|Year : 2019 | Volume
| Issue : 6 | Page : 1919-1924
Effects of liraglutide addition to multiple diabetes regimens on weight and risk of hypoglycemia for a cohort with type 2 diabetes followed in primary care clinics in Saudi Arabia
Yasser A Albarkah1, Ayla M Tourkmani2, Abdulaziz M Bin Rsheed2, Turki J Al Harbi2, Yasser A Ebeid2, Reuof A Bushnag2
1 Department of Pharmaceutical Care, Medical Services Directorate; Family and Community Medicine, Chronic Diseases Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
2 Department of Pharmaceutical Care, Medical Services Directorate, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
|Date of Submission||06-May-2019|
|Date of Decision||04-Jun-2019|
|Date of Acceptance||05-Jun-2019|
|Date of Web Publication||26-Jun-2019|
Dr. Ayla M Tourkmani
Prince Sultan Military Medical City, Family and Community Medicine, Chronic Diseases Center, Al-Wazarat Health Center, Al-Wazarat District, Riyadh
Source of Support: None, Conflict of Interest: None
Context: Available therapies for type 2 diabetes mellitus (T2DM) do not adequately control glycemia in the long term as they do not address the issue of declining beta cell function and do not impact positively on weight or cardiovascular concerns associated with the disease. Aims: To measure changes in hemoglobin A1c, weight, and hypoglycemia after the addition of liraglutide to 3 therapeutic regimens of patients with T2DM. Settings and Design: An observational cohort study that was implemented in Al-Wazarat Health Center in Riyadh, Saudi Arabia. Methods and Materials: The study included 38 T2DM patients who were screened for initiation of liraglutide in combination with their treatment regimens; sulphonylurea, sulphonylurea with basal insulin (glargine), and multiple daily injections of insulin. The cohort was followed for 12 months, and the liraglutide was started with 0.6 mg dose that escalated to 1.2 and 1.8 mg. Glycemic level and weight were measured 3 times, whereas hypoglycemia was measured 2 times. Statistical Analysis Used: Quantitative continuous paired data were compared using a paired t-test and the nonparametric Wilcoxon signed rank test. Results: There was a statistically significant reduction of hemoglobin A1c with 1.2 mg dose (mean difference = 0.84%, P = 0.003). There were no statistically significant differences regarding the effect of liraglutide in addition to the 3 treatment regimens on patients' weight (P = 0.08, 0.472, 0.08, respectively). Regarding hypoglycemia, liraglutide has showed minimal effect. Conclusions: Sustained effect of liraglutide on glycemic control in patients with T2DM without any major hypoglycemic episodes.
Keywords: Glycemic control, hypoglycemia, liraglutide, type 2 diabetes mellitus, weight
|How to cite this article:|
Albarkah YA, Tourkmani AM, Bin Rsheed AM, Al Harbi TJ, Ebeid YA, Bushnag RA. Effects of liraglutide addition to multiple diabetes regimens on weight and risk of hypoglycemia for a cohort with type 2 diabetes followed in primary care clinics in Saudi Arabia. J Family Med Prim Care 2019;8:1919-24
|How to cite this URL:|
Albarkah YA, Tourkmani AM, Bin Rsheed AM, Al Harbi TJ, Ebeid YA, Bushnag RA. Effects of liraglutide addition to multiple diabetes regimens on weight and risk of hypoglycemia for a cohort with type 2 diabetes followed in primary care clinics in Saudi Arabia. J Family Med Prim Care [serial online] 2019 [cited 2020 Nov 29];8:1919-24. Available from: https://www.jfmpc.com/text.asp?2019/8/6/1919/261436
| Introduction|| |
Type 2 diabetes mellitus (T2DM) is a progressive multisystem disease in which individuals exhibit varying degrees of declining beta cell function, insulin resistance, and a failure to suppress postprandial glucagon secretion. Currently, available therapies do not adequately control glycemia in the long term as they do not address the issue of declining beta cell function and do not impact positively on weight or cardiovascular concerns associated with the disease such as edema and weight gain.
