 0.05 vs. placebo.

b

P ⬍ 0.05 vs. comparator.

c

P ⬍ 0.05 vs. baseline.

d

Least squares mean values.

e

No or ⱕ 7 d nausea.

f

⬎ 7 d nausea.

enous insulin secretion, with reductions in HbA1c of 1.5 to 3.5% achievable with insulin alone (68). However, multiple large studies typically show weight gain associated with insulin use, either as monotherapy or in combination with OAD (Table 2). Factors implicated in insulin-associated weight gain include interactions between improved glycemic control and decreased glycosuria (69), suppression of hepatic glucose production (70, 71), anabolic effects increasing fat deposition (3), and increased food intake from defensive snacking to preempt hypoglycemia. Patients most at risk for insulin-associated weight gain are those with high baseline glycemia; it has been suggested that this weight gain may be beneficial to some degree because it may be related to a reduced basal metabolic rate and glucosuria. However, patients on both metformin and insulin may experience similar benefit with decreased glucose, without excessive additional weight gain (72). Some weight benefits have been seen with the basal insulin analogs, relative to biphasic and prandial insulin analog reg-

imens. The 1-yr results from the 4-T trial in patients receiving metformin/SU compared the initiation of basal insulin detemir (twice daily if required) to that of biphasic insulin aspart twice daily or prandial insulin aspart three times daily. Basal insulin use was associated with the least weight gain (⫹1.9 vs. ⫹4.7 vs. ⫹5.7 kg, detemir vs. biphasic vs. prandial, respectively) (42). After 3 yr, and despite intensification to full basal and prandial insulin in all three regimens, patients originally initiating basal insulin detemir had a sustained weight advantage over patients treated with biphasic or prandial insulin regimens (43). Notably, insulin detemir has also consistently been shown to result in reduced weight gain in comparison to NPH insulin. Monami et al. (73) conducted a meta-analysis of 14 RCT of insulin glargine (11 trials) and insulin detemir (three trials). In this analysis, significant reductions in weight gain relative to NPH were reported in two of three trials involving insulin detemir (74 –76) and in only one of 11 trials of insulin glargine (77). Pooled analysis of two 22- to 24-wk trials assessing basal detemir vs.

3344

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TABLE 2. Weight change in insulin clinical trials in patients with T2D

n

Mean BMI (kg/m2)

HbA1c %, decrease from baseline

20

31.5

0.6

⫺3.8

P ⫽ 0.22

Detemir/aspart

195

29.8

0.65

⫹0.51

NPH/human insulin Detemir/aspart

200 341

28.7 30.1

0.58 0.2

⫹1.13 ⫹1.0

P ⫽ 0.038 (vs. NPH/human insulin

NPH/aspart

164

31.1

0.4

⫹1.8

OAD (25% MET; 75% MET ⫹ 122 OAD) ⫹ detemir QD FPG target, 3.9 –5.0 mmol/liter OAD (25% MET; 75% MET ⫹ 122 OAD) ⫹ detemir QD FPG target, 4.4 – 6.1 mmol/liter OAD ⫹ detemir, QD prebreakfast 168 (165) dose

33.0

1.22

⫹0.89

NS

33.6

0.94

⫹0.12

NS

29.8

1.58

⫹1.2

OAD ⫹ detemir, QD evening dose 170 (169) OAD ⫹ NPH, evening dose 166 (164) 26-wk R, MC, OL, OAD ⫹ detemir 237 PG trial; n ⫽ 476 (76) OAD ⫹ NPH 237 1-yr data, R, OAD ⫹ detemir QD or BID 234 controlled, MC, OL trial (42)

29.7 30.4 28.9

1.48 1.74 1.8

⫹0.7 ⫹1.6 ⫹1.2

29.0 29.7

1.9 0.8

⫹2.8 ⫹1.9

Study design Insulin detemir 20-wk case series; n ⫽ 20 (79) 22-wk MC, OL, symmetrically R, PG trial; n ⫽ 395 (78) 26-wk R, MC, OL, PG trial; n ⫽ 505 (75) Detemir/OAD 20-wk R, controlled, OL, MC, PG (80)

