At Glnce Prcticl Implictio p e102 Author Informtion p e107 Full text nd PDF Web exclusive Potentil Gender Differences of Exentide in Outptients With Type 2 Dibetes Mellitus Originl Reserch Antonio C. Bossi, MD; Ann Pulcin, MD; Eunice O. Ah, MD; Annlis Blini, MD; Denise Berzi, MD; Gincrl Mereglli, MD; nd Giovnni Veronesi, PhD Type 2 dibetes mellitus (T2DM) represents n emerging burden in developing countries nd in developed ntio. In Itly, the prevlence ws 3.9% in 2001, but in 2007 it reched 4.7% n increse of 15% in 6 yers. Itly s ntionl helth system hs to ber the cost of this expeive disese nd its chronic complictio, 1 mong which, crdiovsculr (CV) disese represents the leding cuse of mortlity. Among women with dibetes, neither ll-cuse nor CV disese mortlity declined between 1971 to 1986, nd 1988 to 2000. The ll-cuse mortlity rte difference between women with nd without dibetes more thn doubled (from difference of 8.3 to 18.2 nnul deths per 1000 perso). 2 Furthermore, the effects of some clssicl glucose-lowering therpies on CV events re controversil. Twice-dily injectio of exentide, GLP-1 receptor gonist (GLP-1 RA), hve recently become vilble for Itlin ptients with dibetes who did not chieve dequte glycemic control with diet, exercise, nd tretment (ie, monotherpy or combintion tretment with metformin nd sulphonylure, or pioglitzone). Exentide reduces glycted hemoglobin (A1C) nd body weight (BW), with improvement in CV risk fctors in some but not ll ptients. 3 Few dt exist bout gender differences concerning the use of exentide in rel-world settings. STUDY DESIGN AND METHODS We retrospectively studied 69 outptients with type 2 dibetes mellitus (34 mle nd 35 femle; men ge = 52.6 yers [SD = 10.3]; men durtion of dibetes = 9.4 yers [SD = 5.4]) with persistent exentide tretment, nd collected nthropometric (ie, height, BW, body mss index [BMI], wist circumference [WC]), clinicl, nd metbolic prmeters (Tble 1). In ccordnce with the Itlin Phrmcologicl Agency, exentide ws dded to clssicl ntidibetic tretment in order to chieve dequte metbolic control. At bseline, men nd women did not differ substntilly in preexisting therpy. Thirty-two men were on metformin (6 on metformin lone nd 26 in combintion with sulphonylure); nd 2 were on sulphonylure (ie, glyburide ABSTRACT Objectives: Exentide, glucgon-like peptide 1 (GLP-1) receptor gonist, reduces glycted hemoglobin (A1C) nd body weight (BW) nd improves crdiovsculr (CV) risk fctors in some but not ll ptients. This study ws plnned to evlute potentil gender difference of exentide s effects in dibetic subjects. Study Design: A retrospective study compring metbolic control nd chnges in weight, wist circumference, nd body mss index ccording to gender. Methods: We retrospectively collected clinicl dt from 69 outptients with type 2 dibetes mellitus (34 mle nd 35 femle), men ge = 52.6 yers (SD = 10.3); men durtion of dibetes = 9.4 yers (SD = 5.4) with persistent exentide tretment, evluting the evolution of nthropometric, clinicl, nd metbolic prmeters. Results: Exentide rpidly reduced A1C, fsting plsm glucose (FPG), BW, nd wist circumference (WC) in both genders (ll P vlues <.0001). WC ws more reduced in women fter 12 months of tretment (P =.02). After 24 months, ptients showed stble reduction of A1C nd FPG (ll P vlues <.0001 vs bseline) without ny gender-relted difference, while BW lowering ws more pronounced in women compred with men (P =.002). Conclusio: Exentide effected sustined improvement in metbolic nd nthropometric prmeters in both genders, but BW nd WC were more reduced in femles. The women with dibetes experienced more prominent therpeutic benefit for some CV risk fctors nd reduction in wist circumference nd body weight. Am J Phrm Benefits. 2015;7(4):e101-e107 Vol. 7, No. 4 The Americn Journl of Phrmcy Benefits e101
