Exenatide Versus Glibenclamide in Patients with Diabetes

G. Derosa, M.D., Ph.D.,1 P. Maffioli, M.D.,1 S.A.T. Salvadeo, M.D.,1 I. Ferrari, M.D.,1

P.D. Ragonesi, M.D.,2 F. Querci, M.D.,3 I.G. Franzetti, M.D.,4 G. Gadaleta, M.D.,5 L. Ciccarelli, M.D.,6

M.N. Piccinni, M.D.,7 A. D’Angelo, B.D.,1 and A.F.G. Cicero, M.D.8

Abstract

Background: Incretin-based therapies have provided additional options for the treatment of type 2 diabetesmellitus. The aim of our study was to evaluate the effects of exenatide compared to glibenclamide on bodyweight, glycemic control, b-cell function, insulin resistance, and inflammatory state in patients with diabetes.Methods: One hundred twenty-eight patients with uncontrolled type 2 diabetes mellitus receiving therapy withmetformin were randomized to take exenatide 5mg twice a day or glibenclamide 2.5 mg three times a day andtitrated to exenatide 10mg twice a day or glibenclamide 5 mg three times a day. We evaluated body weight, bodymass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG),fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR) index, homeostasismodel assessment b-cell function (HOMA-b) index, plasma proinsulin (PPr), PPr=FPI ratio, resistin, retinol bindingprotein-4 (RBP-4), and high-sensitivity C-reactive protein (Hs-CRP) at baseline and after 3, 6, 9, and 12 months.Results: Body weight and BMI decreased with exenatide and increased with glibenclamide. A similar im-provement of HbA1c, FPG, and PPG was obtained in both groups, whereas FPI decreased with exenatide andincreased with glibenclamide. The HOMA-IR index decreased and the HOMA-b index increased with exenatidebut not with glibenclamide. A decrease of PPr was reported in both groups, but only glibenclamide decreasedthe PPr=FPI ratio. Resistin and RBP-4 decreased with exenatide and increased with glibenclamide. A decrease ofHs-CRP was obtained with exenatide, whereas no variations were observed with glibenclamide.Conclusions: Both exenatide and glibenclamide gave a similar improvement of glycemic control, but onlyexenatide gave improvements of insulin resistance and b-cell function, giving also a decrease of body weight andof inflammatory state.

Introduction

The importance of an early, intensified approach tometabolic control has been clearly demonstrated by the

long-term results of the United Kingdom Prospective Dia-betes Study, showing that the benefits of tight blood glucosecontrol extended well beyond the end of the study and per-sisted after over 10 years.1 Recent breakthroughs in the un-derstanding of incretin-based therapies have providedadditional options for the treatment of type 2 diabetes melli-tus (T2DM). There are two incretins, known as glucagon-likepeptide-1 (GLP-1) and glucose-dependent insulinotropicpeptide (GIP), that share many common actions in the pan-

creas but have distinct actions outside of the pancreas. Themost important one is GLP-1: it is secreted by intestinal L-cells, mainly in response to food intake. It has several actions,including stimulation of insulin secretion and reduction ofglucagon secretion, both in a glucose-dependent manner, andresulting in a reduced hepatic glucose production. Further-more, GLP-1 slows gastrointestinal motility and increasessatiety, reducing the food intake. It also promotes b-cell pro-liferation and probably neogenesis, while reducing apoptosisin animal models.2–4 In T2DM, GLP-1 concentrations are re-duced in response to a meal, whereas GIP concentrationsare normal or increased. This observation suggests resistanceto the action of GIP, making GLP-1 the favored potential

1Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.2Diabetes Care Unit, S. Carlo Hospital, and 6RSA Don Leone Porta, Milano, Italy.3Ospedale Pesenti Fenaroli, Alzano Lombardo, Bergamo, Italy.4Metabolic Unit, Regional Hospital, Varese, Italy.5Division of Medicine, Civic Hospital, Cittiglio, Varese, Italy.7Fondazione Ospedale della Carita, Casalbuttano, Cremona, Italy.8‘‘G. Descovich’’ Atherosclerosis Study Center, ‘‘D. Campanacci’’ Clinical Medicine and Applied Biotechnology Department, University

of Bologna, Bologna, Italy.