20-wk R, OL, 3-arm, PG, MC (83)

24-wk R (112) Glargine 28-wk MC, OL, R trial; n ⫽ 518 (113) 14-wk MC, R, 2 ⫻ 2 factorial trial of OL insulin glargine; n ⫽ 500 (37)

Regimen and insulin type by arm Detemir, prior therapy NPH


OAD ⫹ biphasic aspart BID OAD ⫹ prandial aspart TID OAD ⫹ detemir BID

235 239 478

30.2 29.6 30.6

1.3 1.4 1.54

⫹4.7 ⫹5.7 ⫹0.6

OAD ⫹ glargine QD

486

29.7

1.46

⫹1.4

Glargine, prior therapy NPH

259

30.7

0.41

⫹0.4

NPH insulin Glargine (⬎50% no prior drug therapy)

259 126

30.4 36.4

0.59 0.8

⫹1.4 ⫹0.23

⌬ weight P

P ⫽ 0.017 (vs. NPH/aspart)

P ⫽ 0.005 (for evening detemir vs. NPH) P ⬍ 0.001 (detemir vs. NPH) P ⬍ 0.001 (overall and for all group comparisons) P ⬍ 0.001 (vs. glargine) P ⬍ 0.0007 (vs. NPH) P ⬍ 0.04 vs. baseline

(Continued)



3345

TABLE 2. Continued

n

Mean BMI (kg/m2)



104

34.6

1.66

⫹1.7

7893

34.0

1.3 to 1.5

OAD ⫹ glargine OAD ⫹ NPH OAD ⫹ glargine evening OAD ⫹ NPH evening

367 389 289 281

32.5 32.2 29.3 28.8

1.65 1.59 0.46 0.38

⫹3.0 ⫹2.8 ⫹2.01 ⫹1.88

OAD ⫹ glargine evening

239

29.2

1.02

⫹2.02

P ⬍ 0.00001 (vs. baseline)

29.2

1.71

⫹3.01

1.7

⫹2.5

P ⫽ 0.23 (betweengroup difference) P ⬍ 0.0001 (vs. lispro)

Regimen and insulin type Study design by arm Glargine ⫹ OAD 24-wk MC, R, OL, MET/SU ⫹ glargine PG; n ⫽ 217 (114)

P ⫽ 0.02 (glargine vs. add-on rosiglitazone) ⫹1.6 to ⫹2.0 P ⬍ 0.0001 (vs. baseline)

24-wk R, PG, MC, 4-arm, OL study (115) 24-wk R, OL, PG, MC (116) 12-month OL, R, MC; n ⫽ 570 (117) 28-month MC, extension study (118) to Massi Benedetti et al., 2003 (117) 44-wk MC, PG, OL; n ⫽ 418 (119)

OAD ⫹ glargine according to 4 titration protocols

OAD ⫹ glargine

205

24-wk initiation phase R, MC, OL, PG study; n ⫽ 2091 (120) 52-wk R, MC trial (36) 24-wk MC, PG, controlled, OL, R trial (121)

OAD ⫹ glargine

1046

32

OAD ⫹ bedtime glargine OAD ⫹ bedtime NPH OAD ⫹ glargine, titrated at every visit or every 3 d (72% of patients previously treated with insulin) Glargine, as above; patients in primary and secondary care

214 208 4961

29.3 28.5 29.0

Glargine, as above; nonobese Obese

2755 1833

25.89 33.68

1.15 1.15

⫹1.21 ⫹1.08

GLI ⫹ glargine

220

24.8

0.99

⫹1.4 BMI

GLI ⫹ NPH

223

25.1

0.77

⫹1.29 BMI

GLI ⫹ glargine morning

237 (236)

28.6

1.24

⫹3.9

GLI ⫹ glargine evening GLI ⫹ NPH

229 (227) 234 (232)

