Effects of Liraglutide , a Glucagon-Like Peptide-1 Analogue , on Metabolic Abnormalities and Body Weight in HIV-infected Subjects with or without Type 2 Diabetes

Objectives: To evaluate the effects of six-month liraglutide treatment on antiretroviral therapy (ART)-induced HIV-associated lipodystrophic syndrome (HALS) including diabetes mellitus (DM), lipodystrophy, and dyslipidemia in HIV-infected subjects with and DM. Methods: We performed a retrospective case-control study in which medical records of lipodystrophic HIV-infected subjects and HIV-uninfected obese subjects with or without DM who were treated with liraglutide for 6 months were analyzed. A group of HIV-uninfected obese subjects served as controls. Subjects were separated into 4 groups: lipodystrophic HIV-infected subjects without DM (HIV-DM) (N=30), lipodystrophic HIVinfected subjects with DM (HIV+DM) (N=32), obese subjects without DM (obese-DM) (N=32), and obese subjects with DM (obese+DM) (N=53). Changes in body weight, blood pressure (BP), and glucose and lipid profiles were investigated over 6 months of liraglutide treatment. Results: Body weights were significantly reduced in all groups except HIV–DM. Glucose profile mainly improved in the obese+DM group. Liraglutide treatment of HIV–DM subjects tended to decrease low density lipoprotein cholesterol (LDL-C) and total cholesterol/ high density lipoprotein cholesterol (TC/HDL-C). In HIV+DM subjects, there was a tendency to lower BP, TC, and non-HDL-C in response to liraglutide. In obese-DM subjects, liraglutide tended to lower TC/HDL, triglyceride (TG), logTG/HDL, non-HDL-C and LDL-C. In obese-DM subjects, fasting blood glucose (FBG) and TC were significantly reduced. In obese+DM subjects, liraglutide treatment tended to lower BP, non-HDL-C, FBG, and logTG/HDL-C. Conclusions: Six months of liraglutide treatment of HIV-infected subjects resulted in weight loss, which was statistically significant only in subjects with diabetes; it also improved several metabolic abnormalities associated with HALS.


Introduction
The widespread use of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection has prolonged survival of HIV-infected patients [1].However, use of ART has been associated with development of HIV-associated lipodystrophic syndrome (HALS), characterized by several metabolic abnormalities including lipodystrophy (body fat redistribution), insulin resistance, diabetes mellitus (DM), and dyslipidemia; all are major risk factors for an increase in incidence of cardiovascular disease [2,3].For the majority of the patients, these changes in body composition have adversely affected their quality of life, led to low self-esteem, and caused poor medication adherence [4].Furthermore, HALS-associated metabolic changes may increase the risk of cardiovascular disease [2,3].Medical therapies, such as recombinant growth hormone releasing factor analogues and metformin, have modest effects on body composition in HIV-infected subjects and/ or have significant metabolic side-effects [5,6].
Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has 97% homology to the peptide hormone secreted in the lower part of small intestine which stimulates glucose-dependent endogenous insulin secretion, reduces glucagon secretion, and promotes weight loss by increasing satiety [7,8].It was initially developed for the treatment of DM.In addition to its blood glucose lowering properties, it also promotes weight loss, reduces subcutaneous fat, reduces systolic blood pressure (sBP) and improves cardiovascular risk profile in patients with and without DM [9][10][11][12].In a case report of a patient with HIV-associated type 2 diabetes, liraglutide use improved glycemic control and lipodystrophy [13].In this retrospective case-control study, we assessed the effect of 6 months liraglutide treatment on metabolic abnormalities and body weight in lipodystrophic HIV-infected patients with or without diabetes.liraglutide on body weight, sBP, glycemic control, and lipid profile.Liraglutide treatment resulted in significant weight loss in obese subjects with and without DM as well as in HIV+DM subjects.In addition, there was a trend in reduction in weight in HIV-DM subjects.The treatment showed a trend to lower sBP only in DM patients with and without HIV.It had no effect on diastolic BP (dBP) in any group.
Liraglutide treatment showed a tendency to improve glycemic control only in patients without HIV.Treatment of HIV-DM subjects with liraglutide tended to decrease LDL-C and TC/HDL-C.In HIV+DM, liraglutide tended to decrease TC and non-HDL-C.In the obese-DM group, while TC was significantly reduced, there were lower LDL-C, non-HDL-C, TG, TC/HDL-C, and Log (TG/HDL-C) trend in response to liraglutide.Liraglutide treatment of the obese+DM subjects tended to lower non-HDL-C and log (TG/HDL-C).

Comparison between HIV-infected subjects and HIVuninfected subjects
When all HIV-infected subjects were compared to non-infected controls, liraglutide tended to reduce HgA1c and FBG only in controls.However, there were no other differences between weight, lipid profile, or BP among HIV-infected and control groups (data not shown).