DIABETES TECHNOLOGY & THERAPEUTICSVolume 12, Number 3, 2010ª Mary Ann Liebert, Inc.DOI: 10.1089=dia.2009.0141

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therapeutic target.5 Because GLP-1 is rapidly degraded bydipeptidyl peptidase-4,6 GLP-1 receptor agonists resistant todipeptidyl peptidase-4 have been developed. Exenatide is thefirst in this class of drugs known as the incretin mimetics7; it issupplied for subcutaneous injection, and prefilled pens areavailable to deliver unit doses of 5 or 10mg. In Europeancountries, exenatide is indicated as adjunctive therapy for theimprovement of glycemic control in patients with T2DM whoare taking metformin, a sulfonylurea, or a combination ofmetformin and a sulfonylurea but have not achieved adequateglycemic control8; in the United States, instead, exenatide isalso indicated as adjunctive therapy for the improvement ofglycemic control in patients with T2DM receiving a thiazoli-dinedione alone or in combination with metformin.9 Exena-tide has been reported to reduce glycated hemoglobin(HbAlc), to improve glycemic control, and to reduce bodyweight, when used as adjunctive therapy in patients withT2DM treated with metformin10 and=or a sulfonylurea11,12 orin combination with a thiazolidinedione, with or withoutmetformin.13 Improvement in glucose control has also beenreported with up to 2 years of exenatide therapy, accompa-nied by sustained HbA1c reductions and progressive weightloss over this period.14 All the studies reported above ana-lyzed the effects of exenatide on glycemic control, bodyweight, insulin resistance, and b-cell function parameters, butnone of these studies analyzed exenatide effects on inflam-mation and on cardiovascular risk.

Glibenclamide is a well-known second-generation sulfo-nylurea, and like all sulfonylureas, it binds a specific site onthe ATP-sensitive potassium channels, subsequently openingcalcium channels and thus triggering insulin exocytosis fromthe pancreatic b-cell.15

The aim of this study was to evaluate the effects of a 1-yeartreatment with exenatide compared to glibenclamide in type 2diabetes patients on body weight, glycemic control, and b-cellfunction but also on insulin resistance and inflammatory stateparameters like resistin, retinol binding protein-4 (RBP-4),and high-sensitivity C-reactive protein (Hs-CRP).

Subjects and Methods

Study design

This multicenter, randomized, single-blind, controlledstudy was conducted at the Department of Internal Medicineand Therapeutics, University of Pavia, Pavia, Italy; the ‘‘G.Descovich’’ Atherosclerosis Study Center, Department of In-ternal Medicine, Aging and Kidney diseases, University ofBologna, Bologna, Italy; the Diabetes Care Unit, S. CarloHospital, Milano, Italy; the Pesenti Fenaroli Hospital, AlzanoLombardo, Bergamo, Italy; the Metabolic Unit, RegionalHospital, Varese, Italy; the Division of Medicine, Civic Hos-pital, Cittiglio, Varese, Italy; the RSA Don Leone Porta,Milano; and the Fondazione Ospedale della Carita, Ca-salbuttano, Cremona, Italy.

The study protocol was approved at each site by institu-tional review boards and was conducted in accordance withthe Declaration of Helsinki and its amendments.

Patients

We enrolled 128 white type 2 diabetes patients �18 yearsold of either sex (Table 1) according to the European Society of

Cardiology and European Association for the Study of Dia-betes guidelines criteria,16 with poor glycemic control (ex-pressed as HbA1c level >8.0%) and overweight (body massindex [BMI] �25 and <30 kg=m2) receiving therapy withmetformin at the mean dosage of 1,500� 500 mg=day. Theywere intolerant to metformin at maximum dosage(3,000 mg=day) with the onset of gastrointestinal disorderslike diarrhea and significant meteorism when metformin wastitrated to the maximum level.

Suitable patients, identified from review of case notes and=or computerized clinic registers, were contacted by the in-vestigators in person or by telephone.

Patients were excluded if they had a history of ketoaci-dosis or had unstable or rapidly progressive diabetic reti-nopathy, nephropathy, or neuropathy, impaired hepaticfunction (defined as plasma aminotransferase and=or g-glutamyltransferase level higher than the upper limit ofnormal for age and sex), impaired renal function (defined asserum creatinine level higher than the upper limit of normalfor age and sex), or severe anemia. Patients with seriouscardiovascular disease (e.g., New York Heart Associationclass I–IV congestive heart failure or a history of myocardialinfarction or stroke) or cerebrovascular conditions within6 months before study enrollment also were excluded.Women who were pregnant or breastfeeding or of child-bearing potential and not taking adequate contraceptiveprecautions were also excluded. All patients provided writ-ten informed consent to participate.