| Literature Review|| |
T2DM therapies often comprise complex treatment and titration regimens and can increase the risk of hypoglycemia and undesirable effects.,, Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin hormone with a wide range of physiological actions that make it a potent blood-glucose-lowering agent with the potential to modify the natural history of T2DM. Currently, liraglutide has been shown to have a positive impact on cardiovascular outcomes and other benefits., Treatment with liraglutide produced substantial and clinically significant reductions in hemoglobin A1c (HbA1c), and fasting and postprandial glucose levels, with a low risk of hypoglycemia, and moderate weight loss.,,,, Also, liraglutide treatment alone or in combination with oral antidiabetic agents demonstrated significantly larger HbA1c reductions compared with glimepiride (monotherapy), rosiglitazone (in combination with sulfonylurea), and insulin glargine (in combination with metformin plus sulfonylurea). Endogenous GLP-1 suppresses appetite and energy intake in both normal weight and obese individuals. As monotherapy, liraglutide lowered HbA1c from the mean baseline value (8.2%) by 0.84% and by 1.14% with 1.2 and 1.8 mg doses, respectively, compared with a 0.51% reduction with glimepiride 8 mg.,,,, The LEAD trials showed a decrease in mean weight ranging from 1 to 3.2 kg (2.2–7.04 pounds) over the course of 26 or 52 weeks with liraglutide except in the LEAD-1 study.,,,, The reduction was more statistically significant for liraglutide than for the comparative treatments. In LEAD-1, when glimepiride was combined with liraglutide, a reduction in body weight was observed with liraglutide 1.8 mg and placebo. Weight loss in both groups was <0.5 kg (1 pound).
The aim of this study is to measure changes in HbA1c, weight, and risk of hypoglycemia (mild, moderate, and severe) because of addition of liraglutide to sulphonylurea, sulphonylurea with basal insulin, or multiple daily injections (MDI) of insulin in obese insulin-resistant patients with T2DM during the study period.
| Subjects and Methods|| |
The study was conducted in Al-Wazarat Health Center (WHC), which is the largest family medicine center in Riyadh, Saudi Arabia. The yearly total number of diabetic patients followed in WHC is ~13,000 patients. They are served by family medicine clinics dedicated for chronic diseases (6 morning and 5 afternoon clinics) which are run by family physicians, a clinical pharmacy clinic (covers 10 sessions per week), diabetic educator, health educator, dietitian, and a social worker. The current data were collected from the clinical pharmacy clinic.
An observational cohort design of all diabetic patients with age 18–75 years followed in chronic diseases center at family and community medicine department in Prince Sultan Military Medical City. Subjects were screened and enrolled if they meet the inclusion criteria for adding liraglutide to their therapeutic diabetic regimen.
Inclusion criteria included any T2DM patient treated with sulphonylurea as monotherapy for a period ≥3 months, sulphonylurea with basal insulin (glargine) during the previous 3 months, or MDI for a period ≥3 months, 18–75 years of age, HbA1c 7%–14%, and body mass index (BMI) ≥30.
Exclusion criteria included impaired renal function, impaired hepatic function (liver enzymes ≥3 times upper normal limit), plasma creatinine >130 μmol/L, diabetic gastroparesis, heart failure (left ejection fraction >30), history of pancreatitis, family history of thyroid cancer, and using any drug that could interfere with glycemic blood level other than metformin or sulphonylurea.
As per good clinical practice guidelines regarding management of diabetes, all diabetic patients starting liraglutide will be screened for agreed criteria for using liraglutide including absence of family history of thyroid cancer, BMI >30, absence of arrhythmia or high heart rate (>90), taking sulphonylurea, sulphonylurea with basal insulin (glargine), or MDI of insulin with inadequate control of blood sugar, and documented weight gain.