n Bossi Pulcin Ah Blini PRACTICAL IMPLICATIONS n Exentide, GLP-1 receptor gonist, reduces glycted hemoglobin (A1C) nd body weight (BW), with improvement in crdiovsculr risk fctors in some, but not ll, ptients with dibetes. This retrospective study evluted potentil gender difference of exentide. n Exentide rpidly reduced A1C nd glycemi in both genders. n Wist girth ws more reduced in women fter 12 months of tretment. After 24 months, BW lowering ws more pronounced in women compred with men. n The women with dibetes experienced more prominent therpeutic benefit from exentide thn men for some CV risk fctors, s well s reduction in wist circumference nd BW. [15], glimepiride [6], gliclzide [5], gliquidone [1], nd repglinide [1]) monotherpy. Thirty-four women were treted with metformin (10 with metformin lone nd 24 in combintion with sulphonylure); nd 1 womn ws on sulphonylure (ie, glyburide [12], glimepiride [6], gliclzide [6], nd repglinide [1]) monotherpy. One womn treted with combintion of metformin nd sulphonylure (glyburide) ws lso in therpy with pioglitzone. Urine nd blood smples were collected in the morning fter 12-hour fst, except for post prndil glucose, which ws collected 2 hours fter lunch; urine nd serum chemistry vlues were determined in our hospitl lbortory with routine methods. Blood pressure (BP) ws mesured with certified sphygmomnometer twice ech visit fter the ptients st for 15 minutes. The men of the 2 mesurements ws recorded. The retrospective study protocol ws pproved by our independent locl ethics committee nd ws conducted in ccordnce with the World Medicl Assocition Declrtion of Helsinki. 4 Sttisticl Anlysis We coidered only ptients with persistent exentide tretment (N = 69); of those, 36 (19 men nd 17 women) reched 2-yer period of follow-up. We did not coider ( priori exclusion) those who bndoned the prescribed exentide therpy, whether for side effects or ny personl or clinicl reson. Metbolic, clinicl, nd nthropometric prmeters were summrized by me of descriptive sttistics for ll the subjects nd by sex. To highlight gender-relted differences t bseline, we dopted t test for independent dt. To describe the vrition over time of given prmeter, we used repeted-mesure model coidering the bseline nd up to 3 follow-up ssessments (month 4, 8, nd 12 from bseline), without specifying ny functionl trend for time. Age nd dibetes durtion were included s covrite into the model. The covrince structure ws compound symmetry; we were not ble to find meningful chnges when more complex models were dopted. In Tble 2, we report the pired t test to ssess whether the chnge from bseline t ny given visit ws different from 0. We then dded sex visit interction term to the model nd tested whether there ws chnge t 12 months from bseline for given prmeter differed by gender. The bovementioned nlysis ws replicted: 1) excluding those with some missing informtion t ny point in time nd 2) dding the 24-month visit for those subjects with 24-month follow-up period (n = 36). All nlyses were conducted using SAS PROC MIXED version 9.1.3 softwre (SAS Ititute, Cry, North Crolin). RESULTS nd women showed typicl gender differences in height nd high-deity lipoprotein cholesterol (where HDL-C is generlly higher in women) (Tble 1). BMI nd low-deity lipoprotein cholesterol were both higher in femles with dibetes thn in mles with dibetes (P =.04 nd P =.05, respectively). As shown in Tble 2, exentide rpidly reduced A1C, fsting plsm glucose (FPG), BW, nd WC in both men nd women (ll P <.0001). Systolic nd distolic BP did not significntly chnge fter the first yer of observtion. When coidering gender distribution of A1C, FPG, nd BP, we did not observe ny difference between mles nd femles; however, both BW nd WC were more reduced in women thn in men (Tble 3). Similr findings were obtined when we excluded those subjects with