28.7 28.9

0.96 0.84

⫹3.7 ⫹2.9

Subanalysis 24-wk MC, OL, R trial (122) Subanalysis 24-wk MC, OL, R trial (82) 24-wk OL, R, PG, MC, noninferiority study; n ⫽ 448 (123) 24-wk MC, OL, R, controlled, PG study; n ⫽ 695 (124)

819

NR

⌬ weight P

NS P ⫽ 0.58

0.76 0.66 1 to 1.2

⫹2.57 NS ⫹2.34 ⫹1 to ⫹1.3 P ⬍ 0.001 (vs. baseline)

0.51 to ⫺0.95

⫹1 to ⫹1.2 P ⬍ 0.05 (vs. baseline) P ⫽ 0.67 (obese vs. nonobese NS (NPH vs. glargine)

NS (treatment group comparison) (Continued)

3346

Meneghini et al.



TABLE 2. Continued

Regimen and insulin type Study design by arm Detemir vs. glargine 52-wk MC, R, OL, OAD ⫹ detemir QD PG, OAD ⫹ glargine noninferiority trial; n ⫽ 582 (85) 26-wk R, OL, PG, OAD ⫹ detemir/aspart MC, OAD ⫹ glargine/aspart noninferiority study; n ⫽ 385, 20% insulin naive (86) OAD ⫹ detemir 52-wk MC, OL, OAD ⫹ glargine PG, noninferiority (125) Lispro or aspart (prandial/biphasic) 52-wk R, MC, OL, Prandial insulin aspart premix BID ⫹ MET ⫹ SU noninferiority trial; n ⫽ 506 (25) Exenatide 5 ␮g BID/4 wk; 10 ␮g thereafter 44-wk R, MC, PG, Prandial insulin lispro TID ⫹ OAD OL; n ⫽ 418 (119) Insulin glargine once daily ⫹ OAD 16-wk MC, R, OL, Prandial biphasic insulin aspart TID PG; n ⫽ 308 Prandial biphasic insulin aspart (126) BID ⫹ MET 12-month single- REP ⫹ biphasic insulin aspart, BID center, R, DB, double-dummy, PG; n ⫽ 102 (44) MET ⫹ biphasic insulin aspart, BID 24-wk MC, R, OL Prandial insulin aspart, QD added trial; n ⫽ 372 to MET or SU Prandial insulin aspart, BID added (26) to MET or SU OAD ⫹ prandial biphasic lispro, 24-wk MC, BID initiation phase R, OL, PG study; n ⫽ 2091 (120) OAD ⫹ glargine (once daily) 24-wk R, OL, PG, Glargine or detemir, once or twice MC study; daily ⫹ prandial analog with or n ⫽ 113 (66) without OAD Pramlintide ⫹ glargine or detemir, with or without OAD

n

Mean BMI (kg/m2)



291

30.6

1.5

⫹2.3

291

30.5

1.5

⫹3.5

254

32.6

1.1

⫹1.2

131

33.0

1.3

⫹2.7

214 105

31.5 31.7

1.52 1.68

⫹2.8 ⫹3.8

P ⬍ 0.05

248

30.2

0.89

⫹2.9

253

30.6

1.04

⫺2.5

P ⬍ 0.001 (vs. exenatide); P ⬍ 0.01 (vs. baseline)

210

29.4

1.87

⫹3.54

205 104

29.2 29.8

1.71 2.9

⫹3.01 ⫹1.71

100

29.2

3.0

⫹1.50

49

24.9

1.23

⫹4.73

52 124

24.5 33.7

1.42 2.34

⫺2.51 ⫹2.85

124

33.5

2.76

⫹4.08

1045

32

1.8

⫹3.6

1046 56

32 36

1.7 1.3

⫹2.5 ⫹4.7

57

36

1.1

0.0

⌬ weight P P ⫽ 0.01 (vs. glargine)

P ⫽ 0.001 (vs. glargine)

P ⫽ 0.23 (glargine vs. lispro) P ⬍ 0.001 (vs. baseline) P ⫽ 0.002 (MET ⫹ insulin vs. REP ⫹ insulin) Not reported