Treatments

Patients were assigned to receive exenatide 5 mg twice a dayor glibenclamide 2.5 mg three times a day and titrated after1 month to exenatide 10 mg twice a day or glibenclamide 5 mgthree times a day for 12 months in a randomized, single-blind,controlled study. Randomization was done using a drawingof envelopes containing randomization codes prepared by astatistician. Medication compliance was assessed by counting

Table 1. Characteristics of Subjects at Baseline

in the Study

Exenatide group Glibenclamide group

Number 63 65Sex (M=F) 30=33 33=32Age (years) 57� 8 56� 7Smoking status (M=F) 16=13 14=12Height (m) 1.69� 0.04 1.70� 0.05Weight (kg) 82.0� 8.3 82.4� 9.1BMI (kg=m2) 28.7� 1.5 28.5� 1.4HbA1c (%) 8.8� 0.7 8.9� 0.8FPG (mg=dL) 144� 16 147� 18PPG (mg=dL) 194� 27 198� 30FPI (mU=mL) 19.8� 4.0 20.2� 4.5HOMA-IR index 7.1� 2.4 7.4� 2.6HOMA-b index 57.8� 50.1 58.3� 51.6PPr (pmol=L) 45.3� 30.6 47.6� 32.1PPr=FPI ratio 0.38� 1.41 0.39� 1.46Resistin (ng=mL) 6.1� 1.5 6.3� 1.6RBP-4 (mg=mL) 38.1� 8.6 38.9� 8.8Hs-CRP (mg=L) 2.1� 0.8 2.0� 0.7

Data are mean� SD values.

234 DEROSA ET AL.

the number of pills or syringes returned at the time of speci-fied clinic visits. Throughout the study, we instructed patientsto take their first dose of new medication on the day after theywere given the study medication. At the same time, all unusedmedication was retrieved for inventory. All medications wereprovided free of charge.

Diet and exercise

Subjects began a controlled-energy diet (near 600 kcal dailydeficit) based on American Heart Association recommenda-tions17 that included 50% of calories from carbohydrates, 30%from fat (6% saturated), and 20% from proteins, with a max-imum cholesterol content of 300 mg=day and 35 g=day of fi-ber. Patients were not treated with vitamins or mineralpreparations during the study.

Standard diet advice was given by a dietitian and=or spe-cialist doctor. Dietitian and=or a specialist doctor periodicallyprovided instruction on dietary intake recording proceduresas part of a behavior modification program and then laterused the subject’s food diaries for counseling. Individualswere also encouraged to increase their physical activity bywalking briskly for 20–30 min, three to five times per week, orby cyclette. The recommended changes in physical activitythroughout the study were not assessed.

Assessments

Before starting the study, all patients underwent an initialscreening assessment that included a medical history, physi-cal examination, vital signs, a 12-lead electrocardiogram, andmeasurements of BMI, HbA1c, fasting plasma glucose (FPG),postprandial plasma glucose (PPG), and fasting plasma in-sulin (FPI). Insulin resistance and b-cell function were evalu-ated by the homeostasis model assessment method; inparticular, we considered the homeostasis model assessmentinsulin resistance (HOMA-IR) index and the homeostasismodel assessment b-cell function (HOMA-b) index. Weevaluated body weight and BMI, HbA1c, FPG, PPG, FPI,HOMA-IR, HOMA-b, plasma proinsulin (PPr)=FPI ratio, re-sistin, RBP-4, and Hs-CRP. We measured these parameters atbaseline and after 3, 6, 9, and 12 months. In order to evaluatethe tolerability assessments, all adverse events were recorded.All plasma parameters were determined after a 12-h over-night fast with the exception of PPG, which was determined2 h after a standardized meal. Venous blood samples weretaken for all patients between 0800 and 0900 h. We usedplasma obtained by addition of disodium EDTA (1 mg=L) andcentrifuged at 3,000 g for 15 min at 48C. Immediately aftercentrifugation, the plasma samples were frozen and storedat �808C for no more than 3 months. All measurements wereperformed in a central laboratory.