Discussion
HALS is observed frequently among HIV-infected patients [2,3].Changes in body fat redistribution in HIV-infected subjects include regional lipohypertrophy and lipoatrophy [2,3].Metabolic changes including insulin resistance, DM, dyslipidemia characterized by elevated LDL-C and TG and decreased HDL-, may be a consequence of changes in body fat redistribution [2,3].In this retrospective case-control study, we found that six months treatment with 1.2 mg of liraglutide of lipodystrophic HIV-infected subjects with and without DM resulted in reduction of body weight, which was significant only in those with DM; it also improved several metabolic parameters.To our knowledge, this is the first report showing liraglutide effect on metabolic parameters as well as body weight changes in HIV-infected subjects with and without DM.
A major finding of the present study was the effect of liraglutide on body weight of lipodystrophic HIV-infected subjects.Six months of liraglutide treatment of HIV+DM resulted in a significant weight loss by mean of 4.4 kg (Table 4).In HIV-DM group, it also led to a modest but not significant, reduction in body weight (mean reduction of 2.4 kg).This difference may be due to a number of factors such as type of ART (96% of the HIV-DM subject received a protease inhibitorcontaining ART, vs 68% in the HIV+DM), duration of HIV, or use of other medications.In our study, 65% of HIV+DM vs. 30% of HIV-DM were on metformin.Metformin is known to cause weight loss in patients with and without diabetes.Metformin may have an additional benefit when combined with liraglutide, as previously shown in non-HIV-infected patients with DM [7].
Liraglutide treatment of obese+DM subjects led to a significant reduction in body weight (mean reduction of 4.0 kg), consistent with other studies [14].It also resulted in significant weight loss (mean reduction of 7.3 kg) in obese-DM group.This finding is higher than is reported in the literature [10].This discrepancy may be due to the difference in life style, use of metformin and other hypoglycemic agents (21% of our subjects were taking metformin), duration or dose of liraglutide, study design, or other factors.Interestingly, as shown in the Tables 1 and 4, even though 54% of obese+DM subjects and 21% of obese-DM were on metformin, the weight loss effect of liraglutide seems to be more in obese-DM than those obese+DM.The reason for this might be due to other factors such as changes in life style, concomitant use of other antiglycemic agents in obese+DM group, or other unknown factors.

Methods
This retrospective case-control study was carried out in lipodystrophic HIV-infected subjects seen at the Immunodeficiency Clinic (IDC)-HIV metabolic Clinic at St. Paul's Hospital, Vancouver, BC, Canada.A group of HIV-negative obese subjects recruited from Healthy Heart Prevention Clinic at St. Paul's Hospital, Vancouver, BC, Canada served as controls.Obesity was defined as body mass index (BMI ≥ 30 kg/m 2 ).We performed chart review including demographic, clinical, and laboratory data of all patients who were prescribed liraglutide between January 2010 and December 2013.Patients were classified into 4 groups: lipodystrophic HIV-infected subjects without DM (HIV-DM), lipodystrophic HIVinfected subjects with DM (HIV+DM), 32 non-DM obese subjects (obese-DM), and 53 DM obese subjects (obese+DM).All patients initially started liraglutide, 0.6 mg once daily for a week, by subcutaneous injection.Then the dose was increased to 1.2 mg once daily and maintained for 6 months.The primary outcome measure was change in body weight at the end of the study.Secondary endpoints were changes in fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), non HDL-C, log(TG/HDL-C), TC/HDL-C, and sBP after 6 months of liraglutide therapy.The protocol and informed consent were approved by the institutional Ethics Board.

Statistical analysis
Data were expressed as mean ± standard deviation (M ± SD), afeter checking the normality of the variables' distributions unpaired t-tests or Mann-Whitney tests were used to determine the differences in patient characteristics between HIV-infected and uninfected subjects.Bonferroni's correction applied to avoid the multiple comparison error and p value less than 0.001 was considered to be statistically significant.All statistical calculations were performed with SPSS software package.

Patient demographics and baseline characteristics
Baseline characteristics of the study population are summarized in Tables 1 and 2. At baseline, subjects with HIV+DM had significantly higher FBG, HgA1c, and log (TG/HDL-C) as compared to HIV-DM subjects.In the HIV+DM group, TG tended to be higher and LDL-C tended to be lower than the HIV-DM group.
Among HIV-negative obese patients, subjects with DM were older than non-DM subjects, had significantly higher FBG and HgA1c as compared to non-DM subjects.When compared to obese-DM subjects, Obese+DM subjects had significantly lower LDL-C.Also there TC and HDL-C tended to be lower in Obese+DM than obese+DM subjects.
Overall, HIV-infected subjects and HIV-uninfected subjects with DM were more likely to receive metformin as compared to their counterparts without DM.Obese+DM subjects were more likely to receive combination therapy for DM than HIV+DM (64% vs. 26%).More DM subjects with and without HIV were on lipid lowering medications compared to their non-DM counterparts.
All, except one with and one without DM, HIV-infected subjects were receiving ART.All patients receiving ART had undetectable HIV-RNA (<40 copies/ml) (Table 3).The HIV-DM subjects were more likely to be receiving a protease inhibitors containing HAART as compared to those with DM (96% vs. 68%).There was no significant differences in CD4 counts among HIV(+) subjects with and without DM.Open Access