some missing informtion (dt not shown). Furthermore, focusing our ttention on ptients with persistent exentide tretment for 24 months (Figure), we recorded stble nd significnt reductio of A1C nd FPG, with progressive decline of BW ( 4.4 kg, 5.5 kg, 5.9 kg, nd 6.7 kg, respectively, fter 4, 8, 12, nd 24 months; P <.0001 vs bsl vlue t ech time of observtion). Once gin, dichotomizing our ptients by gender, we did not find ny differences in the reduction of A1C nd FPG, lthough BW lowering ws more rpid nd pronounced in women compred with men (Tble 4). DISCUSSION cotitute 51.45% (pproximtely 30 million) of the Itlin popultion. Currently, dibetes is more frequent mong Itlin femles thn mles (5% prevlence vs 4.6%), nd it is estimted tht nerly 3 million Itli e102 The Americn Journl of Phrmcy Benefits July/August 2015
Possible Gender Effects of Exentide Tble 1. Clinicl Fetures of Studied Subjects With Dibetes t the Bsl Level Subjects With Dibetes P N 69 34 35 Age (yers) 52.6 (10.3) 51.7 (11.0) 53.4 (9.7) Durtion of dibetes (yers) 9.4 (5.4) 10.0 (5.6) 8.8 (5.2) Weight (kg) 107.0 (21.3) 111.0 (23.2) 103.0 (18.7) Height (cm) 167.5 (9.7) 174.8 (6.7) 160.4 (6.5) <.0001 BMI 38.2 (7.3) 36.4 (7.5) 40.0 (6.7).04 Wist circumference (cm) 119.0 (12.1) 118.7 (13.1) 119.3 (11.3) SBP (mm HG) 136.9 (17.0) 136.6 (18.0) 137.1 (16.3) DBP (mm HG) 80.2 (7.8) 79.7 (8.9) 80.7 (6.8) A1C (%) 9.4 (1.3) 9.4 (1.2) 9.5 (1.4) (mmol/mol) 79 (11.9) 79 (10.8) 108 (13) FPG (mg/dl) 204.2 (52.1) 213.8 (58.6) 194.9 (43.9) (mmol/l) 11.25 (2.87) 11.78 (3.22) 10.73 (2.41) Post prndil glucose (mg/dl) 198.4 (59.7) 204.3 (57.9) 192.5 (61.9) (mmol/l) 10.93 (3.28) 11.25 (3.19) 10.6 (3.41) Microlbuminuri (mg/l) 54.8 (141.7) 57.1 (159.5) 52.2 (121.9) Totl cholesterol (mg/dl) 192.4 (37.2) 186.0 (35.4) 198.9 (38.5) (mmol/l) 4.97 (0.96) 4.80 (0.91) 5.14 (0.99) HDL-C b (mg/dl) 43.5 (12.2) 39.6 (8.9) 47.6 (13.9) (mmol/l) 1.12 (0.31) 1.02 (0.23) 1.23 (0.35).007 LDL-C b (mg/dl) 109.0 (30.4) 101.0 (33.2) 116.9 (25.5) (mmol/l) 2.81 (0.78) 2.61 (0.85) 3.02 (0.65).05 Triglycerides (mg/dl) 212.5 (147.7) 214.8 (82.0) 210.2 (195.1) (mmol/l) 2.42 (1.68) 2.44 (0.93) 2.39 (2.22) BMI indictes body mss index; DBP, distolic blood pressure; FPG, fsting plsm glucose; HDL-C, high-deity lipoprotein cholesterol; LDL-C, low-deity lipoprotein cholesterol;, not significnt; SBP, systolic blood pressure. Dt vilble for 57 subjects (30 men, 27 women). b Dt vilble for 54 subjects (27 men, 27 women). Dt re expressed s men ± SD. The P vlue is testing the difference between men nd women (noignificnt = P >.05). suffer from this metbolic disese. 5 The prevlence of T2DM increses proportionlly with ge, nd the difference in life expectncy my ccount for the different prevlence of dibetes between genders, with the verge lifespn being 6 yers longer in women thn in men. Furthermore, CV disese is the leding cuse of deth mong women in Itly, with >40% of deths ttributed to this disese, nd ccounting for 50% of deths in femles 65 yers or older. For this reson, conditio in women require prticulr ttention s fr s both prevention nd therpy re concerned. Gender differences my lso be relevnt in the mngement of T2DM, s dt from the Dibetes Prevention Progrm showed some sex-specific differences, 6 while other popultion trils hve underlined the differences between men nd women in the effects of vrious CV risk fctors. 7,8 Additionlly, the reltive risk of ftl coronry hert disese ssocited with dibetes ws found to be 50% higher in women thn in men. 9 In study of outptients with dibetes, 3 women with T2DM hd worse CV risk profile nd chieved therpeutic gols less frequently thn did men. Add-on therpy with exentide my provide n dvntge, s suggested by some studies 10,11 in which djunctive exentide tretment resulted in sustined improvement in glucose metbolism nd nthropometric prmeters, s well s in CV risk fctors. In our study, we observed uniform reduction of A1C nd decrese of FPG in the group treted with exentide, even if not t levels reching the desired therpeutic trgets (Tble 2; Figure). However, the observed A1C reduction ws even better thn tht recorded by the Itlin report on new ntidibetic drugs (Δ = 0.93%). 12 Although we cnnot exclude tht our findings could t lest in prt be explined by lifestyle differences, gender-relted psychologicl/body imge issues, nd the Vol. 7, No. 4 The Americn Journl of Phrmcy Benefits e103