BMI was calculated as weight in kilograms divided by thesquare of height in meters. HbA1c level was measured by ahigh-performance liquid chromatography method (DIAMAT,Bio-Rad, Hercules, CA, USA) (normal values, 4.2–6.2%), withintra- and interassay coefficients of variance of<2%.18 Plasmaglucose was assayed by the glucose oxidase method (GOD=PAP, Roche Diagnostics, Mannheim, Germany) with intra-and interassay coefficients of variance of <2%.19 Plasmainsulin was assayed with the Phadiaseph insulin radioim-munoassay (Pharmacia, Uppsala, Sweden) by using a secondantibody to separate the free and antibody-bound 125I-insulin

(intra- and interassay coefficients of variance, 4.6% and 7.3%,respectively).20

The HOMA-IR index was calculated as the product of basalglucose (in mmol=L) and insulin levels (in mU=mL) divided by22.5.21,22 The HOMA-b index was calculated as the product of20 and basal insulin levels (in mU=mL) divided by the value ofbasal glucose concentrations (in mmol=L) minus 3.5; thisformula has been proposed to be a good measure of b-cellfunction.22

Proinsulin was determined using an enzyme-linked im-munosorbent assay (Mercodia, Uppsala). The intra- and in-terassay coefficients of variance were 2.4% and 8.9%,respectively.23

The resistin value was measured by a commercially avail-able enzyme-linked immunoassay kit (BioVendor LaboratoryMedicine, Brno, Czech Republic). The intra-assay coefficientof variance was 3.4%, and the interassay coefficient of vari-ance was 6.9%.24

RBP-4 was measured using an RBP-4 (human) enzymeimmunoassay kit (Phoenix Pharmaceuticals, Inc., Burlingame,CA). The intra- and interassay coefficients of variance were<5.0% and <14.0%, respectively.25

Hs-CRP was measured with use of latex-enhanced im-munonephelometric assays on a BN II analyzer (Dade Behr-ing, Newark, DE). The intra- and interassay coefficients ofvariance were 5.7% and 1.3%, respectively.26

Statistical analysis

Every patient who had received at least one dose of thestudy medication underwent a tolerability observation toexclude the presence of acute adverse reactions. After that anintention-to-treat analysis was conducted in patients who hadreceived one or more doses of study medication, did not showany acute adverse reaction, and had a subsequent efficacyobservation. Continuous variables were compared by analy-sis of variance. Intervention effects were adjusted for addi-tional potential confounders using analysis of covariance.Annalysis of variance was also used to assess the significancewithin and between groups. The statistical significance of theindependent effects of treatments on the other variables wasdetermined using analysis of covariance. A one-sample t testwas used to compare values obtained before and after treat-ment administration; two-sample t tests were used forbetween-group comparisons. The Bonferroni correction formultiple comparisons was also carried out.27 Statistical anal-ysis of data was performed using the Statistical Package forSocial Sciences software version 11.0 (SPSS Inc., Chicago, IL).Data are presented as mean� SD values. For all statisticalanalyses, P< 0.05 was considered statistically significant.

Results

Study sample

A total of 128 patients were enrolled in the study. Of these,116 completed the study, and 59 (50.8%) were allocated to theexenatide group and 57 (49.2%) to the glibenclamide group.There were 12 patients (five men and seven women) who didnot complete the study, and the reasons for premature with-drawal included side effects as nausea (two women in theexenatide group, one woman in the glibenclamide group, andone man in the glibenclamide group, after 3 months), diarrhea

EXENATIDE VERSUS GLIBENCLAMIDE IN DIABETES 235

(one man and one woman in the exenatide group and oneman in the glibenclamide group, after 6 months), vomiting(one woman in the glibenclamide group, after 12 months),and lost to follow-up (one man in the glibenclamide group,after 12 months). Moreover, one woman had hypoglycemia(FPG <60 mg=dL) in the glibenclamide group after 3 months,one woman in the glibenclamide group after 9 months, andone man in the glibenclamide group at 12 months. The char-acteristics of the patient population at study entry are shownin Table 1.

Body weight and BMI

At the end of the study there was a statistically significantdecrease of body weight and BMI compared to baseline withexenatide, whereas there was a significant increase withglibenclamide. Furthermore, the body weight and BMI valuesobtained with exenatide were significantly lower than thevalues obtained with glibenclamide after 6, 9, and 12 months(Tables 2 and 3).