P ⬍ 0.001 (lispro vs. glargine) P ⬍ 0.0001 (insulin vs. pramlintide)

Endpoint analysis was carried out on intent to treat (ITT) population unless otherwise indicated. Where two n values are presented, ITT values are followed by the analysis set (numbers exposed or numbers completed). Selection of representative studies for inclusion was based on author consensus. BID, Twice daily; DB, double blind; GLI, glimepiride; MC, multicenter; MET, metformin; NS, not significant; OL, open label; PG, parallel group; PIO, pioglitazone; QD, once daily; R, randomized; REP, repaglinide; TID, three times daily.


NPH insulin found a relationship between higher baseline body mass index (BMI) and the enhanced weight-sparing effect of insulin detemir (78). Specifically, patients with higher baseline BMI levels (⬎35 kg/m2) lost an average of 0.5 kg, whereas those with BMI levels below 35 kg/m2 tended to gain between 0.4 and 0.6 kg. This finding has also been reported in subsequent RCT and observational trials (79 – 81). Conversely, a post hoc subgroup analysis of a large randomized trial comparing two algorithms for initiation and titration of insulin glargine showed that, at 24 wk, weight gain with insulin glargine was independent of baseline BMI (weight gain of 1.21 vs. 1.08 kg for nonobese vs. obese individuals, respectively) (82). In line with results seen when insulin is used in combination with metformin alone, combination studies with insulin analogs and OAD confirm that the weight effects of basal insulins are not uniform. In particular, trials of insulin detemir show similar glycemic control, but less weight gain not only vs. NPH (39, 76, 83) but also vs. insulin glargine (76, 83– 86). An indirect comparison of five trials in patients currently receiving OAD showed that evening insulin detemir was associated with less weight gain vs. evening insulin glargine (unadjusted weighted mean difference, ⫺1.2 kg in favor of detemir) (87). Additionally, a pooled analysis of data from 22 RCT found that whereas weight gain per HbA1c change was similar for glargine and detemir, treatment with glargine resulted in a higher absolute weight gain of borderline significance (⫹2.5 vs. ⫹1.7 kg with detemir, P ⫽ 0.049). However, weight changes per 1% reduction of HbA1c were not statistically different for glargine vs. detemir (1.8 vs. 1.2 kg; P ⬎ 0.05) (88). These observations have fueled investigation into the combination of insulin detemir with weight-beneficial


3347

agents such as the weight-neutral DPP-4 inhibitor sitagliptin (89) and weight-reducing combination therapy with liraglutide and metformin. A study by Buse et al. (90) investigated the addition of exenatide or placebo to regimens of insulin glargine alone or in combination with metformin or pioglitazone or both, in adult T2D patients with HbA1c of 7.1 to 10.5%. HbA1c levels decreased by 1.74% in the exenatide group and by 1.04% in the placebo group [between-group difference, ⫺0.69%; 95% confidence interval (CI), ⫺0.93 to ⫺0.46%; P ⬍ 0.001]. However, weight decreased by 1.8 kg in the exenatide group but increased by 1.0 kg in the placebo group (between-group difference, ⫺2.7 kg; 95% CI, ⫺3.7 to ⫺1.7). Average increases in insulin dosage were 13 and 20 U/d in the exenatide and placebo groups, respectively (90). In the TRANSITION study, insulin-naive patients on a regimen of metformin with or without a second OAD experienced significantly greater HbA1c reductions when transitioned to insulin detemir and sitagliptin than subjects receiving sitagliptin with or without SU. Notably however, small decreases in weight were seen in both groups (91). Practical recommendations for intensifying therapy Table 3 shows a summary of mean HbA1c reductions and impact on FPG, PPG, and weight change associated with the antidiabetic agents presented. For patients who do not reach glycemic goals on metformin alone, we recommend considering treatment choices by weight benefit as well as glycemic benefit, particularly in patients who are obese. This might be particularly relevant in patients whose HbA1c levels are close (within 1 to 1.5%) to recommended glycemic targets. Although relative risk reduction for microvascular disease is approximately 20 –30%