n Bossi Pulcin Ah Blini Tble 2. Evolution of Min Clinicl Prmeters 4, 8, nd 12 Months After Exentide Add-on Tretment Bsl After 4 Months After 8 Months After 12 Months Vlue N Difference N Difference N Difference A1C (%) 9.5 1.5 b 1.5 b 1.6 b 63 55 51 (mmol/mol) 80 14 b 14 b 15.1 b FPG (mg/dl) 207.7 37.5 b 43.6 b 46.5 b 64 58 53 (mmol/l) 11.44 2.06 b 2.40 b 2.56 b Weight (kg) 105.7 65 4.2 b 59 4.8 b 53 5.6 b Wist circumference (cm) 118.5 59 4.1 b 49 4.9 b 50 5.2 b SBP (mm Hg) 136.8 63 1.2 55 1.0 50 4.8 DBP (mm Hg) 80.2 62 0.2 55 0.2 50 1.2 A1C indictes glycted hemoglobin; DBP, distolic blood pressure; FPG, fsting plsm glucose; N, number of nonmissing observtio; SBP, systolic blood pressure. Averge difference between bseline vlue nd every follow-up ssessment, t 4, 8, nd 12 months fter the beginning of the tretment with exentide. b Difference test = 0; t test for pired dt; P <.0001. fct tht femles with dibetes hd significntly higher BMIs t bseline compred with the mle ptients, we observed tht BW nd WC reductio were more pronounced in women thn in men fter 12 months of exentide tretment (Tble 3). Our ptients showed reduction of BW with significnt gender difference ( 7.6 kg in women nd 3.4 kg in men; P =.0001) (Tble 2); women lso hd greter reduction of wistline ( 6.5 cm) in comprison with men ( 3.6 cm; P =.02) (Tble 3). In those completing 24 months of tretment, we did not record ny significnt gender difference in the reduction of A1C or of FPG (Figure; Tble 4). However, on weight mesures, femles showed reduction of 8.7 kg versus 3.7 kg in men (P =.002) (Tble 4). Our rel-world dt, while confirming the cceptble glycemic efficcy of exentide in both sexes, demotrted better nthropometric respoe in women with dibetes. A recent retrospective met-nlysis of 16 studies, including 2067 ptients with dibetes treted with exentide, did not show ny gender difference regrding glycemic control, lthough the observed weight loss ws significntly higher in femles thn in mles. 13 To potentilly explin the observed gender difference in our ptients, it ws suggested tht in norml-weight individuls, the elicited secretion of endogenous GLP-1 by me of fiber-rich nutrients is greter in women. 14 Phrmcologiclly, possible interference with previous clssic ntidibetic tretment ppers unlikely, becuse similr proportio of men nd women were treted with metformin s monotherpy, nd metformin nd sulphonylure in combintion. Moreover, t the end of the observtion (24-month completers), we registered the suspeion of sulphonylure in 6 men nd in 6 women, nd sulphonylure dose-reduction in 9 men nd in 2 women; however, men demotrted no dvntge of this reduction in terms of mjor decrese in BW. We did not dd exentide to iulin-treted T2DM ptients becuse of specific contrindiction defined by the Itlin regultory system. However, the ddition of GLP-1 nlogues to iulin in ptients with T2DM should be ssocited with reduction in A1C, BW, nd iulin dose, long with low risk of hypoglycemi nd high tretment stisfction, s reported by recent Swedish study. 15 According to efficcy-bsed guidelines for prevention of CV disese in femles, weight mngement (mong other recommendtio) hs to be implemented for ll women, becuse obesity is one of the most importnt risk fctors for developing T2DM, nd becuse the presence of dibetes increses womn s risk for CV disese. 