Glycemic parameters

After 12 months we observed a statistically significant im-provement of HbA1c, FPG, and PPG compared to baseline inboth groups without any significant differences between thetwo groups. In contrast, the FPI value was significantly de-creased compared to baseline after 9 and 12 months of therapywith exenatide, whereas it was significantly increased withglibenclamide. Furthermore, the FPI value obtained with ex-enatide was significantly lower than the value obtained withglibenclamide after 9 and 12 months.

b-Cell function

The HOMA-b index increased after 9, and 12 monthscompared to baseline with exenatide, whereas there were nostatistically significant variations with glibenclamide. At theend of the study the HOMA-b index observed with exenatide

was significantly higher than the value recorded with glib-enclamide.

There was a similar decrease of PPr after 9 and 12 monthscompared to baseline in both groups, although we observed asignificant decrease of PPr=FPI ratio with glibenclamide butnot with exenatide. The PPr=FPI ratio obtained with exenatidewas significantly higher than the value recorded with glib-enclamide after 9 and 12 months (Tables 2 and 3).

Insulin resistance parameters

A statistically significant decrease of HOMA-IR index wasrecorded after 9 and 12 months compared to baseline withexenatide, whereas we did not observe any statistically sig-nificant variations with glibenclamide. Furthermore, theHOMA-IR index obtained with exenatide was significantlylower than the value obtained with glibenclamide after 9 and12 months (Tables 2 and 3).

Resistin and RBP-4 values were significantly decreasedafter 6, 9, and 12 months compared to baseline with exenatide,whereas they increased with glibenclamide after 12 months.Moreover, resistin and RBP-4 value obtained with exenatidewere significantly lower than the values recorded with glib-enclamide after 9 and 12 months (Tables 2 and 3).

Inflammatory state

A significant decrease of Hs-CRP value was obtained after6, 9, and 12 months compared to baseline with exenatide,whereas there were no statistically significant variations withglibenclamide. Furthermore, the Hs-CRP value obtained withexenatide was significantly lower than the value observedwith glibenclamide after 12 months (Tables 2 and 3).

Correlations

There was a significant correlation between BMI valuedecrease and RBP-4 (r¼ 0.64, P< 0.001) (Fig. 1) and resistindecrease (r¼ 0.59, P< 0.001) in the exenatide group after

Table 2. Data During the Study for Patients in the Exenatide Group

Exenatide group

3 months 6 months 9 months 12 months

Number 61 60 59 59Sex (M=F) 30=31 29=31 29=30 29=30Smoking status (M=F) 16=12 13=12 13=12 13=12Weight (kg) 80.3� 7.9 78.0� 6.8*{ 76.0� 5.3**{{ 74.0� 4.1***{{{

BMI (kg=m2) 28.1� 1.4 27.3� 1.1*{ 26.6� 0.8**{{ 25.9� 0.7***{{{

HbA1c (%) 8.3� 0.6 8.1� 0.5* 7.7� 0.4** 7.3� 0.3***FPG (mg=dL) 137� 14 132� 12* 123� 10** 117� 8***PPG (mg=dL) 188� 25 179� 21* 172� 19** 164� 17***FPI (mU=mL) 18.3� 3.8 17.2� 3.4 15.6� 2.9*{ 14.1� 2.6**{{

HOMA-IR index 6.2� 2.1 5.7� 1.8 4.8� 1.5*{ 4.1� 1.1**{{

HOMA-b index 60.1� 53.4 63.2� 55.8 66.9� 54.7* 69.5� 56.2**{

PPr (pmol=L) 42.6� 28.2 39.4� 27.1 34.3� 25.7* 30.3� 23.8**PPr=FPI ratio 0.39� 1.51 0.38� 1.42 0.37� 1.38{ 0.36� 1.36{{

Resistin (ng=mL) 5.9� 1.3 5.8� 1.2* 5.2� 1.1**{ 5.0� 0.9***{{

RBP-4 (mg=mL) 34.2� 8.3 29.2� 7.8* 24.8� 6.7**{ 20.6� 5.4***{{

Hs-CRP (mg=L) 1.9� 0.6 1.8� 0.5* 1.6� 0.4** 1.5� 0.3***{

Data are mean� SD values.*P< 0.05, **P< 0.01, ***P< 0.001 versus baseline; {P< 0.05, {{P< 0.01, {{{P< 0.001 versus glibenclamide.