TABLE 3. Summary of treatment effects on HbA1c, weight, PPG, and FPG (1, 49, 68, 103) Expected reduction in HbA1c with monotherapy (%) 0.5– 0.8

Expected weight ⌬ over 6 months (kg) Weight neutral

Impact on PPG ⫹⫹

0.5–1.0

Weight neutral or loss 0 to ⫺1.5 kg

⫹⫹ to ⫹⫹⫹

Basal insulin Detemir

1.5–3.5

Glargine GLP-1 analogs

1.5–3.5 0.5–1.0

DPP-4 inhibitors Metformin

0.5– 0.8 1.0 –2.0

SU

1.0 –2.0

TZD

0.5–1.4

Weight neutral or gain 0 to ⫹1.5 kg Weight gain up to ⫹4 kg Weight loss ⫺1.0 to ⫺3.0 kg Weight neutral Weight neutral or loss 0 to ⫺1.5 kg Weight gain ⫹1 to ⫹5 kg Weight gain: ⫹3 kg

␣-Glucosidase inhibitors (acarbose) Amylin analogs

⫹

Impact on FPG ⫺ ⫹ ⫹⫹ to ⫹⫹⫹

⫹ ⫹⫹ to ⫹⫹⫹

⫹⫹ to ⫹⫹⫹ ⫹ to ⫹⫹

⫹⫹ ⫹

⫹ ⫹⫹

⫹⫹

⫹⫹

⫹

⫹⫹

3348

Meneghini et al.


for every 1% fall in HbA1c (92–94), the absolute risk reduction tends to decrease as HbA1c approaches nondiabetic levels. A few reports and comments in the literature seem to point to an HbA1c of around 8% as a threshold for a substantial increase in the risk for microalbuminuria (95–97). A Kaiser Permanente study also found a significantly increased risk of complications or mortality for HbA1c of 8% or higher in patients 60 yr or older (98). There is also a clear relationship between disease duration and risk of vascular complications. Given this information, for patients with an HbA1c approaching target, the preference might be given to therapies that promote weight loss (or minimize weight gain), which coincidentally are also associated with a low hypoglycemia risk. Additionally, in patients that are more vulnerable to hypoglycemia, have a long disease duration, already have advanced vascular complications, or have significant resistance to using insulin due to weight concerns, an approach that minimizes weight gain at the expense of a smaller expected reduction in HbA1c might be appropriate. On the other hand, in individuals with very poor glycemic control (HbA1c values over 8 – 8.5%), priority should clearly be given to improving glycemia and secondarily mitigating weight gain (99). Either therapeutic strategy would need to be reevaluated according to the individual patients’ response to treatment and patient concerns about weight gain and the impact that weight loss may have on patient quality of life (100 –102). The current treatment approach in T2D, as outlined by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) treatment algorithm, encourages flexibility and clinical judgment but is cautious in recommending the use of newer agents. In line with current guidelines, the decision to intensify therapy is based on HbA1c targets of no more than 7% (68). Interventions can be further tailored by using self-monitoring of blood glucose to identify whether the predominant glycemic burden is elevated FPG or elevated PPG. A weightconscious approach to glycemic management might stratify weight-friendly treatment choices based on two general parameters: 1) overall glycemic reduction; or 2) specific effects on fasting and postprandial glycemia identified through patient self-monitoring of blood glucose. Antiglycemic agents have varying effects on fasting and postprandial glycemia (103) and should allow for tailoring of therapy to specific patient needs. For metformin-treated patients who fail to achieve ADA/EASD targets for FPG of 70 to 130 mg/dl (3.9 to7.2 mmol/liter) (9), second-line treatment choices in order of weight benefit first and FPG reduction second would be: GLP-1 agonists [long-acting (i.e. liraglutide) favored over short-acting (i.e. exenatide) GLP-1 preparations], DPP-4