Safety variables included adverse events, vital signs, ECG, biochemical and hematology measures, and subject-reported hypoglycemic episodes. The later variable encompassed the number of hypoglycemia events per hypoglycemia category that were reported through self-monitoring of blood glucose (mild hypoglycemia: glycemic blood level <70 mg/dL, an urgent need to eat, and shakiness perspiration; moderate hypoglycemia: glycemic blood level <55 mg/dL, dizziness, sleepiness confusion, difficulty speaking, and feeling anxious or weak; severe hypoglycemia: glycemic blood level <35–40 mg/dL, seizure or convulsion, loss of consciousness, coma, and third-party assistance or medical intervention).
Sample size calculation
Convenience sample that included all obese diabetic patients who meet the inclusion criteria.
Thirty-eight diabetic patients who met the inclusion criteria and agreed to participate in the study were included in the study. Demographic and clinical data included age, gender, duration of diabetes and date of starting liraglutide, the liraglutide dose at the beginning and at the end of the study after titration, and the treatment group. There were 3 treatment groups; group 1 included 6 patients on sulphonylurea, group 2 included 9 patients on sulphonylurea and basal insulin, and group 3 included 23 patients on MDI of insulin.
The cohort was followed for 12 months and liraglutide starting dose was 0.6 mg that escalated to 1.2 and 1.8 mg based on patient tolerance. The glycemic level and weight were measured at baseline and 2 follow-up visits throughout the 12 months. The self-reported blood glucose readings were recorded twice during the period of the study including before breakfast, after breakfast, after lunch, and after dinner periods each time to detect hypoglycemia which was categorized into 4 groups: no hypoglycemia, mild hypoglycemia, moderate hypoglycemia, and severe hypoglycemia.
Data entry and statistical analysis were done using Microsoft Excel 2016 and SPSS 20.0 statistical software packages. Data were presented using descriptive statistics in the form of frequencies and percentages for qualitative variables, and means, standard deviations, and medians for quantitative variables. Quantitative continuous paired data were compared using a paired t-test and the nonparametric Wilcoxon signed rank test. Statistical significance was considered at P value <0.05.
The approval for this study was taken from the research ethics committee at the Prince Sultan Military Medical City (registration no.: HAP-01-R-079). Informed consent was obtained from each participant after a full explanation of the study. Participant's confidentiality was maintained throughout the study, and his/her information was not used for other purposes other than this study.
| Results|| |
The study enrolled 38 patients with T2DM. [Table 1] illustrates the demographic characteristics of the participants. It shows that the participants included 17 males (44.7%) and 21 females (55.3%), with a mean age of 50.6 ± 10.8 years.
|Table 1: Demographic characteristics of participants in the study sample|
Click here to view
[Table 2] illustrates the clinical characteristics of the participants. It shows that the mean duration of T2DM was 13.5 ± 7.4 years, whereas the mean duration of using liraglutide was 11.3 ± 1.4 months. According to their treatment regimens, participants were divided into 3 groups: the sulphonylurea treatment group which included 6 patients; the sulphonylurea and basal insulin group which included 9 patients; and finally, the MDI group which included 23 patients. Regarding hypoglycemia, there was only 1 mild case at the baseline “Before Breakfast” period as shown in [Table 2]. In addition to this case, there were only 5 cases of hypoglycemia throughout the whole 8 times of measuring blood sugar; 1 mild case and 1 moderate case during the follow-up “before breakfast” period, 1 moderate case during the baseline “after lunch” period, 1 mild case during the baseline “after dinner” period, and 1 mild case during the follow up “after dinner” period.