16 GLP-1 RAs (eg, exentide twice dily, exentide once week, lirglutide, lixisentide) nd dipeptidyl peptidse-4 (DPP-4) inhibitors (eg, sitgliptin, vildgliptin, sxgliptin, lingliptin, logliptin), presently vilble in Itly, re new drugs tht cn significntly reduce A1C if given in monotherpy or in combintion with other ntidibetic drugs. These incretin-bsed therpies hve very low risk for the development of hypoglycemi, nd either decrese BW (GLP-1 nlogues) or hve neutrl effect on it (DPP-4 inhibitors). 17 The low risk of hypoglycemi is very importnt dvntge becuse, ccording to the Action to Control Crdiovsculr Risk in Dibetes (ACCORD) Study, 18 higher mortlity is ssocited with hypoglycemi in both inteive glycemic nd conventionl tretment rms. Therefore, when there is need to inteify glucose control, hypoglycemi my increse CV risk nd counter the benefits of reducing hyperglycemi. Moreover, incretin drugs offer coiderble promise s me of trgeting the primry defect in T2DM: exentide (nd other GLP-1 RAs) exert positive beneficil effects on the β-cells, thereby limiting the disese progression nd e104 The Americn Journl of Phrmcy Benefits July/August 2015
Possible Gender Effects of Exentide Tble 3. Gender Evolution of Clinicl Prmeters After 12 Months Bsl Δ After 12 Months Bsl Δ After 12 Months P A1C (%) 9.4 1.5 9.6 1.7 (mmol/mol) 79 14 81 16.59 FPG (mg/dl) 217.3 49.1 198.4 43.8 (mmol/l) 11.97 2.70 10.93 2.41.68 Weight (kg) 108.5 3.4 102.9 7.6.0001 Wist circumference (cm) 117.9 3.6 119.1 6.5.02 SBP (mmhg) 137.0 2.1 136.6 7.1.30 DBP (mmhg) 79.7 0.1 78.2 2.4.32 A1C indictes glycted hemoglobin; Δ (delt), difference; DBP, distolic blood pressure; FPG, fsting plsm glucose; SBP, systolic blood pressure. P difference test: the nlysis performed to ssess potentil sttisticl difference between men nd women of the observed vrition during time of the interested prmeters (djusted for ge nd durtion of dibetes). Evolution expressed s Δ: the verge difference from bsl vlues. the development of its complictio. 19 Furthermore, exentide improved glycemic control, reduced BW, nd ws ssocited with lower risk of CV events in comprison with other hypoglycemic gents. 20 In recent observtion from nother Itlin group, 21 trget glycemic respoe ws chieved in significntly higher proportion of mles thn femles, while trget weight loss rbitrrily expressed s 1-yer percent loss 75th percentile in the whole popultion (8.5%) ws more often chieved mong femles t 8 months (28% vs 15%; χ 2 = 8.04; P =.004) nd 12 months (33% vs 17%; χ 2 = 10.98; P =.0009). After substituting body weight with BMI, the results did not chnge. These observtio highlight gender difference in the nthropometric evolution during exentide tretment. We observed similr A1C evolution in both genders with dibetes, with more fvorble reduction in BW nd WC in women, confirming the observtion of the Itlin group 21 nd tht in the nlysis by Pencek nd collegues, 13 in which the finl weight loss observed in ptients ws likewise significntly higher in femles thn in mles. However, lthough the evolution of glycemic control nd BW loss fter 12 months of exentide therpy should be predicted Figure. Evolution of Some Clinicl Prmeters in 36 Ptients Tht Reched 2-Yer Period of Follow-up A1C Fsting Plsm Glucose Weight A1C (%) 10.0 9.5 9.0 8.5 8.0 7.5 All subjects Fsting Plsm Glucose (mg/dl) 220 210 205 190 180 170 160 150 140 All subjects Weight (kg) 110 105 100 95 All subjects 7.0 130 90 0 4 8 12 24 0 4 8 12 24 0 4 8 12 24 Months From Bseline Months From Bseline Months From Bseline A1C indictes glycted hemoglobin. The 36 ptient were comprised of 19 men nd 17 women. A1C (%), fsting plsm glucose (mg/dl), nd body weight (kg) fter 4, 8, 12, nd 24 months of persistent tretment with exentide. Difference test = 0; t test for pired dt; P <.0001 for ll subjects in comprison with bseline levels, t every period of observtion (4, 8, 12, nd 24 months). Vol. 7, No. 4 The Americn Journl of Phrmcy Benefits e105