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As we shown in the Table 1, the percentages of subjects in HIV+ DM using metformin are 35% more than HIV-DM.However, there is also 33% difference in non-HIV control groups on metformin, and the weight loss effect of liraglutide seems to be more in both non-HIV control groups than in HIV groups.speculate that such differences and non-HIV subjects may be due to HIV infection itself, type of ART, use of other medications, or other unknown factors.
Liraglutide has been shown to improve glycemic control in patients with DM which is consistent with our finding [9,[12][13][14][15][16].In our study there was a 0.5% statistically significant reduction in HgA1c in obese+DM subjects.Interestingly, liraglutide treatment of HIV+DM did not improve their glycemic control, possibly due to effects of other medications such as ART, HIV infection, higher insulin resistance, or lower concomitant use of other antidiabetic agents (26% of HIV+DM subjects were on combination antidiabetic drugs while 64% of obese-DM subjects were on combination treatment).In addition, due to the retrospective nature of our study, we did not have HbA1c measurements in all subjects.
In this study, liraglutide treatment showed a trend to lower sBP in both DM groups.The effect of liraglutide on BP is not consistent with some studies showing improvement [12][13][14][15][16][17] and others showing no effect [8].We can speculate that the reduced sBP may be, at least in part, related to weight loss since HIV infected and non-infected subjects with DM lost more weight.
In addition to the beneficial effects on body weight, liraglutide appears to significantly lower certain lipid parameters such as TC, LDL-C, and TG [18].In the current study, we found that in obese+DM subjects, liraglutide treatment tended to lower non-HDL-C, and log (TG/HDL-C).It also had a beneficial effect on lipid profile in obese-DM subjects with a significant reduction in TC and tendency to lower LDL-C, non-HDL-C, TG, TC/ HDL-C, and log (TG/HDL-C).The differences between our study and others may be due to the dose and duration of treatment with liraglutide, concomitant use of other lipid-lowering medication, or changes in lifestyle.In HIV-infected patients, there was a trend in improvement in some of the lipid parameters including TC and non-HDL-C in HIV+DM group      Open Access 6 and LDL-C and TC/HDL-C in HIV-DM group.Decrease in some of the lipid parameters, possibly due to missing of data.The reasons that we did not see much beneficial effect in lipid parameters in HIV-infected subjects as we observed in non-HIV subjects could be due to concomitant use of ART, changes in lifestyle, type and dose of statin, lack of measurement of lipid parameters in all patients, or other undefined factors.Overall the improvement in lipid parameters by administration of liraglutide observed in current study may have beneficial effect on cardiovascular risk profile.
The present study has a number of limitations mainly due to its retrospective and non-randomized nature.Complete blood work data was not available in all patients.Furthermore, patients received concomitant medications that may have affected the measured outcomes.However, all the study participants were on a stable medication regimen and not changes in ART or other medications occurred during the study period.
In conclusion, liraglutide treatment of HIV-infected subjects with and without DM resulted in weight loss, and improvement in some metabolic parameters.These beneficial effects of liraglutide in these subjects may improve and doing so, improve cardiovascular risk profile.
n H U B f o r S c i e n t i f i c R e s e a r c h Citation: Saeedi R, Dabirvaziri P, Nashta NF, Yousefi M, Guillemi S, et al. (2015) Effects of Liraglutide, a Glucagon-Like Peptide-1 Analogue, on Metabolic Abnormalities and Body Weight in HIV-infected Subjects with or without Type 2 Diabetes.J HIV AIDS 1(2): http://dx.doi.org/10.16966/2380-5536.107

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p e n H U B f o r S c i e n t i f i c R e s e a r c h Citation: Saeedi R, Dabirvaziri P, Nashta NF, Yousefi M, Guillemi S, et al. (2015) Effects of Liraglutide, a Glucagon-Like Peptide-1 Analogue, on Metabolic Abnormalities and Body Weight in HIV-infected Subjects with or without Type 2 Diabetes.J HIV AIDS 1(2): http://dx.

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p e n H U B f o r S c i e n t i f i c R e s e a r c h Citation: Saeedi R, Dabirvaziri P, Nashta NF, Yousefi M, Guillemi S, et al. (2015) Effects of Liraglutide, a Glucagon-Like Peptide-1 Analogue, on Metabolic Abnormalities and Body Weight in HIV-infected Subjects with or without Type 2 Diabetes.J HIV AIDS 1(2): http://dx.doi.org/10.16966/2380-5536.107

Table 4
shows the effect of 6 months of treatment with 1.2 mg of

Table 4 :
Changes in body weight, blood pressure, glycemic control and lipid profile with lariglutide treatment Only values of p<0.001 are significant (see the statistical analysis)