[Table 3] shows the results of measuring the study variables during the baseline period and the 2 follow-up periods. It shows that the HbA1c levels have declined in all groups; from 8.3 ± 0.8% to 7.7 ± 0.7% in group 1, from 8.8 ± 1.6% to 8.3 ± 1.4% in group 2, and from 9.0 ± 1.5% to 8.4 ± 1.6% in group 3. However, this decline in HbA1c levels was not statistically significant [see [Table 3]].
|Table 3: Results of the study variables according to the treatment groups of participants in the study sample through the 3 measurements periods|
Click here to view
[Figure 1] illustrates the mean HbA1c levels through the baseline and the 2 follow-up measurements according to 3 treatment groups.
|Figure 1: Mean HbA1c levels for study participants throughout the measurement periods|
Click here to view
[Figure 2] illustrates the mean weight measurements through the baseline and the 2 follow-up measurements according to 3 treatment groups.
|Figure 2: Mean weight for study participants throughout the measurement periods|
Click here to view
[Table 4] illustrates the effect of the 3 treatment regimens on HbA1c, weight, and blood sugar. There was no statistically significant difference regarding the effect of the 3 treatment regimens on the HbA1c level (P = 0.254, 0.259, 0.055, respectively). Also, there was no statistically significant difference regarding the effect of the 3 treatment regimens on patients' weight (P = 0.08, 0.472, 0.08, respectively). Finally, there were no statistically significant differences regarding blood sugar measurements for all groups (P > 0.05 for all measures).
|Table 4: Comparison between the results of the baseline and the follow-up periods of the study variables according to the treatment groups of the participants in the study sample|
Click here to view
[Table 5] shows the effect of the liraglutide current treatment dose on the HbA1c level. It shows that there was statistically significant difference regarding the effect of the 1.2 mg dose compared with the initial treatment dose (mean difference = 0.84%, P = 0.003), whereas there was no statistically significant difference associated with the other 2 doses, namely the 0.6 mg dose and the 1.8 mg dose when compared with the initial treatment dose (P = 0.363 and 0.855, respectively). Also, there was no statistically significant difference associated with the 3 liraglutide doses regarding their effect on patients' weight (P = 0.14, 0.053, 0.677, respectively).
|Table 5: Comparison of the study variables according to the current dose of liraglutide used by the participants in the study sample|
Click here to view
| Discussion|| |
In this observational study, a cohort of 38 diabetic patients with HbA1c (7%–14%) was followed at the chronic diseases center for a duration of 12 months after adding liraglutide with different doses (0.6, 1.2, and 1.8 mg) to their treatment regimens which included sulphonylurea and MDI of insulin and basal Insulin on the top of metformin. The results showed statistically significant improvement in glycemic control with the 1.2 mg dose of liraglutide compared with the initial treatment dose. This was associated with an inconsistent effect on weight, which was statistically not significant, and very few mild and moderate hypoglycemic episodes in obese insulin-resistant patients with T2DM.
Prospective studies of the combination of GLP-1 RA plus insulin therapy have shown either superior or equivalent efficacy in glycemic control compared with insulin only.,, Many studies showed that liraglutide produced a substantial and clinically significant reduction in HbA1c and postprandial glucose level, with a low risk of hypoglycemia and moderate weight reduction.,,, In addition to its effect on glycemic control, liraglutide treatment resulted in significant weight loss compared with placebo (−1.4 kg difference), and a favorable weight difference compared with insulin glargine (−3.4 kg loss). In our study, the results showed that there was no statistically significant difference on patients' weight of the 3 treatment regimens: sulphonylurea, sulphonylurea plus basal insulin, and MDI of insulin, in addition to liraglutide (P = 0.08, 0.472, 0.08, respectively). The beneficial effect on weight might be masked or diminished because of associated weight gain with sulphonylurea and insulin, which increases weight by 1.7–4 kg, respectively.
As for the effect of the liraglutide to the current treatment dose on the HbA1c level, there was statistically significant difference regarding the effect of the 1.2 mg dose (P = 0.003), whereas there was no statistically significant difference associated with the other 2 doses, namely 0.6 and 1.8 mg dose (P = 0.363 and 0.855, respectively).