n Bossi Pulcin Ah Blini Tble 4. Gender Evolution of Some Clinicl Prmeters After 4, 12, nd 24 Months in 36 Ptients With Complete 2-Yer Follow-up Period Vlue Δ From Bsl Vlue Vlue Δ From Bsl Vlue P b A1C % (mmol/mol) Bsl 9.2 (77) 9.4 (79) 4 months 7.7 (61) 1.5 ( 16) 7.8 (62) 1.6 ( 17) 12 months 7.8 (62) 1.4 ( 15) 7.5 (61) 1.9 ( 18) 24 months 7.7 (61) 1.5 ( 16) 7.6 (60) 1.8 ( 19) FPG mg/dl Bsl 213.5 (11.76) 193.6 4 months 168.6 (9.28) 44.9 ( 2.47) 148.7 44.9 ( 2.47) 12 months 165.8 (9.13) 47.7 ( 2.62) 146.0 47.6 ( 2.62) 24 months 163.5 (9.0) 50.1 ( 2.76) 149.1 44.5 ( 2.45) Weight (kg) Bsl 104.5 100.5 4 months 101.9 2.6 94.1 6.4.01 12 months 100.7 3.8 92.0 8.5.003 24 months 100.9 3.7 91.8 8.7.002 A1C indictes glycted hemoglobin; Δ (delt), difference; FPG, fsting plsm glucose;, not significnt. The 36 ptient were comprised of 19 men nd 17 women. b P difference test: the nlysis performed to ssess potentil sttisticl difference between men nd women of the observed vrition during time of the interested prmeters (djusted for ge nd durtion of dibetes). Evolution expressed s Δ: the verge difference from bseline. in different wys between genders in T2DM, 21 the intriic mechnisms of weight loss obtined with GLP-1 receptor gonists re not fully understood. The higher men BMI observed in women (Tble 1) my hve contributed to greter weight loss fter exentide, but this difference is not reported in the popultion of Anichini nd collegues. 21 Moreover, GLP-1 RAs decrese the rte of gstric emptying, reduce ppetite, nd promote stiety, but they my lso provide chnges in energy expenditure nd in leptin seitivity, or cuse nuse resulting in decresed food intke fctors ll leding to dipose tissue reduction. Ltely, short-term exentide tretment hs been ssocited with modest weight loss nd decresed WC in cohort of obese nondibetic women. 22 Recent dt suggest tht, during mel, GLP-1 cn simultneously exert n incretin effect on iulin secretion nd protective effect on endothelil function, resonbly controlling oxidtive stress genertion. 23 The prospect of CV protection in ptients treted with exentide is very encourging becuse these ptients usully hve other comorbidities in ddition to T2DM. ctully hve fewer bsl risk fctors thn men, but ccording to n Itlin report, they re more sedentry nd re dignosed to hve dibetes 3 yers lter thn men. 24 Furthermore, recent study reports tht women re more obese thn men t the time of dignosis of dibetes. 25 So, we my hypothesize tht femles should revel greter seitivity to reducing weight fter exentide therpy. Limittio nd Strengths There re severl limittio of this study, primrily the smll number of studied subjects nd the inclusion of only completers in the nlysis. Another limittion is the study s retrospective observtionl design nd the lck of control group. Possible confounding fctors to be coidered in the results evlution re incresed physicl ctivity or chnges in eting hbits due to initil fvorble results obtined with the novel therpy, which could prtilly explin the noted effects. Generl side effects such s nuse nd vomiting were not studied in detil since we coidered only ptients with persistent exentide tretment; those who bndoned the prescribed therpy were excluded priori. Moreover, we were not ble to record hypoglycemic events, once gin becuse of the retrospective design of the study. On the other hnd, in our rel-world study popultion, we did not observe ny mjor dverse event such s pncretitis or pncretic cncer. A strength of the study is the quite long period of observtion, nd the opportunity to strtify our ptients by gender, prtilly confirming nd reinforcing previous e106 The Americn Journl of Phrmcy Benefits July/August 2015