inhibitors, bile acid sequestrants, and amylin analogs. If insulin treatment is indicated, a basal insulin supplementation should be considered (insulin detemir favored over insulin glargine or NPH with respect to weight effects). The current ADA/EASD targets for PPG are below 180 mg/dl (⬍10.0 mmol/liter) (9). For patients who fail to achieve this target on metformin therapy, the treatment choices in order of weight benefit first and PPG reduction second would be: GLP-1 agonists (short-acting favored over long-acting GLP-1 preparations), amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants. Shortacting GLP-1 agonists are recommended over long-acting GLP-1 agonists in this situation because the LEAD-6 trial, which compared liraglutide and exenatide, found that patients receiving exenatide achieved significantly reduced PPG increments compared with liraglutide (23).

Discussion Normalization of glycemia remains the cornerstone of diabetes management in patients of all body weights, and insulin use is often key to meeting glycemic targets. However, the close link between excess body weight, T2D disease progression, and the development of late complications highlights the need for physicians to consider weight management as well. Optimizing weight should be a priority in T2D, and physicians should consider weight issues at every stage of the disease through the use of appropriate therapy. Lifestyle modification should be encouraged at all stages of diabetes management; however, this is seldom sufficient to achieve stringent glycemic control or adequate weight control, and as T2D progresses, therapeutic intervention will be required. Although traditional therapies such as human insulin and some older OAD are associated with weight gain, newer therapies have a more beneficial effect on weight. This review reaffirms the weight benefits of metformin, alone and in combination with other noninsulin and insulin therapies, and highlights the weight effects of certain newer agents. The GLP-1 agonists and amylin analogs promote weight loss, whereas the DPP-4 inhibitors, bile acid sequestrants, and carbohydrate inhibitors tend to be weight-neutral. In light of the data presented in this review, earlier and preferential introduction of weight-beneficial agents such as GLP-1 agonists should be considered, particularly in obese patients. In severely uncontrolled diabetes, lifestyle intervention plus insulin remains a key strategy. Initiation of insulin early in a treatment algorithm, after metformin and GLP-1 analogs, might be an effective strategy. Of the insulin preparations, insulin detemir provides the most


favorable weight profile, especially in patients with high baseline BMI, because these patients can least afford to incur further weight gain.


8. 9.

Acknowledgments

10.

Writing and editorial support was provided by Janet Stephenson, Dan Booth, and Caitlin Rothermel of Bioscript Stirling Ltd., with funding from Novo Nordisk. Address all correspondence and requests for reprints to: Luigi F. Meneghini, M.D., MBA, Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 N.W. 10th Avenue, Miami, Florida 33136. E-mail: LMeneghi@ med.miami.edu. L.F.M., D.O.-B., K.K., S.C., T.D., A.L., and S.R. provided substantial contributions to literature review conception and design, drafting and critically revising the manuscript for intellectual content, and giving final approval of the manuscript before publication. Disclosure Summary: A.L. is a board member and/or a speaker for Astra Zeneca, Eli Lilly, MSD, Novo Nordisk, and Roche. D.O.-B. is a board member for Eli Lilly, Novo Nordisk and Sanofi Aventis, a speaker for MSD and Sanofi Aventis, and has received research funding from MSD. K.K. is a board member for Bristol Meyers Squibb, MSD, Novo Nordisk, and Roche; and a speaker for Eli Lilly, MSD, Novartis, Novo Nordisk and Sanofi Aventis. L.F.M. has received consultancy and/or speaker bureau fees from Eli Lilly, Novo Nordisk and Sanofi Aventis. S.C. is a board member for MSD and Novo Nordisk and has additionally received speaker bureau fees from Eli Lilly, Merck, Sanofi Aventis and Takeda. S.R. has received consulting fees from Novo Nordisk and additionally has received lecture fees and research grants from Eli Lilly. T.D. is a board member and consults for Astra Zeneca, Bristol Meyers Squibb, Eli Lilly, MSD, Novo Nordisk, and Sanofi Aventis.

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