Flint et al.'s study showed no significant difference between fasting and postprandial control between liraglutide and insulin glargine. Similarly, in this study, there was no statistically significant effect of liraglutide on patient home blood monitoring before breakfast and postprandial and this could be explained because of normal blood sugar readings of patients at baseline, so the effect of liraglutide is continuing the normal range of the readings.
The LEADER trial, which was a safety cardiovascular outcome trial that included >9300 patients with a mean follow-up period of 3.5–5 years, has shown that there was a 31% lower rate of severe hypoglycemia and a 20% lower rate of the combination of severe and confirmed hypoglycemia (plasma glucose level <56 mg/dL) in the liraglutide group than in the placebo group. The incidence of hypoglycemia in this study's cases was considered negligible and minimal. There were only 6 cases throughout the whole 8 times of measuring blood sugar; 1 mild case at the first “before breakfast” period, 1 mild case, and 1 moderate case during the second “before breakfast” period, 1 moderate case during the first “after lunch” period, 1 mild case during the first “after dinner” period, and 1 mild case during the second “after dinner” period.
| Strengths and Limitations|| |
This study had strength. The addition of liraglutide to varieties of T2DM treatment regimens considered as a challenge to clinicians to adjust the doses with utilizing the good safety profile and minimal side effects that could be a kind of art in therapeutic T2DM management.
The study had several limitations. First, the relatively small sample size could affect the results' generalizability to some extent. Second, also, not to account there was insulin dose reduction during measurement when combining liraglutide injection with multiple days of insulin in the study. Additionally, the limited time for follow-up as 2 visits throughout the study period did not permit to show the true effect of liraglutide. Furthermore, the combination of liraglutide with sulphonylurea and MDI of insulin that lead to a pronounced effect on weight could decrease the benefit of liraglutide on weight reduction.
| Conclusion|| |
This study demonstrated a sustained effect of the liragulitde on glycemic control in obese insulin-resistant patients with T2DM without any major hypoglycemic episodes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Turner RC, Cull CA, Frighi V, Holman RR, Group UPDS. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-12.
Nauck M. Incretin therapies: Highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2016;18:203-16.
Du Q, Wang Y-J, Yang S, Zhao Y-Y, Han P. Liraglutide for the treatment of type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials. Adv Ther 2014;31:1182-95.
Robinson LE, Holt TA, Rees K, Randeva HS, O'Hare JP. Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis. BMJ Open 2013;3:e001986.
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87:1409-39.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al
. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;2016:311-22.
Russell-Jones D, Vaag A, Schmitz O, Sethi B, Lalic N, Antic S, et al
. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): A randomised controlled trial. Diabetologia 2009;52:2046-55.
Marre M, Shaw J, Brändle M, Bebakar WW, Kamaruddin NA, Strand J, et al
. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med 2009;26:268-78.
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al
. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes. Diabetes Care 2009;32:84-90.
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al
. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373:473-81.
Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 1998;101:515-20.
Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al
. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009;32:1224-30.
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al
. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009;374:39-47.
Tzefos M, Olin JL. Glucagon-like peptide-1 analog and insulin combination therapy in the management of adults with type 2 diabetes mellitus. Ann Pharmacother 2010;44:1294-300.
Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al
. Use of twice-daily exenatide in basal insulin–treated patients with type 2 diabetes: A randomized, controlled trial. Ann Intern Med 2011;154:103-12.
Zaccardi F, Pitocco D, Ghirlanda G. Glycemic risk factors of diabetic vascular complications: The role of glycemic variability. Diabetes Metab Res Rev 2009;25:199-207.
Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courreges JP, et al
. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care 2007;30:1608-10.
Cheng V, Kashyap SR. Weight considerations in pharmacotherapy for type 2 diabetes. J Obes 2011;2011. pii: 984245. doi: 10.1155/2011/984245. Epub 2010 Sep 19.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]