Possible Gender Effects of Exentide observtio. 13,21 Finlly, it is to be coidered tht this investigtion took clinicl settings into ccount; new incretin-bsed therpies cnnot, however, be detched from lifestyle modifiction. Preventing CV disese is fundmentl in both sexes, especilly in women who tend to be less physiclly ctive thn men. The most dngerous risk fctor for women, in Itly, is not coidering CV disese s pthology prticulrly relevnt to femles. Tretment strtegies should be improved in both sexes, but women with dibetes should receive more ggressive therpy, especilly when CV complictio re present. CONCLUSIONS Persistent exentide tretment s dd-on therpy in T2DM my show gender difference in terms of clinicl results. In our clinicl prctice, s result of the study, we suggest exentide s the drug of choice in obese or overweight ptients suffering from T2DM, with the likelihood tht women with dibetes should experience more prominent therpeutic effect (in comprison with men) on some of their CV risk fctors but, due to the observtionl retrospective design of the present study, ny suggested gender difference during tretment with GLP-1 RAs needs confirmtion by trils designed specificlly to ddress this topic. Author Affilitio: Metbolic Diseses nd Dibetes Unit, Treviglio-Crvggio Hospitl (ACB, AP, AB, DB, GM), Treviglio, Itly; Komfo Anokye Teching Hospitl (EOA), Kumsi, Republic of Ghn; Iubri University of Studies, EPIMED Reserch Center (GV), Vrese, Itly. Funding Source: None. Author Disclosures: Dr Bossi received reserch grnts from Eli Lilly, Novo Nordisk, nd coultnt/dvisor honorri from Johon & Johon nd Boehringer Ingelheim. Dr Blini obtined spoorship from Eli Lilly, nd reserch grnts from Novo Nordisk. Dr Berzi received spoorship from Snofi-ventis nd Eli Lilly. Drs Mereglli nd Veronesi obtined spoorship from Eli Lilly. Drs Pulcin nd Ah report no reltiohip or finncil interest with ny entity tht would pose conflict of interest with the subject mtter of this rticle. Authorship Informtion: Concept nd design (ACB); cquisition of dt (ACB, AP, AB, DB, GM); nlysis nd interprettion of dt (ACB, EOA, AP, AB, DB, GM, GV); drfting of the mnuscript (ACB, EOA); criticl revision of the mnuscript for importnt intellectul content (ACB, GV); sttisticl nlysis (GV); nd supervision (ACB). Send correspondence to: Antonio C. Bossi, MD, Metbolic Diseses nd Dibetes Unit Treviglio-Crvggio Hospitl, P.le Ospedle, 1 24047 Treviglio (BG), Itly. E-mil: ntonio_bossi@ospedle.treviglio.bg.it. REFERENCES 1. Lucioni C, Grncini MP, Mssi-Benedetti M, Mzzi S, Serr G; CODE-2 Itlin Advisory Bord. The costs of type 2 dibetes mellitus in Itly: CODE-2 sub-study. Tret Endocrinol. 2003;2(2):121-133. 2. Gregg EW, Gu Q, Cheng YJ, Nryn KM, Cowie CC. Mortlity trends in men nd women with dibetes, 1971-2000. Ann Intern Med. 2007;147(3):149-155. 3. Klonoff DC, Buse JB, Nielsen LL, et l. Exentide effects on dibetes, obesity, crdiovsculr risk fctors nd heptic biomrkers in ptients with type 2 dibetes treted for t lest 3 yers. Curr Med Res Opin. 2008;24(1):275-286. 4. Declrtion of Helsinki: Ethicl Principles for Medicl Reserch Involving Humn Subjects (2008 revision). World Medicl Assocition website. http://www. wm.net/en/30publictio/10policies/b3/17c.pdf. Published 2008. Accessed September 19, 2015. 5. Annurio Istt 2009: snità e slute in Itli. Centro Nzionle di Epidemiologi, Sorveglinz e Promozione dell Slute website. http://www.epicentro.iss.it/temi/ politiche_snitrie/nnurio_istt_09.sp [Itlin]. Published 2009. Accessed September 19, 2015. 6. Perreult L, M Y, Dgogo-Jck S, et l; Dibetes Prevention Progrm. Sex differences in dibetes risk nd the effect of inteive lifestyle modifiction in the Dibetes Prevention Progrm. Dibetes Cre. 2008;31(7):1416-1421. 