236 DEROSA ET AL.

12 months of therapy (Fig. 2). In contrast, there was no cor-relation between RBP-4 or resistin with BMI in the grouptreated with glibenclamide.

Discussion

Results from three large 30-week trials testing the additionof exenatide to metformin alone,10 sulfonylurea alone,11 ormetformin and sulfonylurea together12 as well as three trialsthat compared exenatide with insulin glargine or biphasicinsulin28–30 are available in the literature. A reduction frombaseline levels of approximately 1.0% in HbA1c was noted inall trials, whereas weight decreased by 0.9–2.5 kg, dependingon the study. The data emerging from our study showed thatboth exenatide and glibenclamide gave a similar improve-ment of glycemic control, improving HbA1c, FPG, and PPG,even if exenatide had more positive effects compared toglibenclamide on body weight, b-cell function, insulin resis-

tance, and inflammation state. We observed that after 12months of treatment there was a body weight decrease of8.0 kg with exenatide and an increase of 4.3 kg with glib-enclamide, partially confirming what already reported by theUnited Kingdom Prospective Diabetes Study about sulfo-nylureas giving a weight gain of about 5 kg over 10 years.31

We observed a greater decrease in body weight with exena-tide compared to the previously reported studies, probablybecause we placed diet and exercise therapy as a high priority.Furthermore, the previously reported studies lasted 30 weeks,whereas our study lasted 52 weeks; the greater weight loss weobserved can also be partially due to the continued weightloss of patients on exenatide between 30 and 52 weeks. Thepositive effects showed by exenatide on body weight need tobe underlined because despite the emphasis placed on weightloss in the management of T2DM and the association of excessweight with poorer metabolic control and cardiovascular riskprofile, many antidiabetes treatments are associated with

Table 3. Data During the Study for Patients in the Glibenclamide Group

Glibenclamide group

3 months 6 months 9 months 12 months

Number 62 61 60 57Sex (M=F) 32=30 31=30 31=29 29=28Smoking status (M=F) 13=12 13=11 13=11 12=11Weight (kg) 82.8� 9.3 83.6� 9.8 84.8� 10.2 86.7� 11.2*BMI (kg=m2) 28.7� 1.5 28.9� 1.7 29.3� 1.8 30.0� 1.9*HbA1c (%) 8.4� 0.6 8.0� 0.5* 7.6� 0.4** 7.1� 0.2***FPG (mg=dL) 135� 13 130� 11* 120� 9** 115� 7***PPG (mg=dL) 186� 23 176� 20* 169� 18** 161� 16***FPI (mU=mL) 21.5� 4.9 22.9� 5.1 23.7� 5.3* 24.2� 5.5**HOMA-IR index 7.2� 2.5 7.4� 2.6 7.1� 2.4 6.9� 2.2HOMA-b index 58.1� 50.3 57.6� 49.2 57.2� 48.6 56.8� 48.1PPr (pmol=L) 43.9� 30.6 40.2� 27.5 33.6� 25.2* 29.1� 23.1**PPr=FPI ratio 0.34� 1.31 0.29� 1.27 0.24� 1.23* 0.20� 1.21**Resistin (ng=mL) 6.3� 1.6 6.4� 1.7 6.6� 1.9 6.7� 2.0*RBP-4 (mg=mL) 39.2� 9.1 39.8� 9.4 41.3� 9.9 42.9� 10.5*Hs-CRP (mg=L) 1.9� 0.6 1.9� 0.6 1.8� 0.5 1.8� 0.5

Data are mean� SD values.*P< 0.05, **P< 0.01, ***P< 0.001 versus baseline.

FIG. 1. Correlation between BMI and RBP-4 after 12months of exanatide treatment.

FIG. 2. Correlation between BMI and resistin after 12months of exanatide treatment.

EXENATIDE VERSUS GLIBENCLAMIDE IN DIABETES 237

weight gain.32 Insulin treatment, for example, is typically as-sociated with an increase in weight, and, with the exception ofmetformin and acarbose, oral agents are also responsible for acertain degree of weight gain. It has been already reported inthe literature that obesity worsens hyperglycemia, hyper-insulinemia, insulin resistance, and dyslipidemia33; obesity isalso a risk factor for nonalcoholic fatty liver disease, hyper-tension, and cardiovascular disease,34,35 and reducing bodyweight with exenatide has positive effects also on these fac-tors.