7. Howrd BV, Cown LD, Go O, Welty TK, Robbi DC, Lee ET. Adverse effects of dibetes on multiple crdiovsculr disese risk fctors in women: the Strong Hert Study. Dibetes Cre. 1998;21(8):1258-1265. 8. Ridker PM, Rifi N, Rose L, Buring JE, Cook NR. Comprison of C-rective protein nd low-deity lipoprotein cholesterol levels in the prediction of first crdiovsculr events. N Engl J Med. 2002;347(20):1557-1565. 9. Huxley R, Brzi F, Woodwrd M. Excess risk of ftl coronry hert disese ssocited with dibetes in men nd women: met-nlysis of 37 prospective cohort studies. BMJ. 2006;332(7533):73-78. 10. Buysschert M, Preumont V, Oriot PR, et l; UCL Study Group for Exentide. One-yer metbolic outcomes in ptients with type 2 dibetes treted with exentide in routine prctice. Dibetes Metb. 2010;36(5):381-388. 11. Kutzky-Willer A, Kmyr MR, Gerht D, et l. Sex-specific differences in metbolic control, crdiovsculr risk, nd interventio in ptients with type 2 dibetes mellitus. Gend Med. 2010;7(6):571-583. 12. Registro frmci ntidibetici sottoposti monitorggio. Rpporto frmci incretino-mimetici e DPP-4 inibitori [Itlin report]. Rome, Itly: AIFA; 2010. 13. Pencek R, Blickederfer A, Li Y, Brunell SC, Anderson PW. Exentide twice dily: nlysis of effectiveness nd sfety dt strtified by ge, sex, rce, durtion of dibetes, nd body mss index. Postgrd Med. 2012;124(4):21-32. 14. Adm TC, Westerterp-Plnteng MS. Nutrient-stimulted GLP-1 relese in norml-weight men nd women. Horm Metb Res. 2005; 37(2):111-117. 15. Lind M, Jendle J, Torffvit O, Lger I. Glucgon-like peptide 1 (GLP-1) nlogue combined with iulin reduces HbA1c nd weight with low risk of hypoglycemi nd high tretment stisfction. Prim Cre Dibetes. 2012;6(1):41-46. 16. Mosc L, Benjmin EJ, Berr K, et l. Effectiveness-bsed guidelines for the prevention of crdiovsculr disese in women 2011 updte: guideline from the Americn Hert Assocition. Circultion. 2011;123(11):1243-1262. 17. Grber AL. Incretin-bsed therpies in the mngement of type 2 dibetes: rtionle nd relity in mnged cre setting. Am J Mng Cre. 2010;16(7 suppl):s187-s194. 18. ACCORD Study Group; Gerstein HC, Miller ME, Genuth S, et l. Long-term effects of inteive glucose lowering on crdiovsculr outcomes. N Engl J Med. 2011;364(9):818-828. 19. Holst JJ, Knop FK, Visbøll T, Krrup T, Mdsbd S. Loss of incretin effect is specific, importnt, nd erly chrcteristic of type 2 dibetes. Dibetes Cre. 2011;34(2 suppl):s251-s257. 20. Best JH, Hoogwerf BJ, Hermn WH, et l. Risk of crdiovsculr disese events in ptients with type 2 dibetes prescribed the glucgon-like peptide 1 (GLP1) receptor gonist exentide twice dily or other glucose-lowering therpies: retrospective nlysis of the LifeLink dtbse. Dibetes Cre. 2011;34(1):90-95. 21. R. Anichini, S. Cosimi, A. Di Crlo et l. Gender difference in respoe predictors fter 1-yer exentide therpy twice dily in type 2 dibetic ptients: rel world experience. Dibetes Metb Syndr Obes. 2013;6:123-129. 22. Dushy J, Go C, Goplkrishnn GS, et l. Short-term exentide tretment leds to significnt weight loss in subset of obese women without dibetes. Dibetes Cre. 2012;35(1):4-11. 23. Ceriello A, Esposito K, Test R, Bonfigli AR, Mrr M, Giuglino D. The possible protective role of glucgon-like peptide 1 on endothelium during the mel nd evidence for n endothelil resistnce to glucgon-like peptide 1 in dibetes. Dibetes Cre. 2011;34(3):697-702. 24. Simon Gimpoli. Istituto Superiore di Snità Rom. Obesità, stili di vit e rischio crdiovscolre. Itlin Ministry of Helth website. http://www.slute.gov.it/ imgs/c_17_newsaree_1092_listfile_itemnme_12_file.pdf [Itlin]. Published 2011. Accessed September 19, 2015. 25. Wnnmethee SG, Ppcost O, Lwlor DA, et l. Do women exhibit greter differences in estblished nd novel risk fctors between dibetes nd non-dibetes thn men? the British Regionl Hert Study nd British s Hert Helth Study. Dibetologi. 2012;55(1):80-87. 26. Vol. 7, No. 4 The Americn Journl of Phrmcy Benefits e107