Regarding insulin resistance and b-cell function parame-ters, it has been observed that a high HOMA-IR index and alow HOMA-b index were independently and consistentlyassociated with an increased diabetes risk in a multiethniccohort of U.S. post-menopausal women.36 Furthermore, inT2DM patients the HOMA-b index was reduced compared tothe normal glucose tolerance subjects, in which the HOMA-IRindex was increased. Also, both the fasting PPr concentrationand the ratio of fasting PPr=FPI of the T2DM patients weresignificantly higher compared to normal glucose tolerancesubjects37 because of the defective conversion of proinsulin toinsulin. Data from our study showed that exenatide gave adecrease of HOMA-IR index, an increase of HOMA-b index, adecrease of FPI, and a decrease of PPr, confirming what hasalready been reported in the literature10–13 that exenatideimproved the insulin resistance and protected b-cell function.Moreover, PPr has also been demonstrated to be an inde-pendent cardiovascular risk factor by stimulating plasmino-gen activator inhibitor-1 secretion and blocking fibrinolysis38;exenatide, by reducing PPr levels, might also give a decreaseof cardiovascular risk.

Our data confirmed what has already been reported byMoretto et al.39: exenatide was associated with an improve-ment of HbA1c, fasting and postprandial glucose control, andb-cell function (HOMA-b index), with a reduction of bodyweight, and was well tolerated. Compared to the other studiesreported in literature, our study also showed the positive ef-fects of exenatide on insulin resistance and inflammatory stateparameters like resistin, RBP-4, and Hs-CRP. We observed anincrease of resistin and RBP-4 in the glibenclamide group,wheres there was a decrease of resistin, RBP-4, and Hs-CRP inpatients treated with exenatide. In humans, resistin is pro-duced by mononuclear cells and activated macrophages; ithas been demonstrated that overexpression of resistin de-creases the ability of insulin to suppress hepatic glucose out-put or increase glucose uptake by muscle.40–42 Available datasupport also a role of resistin in determining an increase ofinflammation and atherosclerosis.43 Also, RBP-4 concentra-tion has been reported to be increased in subjects with obesity,insulin resistance, or type 2 diabetes compared with leansubjects,44 even if the mechanisms by which RBP-4 inducesinsulin resistance are not well understood. Hs-CRP is a mar-ker of inflammation, which has been shown in several pro-spective studies to independently predict myocardialinfarction, stroke, and peripheral artery disease.45 Exenatidedecreased resistin, RBP-4, and Hs-CRP; considering what isreported above about these parameters, we can safely assumethat their improvement can be related to a reduction of in-flammatory state, atherosclerosis, and insulin resistance inpatients with diabetes.

Regarding adverse reactions to exenatide, nausea andgastrointestinal complaints were the most common side ef-

fects reported in literature10–13 and were often temporary innature; in our study there were no statistically significantdifferences between the exenatide and glibenclamide groups.

Of course, our study has some limitations: for example, wedid not evaluate if the beneficial effects on b-cell function,glycemic control, body weight, and inflammatory parameterswere sustained after the cessation of therapy, even if it hasalready been reported46 that active treatment is necessary tomaintain these beneficial effects of exenatide in patients inwhom oral blood glucose-lowering therapy has failed. An-other limitation is that we evaluated a limited number of in-flammation biomarkers, concentrating our attention on a fewof these. However, at the best of our knowledge, this is thefirst study investigating the effect of exenatide on inflamma-tion parameters.

Conclusions

Both exenatide and glibenclamide gave a similar im-provement of glycemic control, but only exenatide was as-sociated with improvements in measures of insulin resistanceand preserved b-cell function, giving also a decrease of bodyweight and a decrease of some inflammatory parameters. Wecan safely say that exenatide was effective and well toleratedin patients with T2DM compared to glibenclamide.

Author Disclosure Statement

The authors certify that they have no affiliation with, orfinancial involvement in, any organization or entity with adirect financial interest in the subject matter or materialsdiscussed in the article.

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Address correspondence to:Giuseppe Derosa, M.D., Ph.D.

Department of Internal Medicine and TherapeuticsUniversity of Pavia

Fondazione IRCCS Policlinico S. Matteo, PaviaP.le C. Golgi, 2

27100 Pavia, Italy

E-mail: giuseppe.derosa@unipv.it

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