Mini-CAT expanded from RT6-WK1 PICO

Clinical Question: 68 y/o M, with a PMHx of hypertension, hyperlipidemia, type 2 diabetes mellitus and obesity (BMI 31.18), who presents for a well visit. Patient is currently on metformin for his diabetes. The patient has been eating a healthy diet and exercising for the last year to try reducing his weight with minimal weight loss achieved. He asks if there is another antidiabetic medication that can aid in weight loss.

PICO Question: In patients with type 2 diabetes mellitus and obesity, are GLP-1 receptor agonists effective in reducing weight?

P	I	C	O
Adults with type 2 diabetes and obesity	GLP-1 agonist	No treatment	Weight loss
T2DM and obesity	Glucagon-like peptide 1	Placebo	Reduction in weight
Type 2 diabetes mellitus and obesity	GLP-1 receptor agonist		Decreased weight
	Glucagon-like peptide-1 receptor agonist

Search Strategy:

Google Scholar:

• GLP-1 receptor agonist in type 2 diabetes and obesity → 32,600 results
  • Last five years → 17,000 results
• GLP-1 for type 2 diabetes and obesity weight loss in adults → 36,000 results
  • Last five years → 16,900 results
• Glucagon-like peptide-1 receptor agonist reduction in weight for patient with type 2 diabetes and obesity → 24,000 results
  • Last five years → 13,200 results

PubMed:

• GLP-1 receptor agonist for type 2 diabetes and obesity → 5,894 results
  • Last five years → 3,722 results
• GLP-1 for weight loss in type 2 diabetics with obesity → 1,490 results
  • Last five years → 830 results
• GLP-1 receptor agonist for weight loss in diabetes and obesity → 4,785 results
  • Last five years → 2,982 results

ScienceDirect:

• GLP-1 receptor agonist for type 2 diabetes and obesity → 5,152 results
  • Last five years → 2,546 results
• Weight loss with GLP-1 in diabetics with obesity → 4.318 results
  • Last five years → 2,002 results

Cochrane:

• GLP-1 for diabetes and obesity  1 result
• GLP-1 agonist for diabetes and obesity  175 results
  • Last five years  117 results

I found the articles below for the stated question by filtering the searches to within the last five years to include the most recent data on this subject. I also used a combination of the terms above, to try to capture all related studies as using too narrow of search terms can reduce the number of articles available. While my primary goal was to find systematic reviews and meta-analyses on this topic, it was not always the case, so I also looked for randomized controlled trials or even cohort studies if needed. While I wanted to ideally find another article to replace the prospective cohort study (article three), I did not find any that I thought were suitable to include, therefore I continued to use this study as I did in the previous PICO. I wanted to focus on GLP-1 receptor agonists for patients with type 2 diabetes mellitus and obesity, not just one or the other. I tried to find articles with larger population sizes and if a randomized controlled trial, I tried to find placebo and double-blinded studies in order reduce bias. Additionally, while there was another systematic review and meta-analysis on this topic, it focused on children, which was not the population for my question and therefore I did not include it in this evaluation.

Articles Chosen:

Article 1:

Link: https://pubmed.ncbi.nlm.nih.gov/33667417/ PDF:

Abstract: Background: This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. Methods: This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated hemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated hemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants. Findings: From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo. Interpretation: In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in body weight compared with placebo.

Article 2:

Link: https://www.sciencedirect.com/science/article/abs/pii/S0149291817301959 PDF:

Abstract: Purpose: The progressive nature of type 2 diabetes mellitus (T2DM) calls for stepwise intensification of therapy for maintaining normal glycemic levels and lowering cardiovascular (CV) risk. Because obesity is a prominent risk factor and comorbidity of T2DM, it further elevates the CV risk in T2DM. Therefore, it is vital to manage weight, obesity, and glycemic parameters for effective T2DM management. Few oral antidiabetic drugs (sulfonylureas and thiazolidinediones) and insulin are not suitable for obese patients with T2DM because these drugs cause weight gain. The present review discusses the place of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of obese patients with T2DM and the significance of these drugs in the prevention of future CV risk in patients with T2DM. Methods: A literature search of PubMed and EMBASE was conducted by using the search terms T2DM, GLP-1RAs, obesity, and cardiovascular complication. Randomized controlled trials measuring the effect of GLP-1RAs versus that of placebo on CV outcomes were included in the review. Findings: GLP-1RAs have emerged as a therapeutic alternative; these drugs exert their actions by providing glycemic control, improving insulin resistance and ö̇-cell function, and reducing weight. The risk of hypoglycemia with GLP-1RAs is minimal; however, GLP-1RAs are associated with gastrointestinal adverse events and raise concerns regarding pancreatitis. Combining GLP-1RAs with insulin analogues results in higher efficacy, a lowered insulin dose, and reduced insulin-related hypoglycemia and weight gain. Longer acting GLP-1RAs are also associated with improvement in medication adherence. Improvement in CV risk factors such as blood pressure and lipid profile further increases their usability for improving CV outcomes. Implications: Overall, the properties of GLP-1RAs make them suitable for combination with oral antidiabetic drugs in the early stages of T2DM and with insulins in the later stages for optimizing comprehensive management of the disease.

Article 3:

Link: https://pubmed.ncbi.nlm.nih.gov/30944827/ PDF:

Abstract: It is well known that diabetes mellitus (DM) exacerbates the mechanisms underlying atherosclerosis. Currently, glucagon-like peptide-1 receptor agonists (aGLP-1) have one of the most prominent cardioprotective effects among the antidiabetic agents. However, the treatment with aGLP-1 is effective only in 50-70% of the cases. Taking into account the high cost of these medications, discovery of the predictors of optimal response to treatment is required. Purpose. To identify the predictors of the greater impact of aGLP-1 on HbA1c levels, weight reduction, and improvement in lipid profile. Methods. The study group consisted of 40 patients with type 2 DM (T2DM) and obesity who were treated with aGLP-1. The follow-up period was 24 weeks. Patients’ evaluation was conducted at baseline and after 24 weeks. In addition, it included the assessment of the hormones involved in glucose and lipid metabolism and appetite regulation. Results. Patients who have initially higher BMI (body mass index), glycemia, and triglycerides (TG) had better improvement in these parameters undergoing aGLP-1 treatment. In patients with a BMI, GLP-1 and fasting ghrelin levels were higher and ghrelin level in postnutritional status was lower. The HbA1c levels decreased more intensively in participants with higher GLP-1 levels. TG responders had lower baseline fasting glucose-dependent insulinotropic peptide (GIP) and postprandial ghrelin levels. Conclusion. The evaluation of the glycemic control, lipid profile, and GLP-1, GIP, and ghrelin levels are usable for estimating the expected efficacy of aGLP-1.

Article 4:

Link: https://jamanetwork.com/journals/jama/fullarticle/2428956 PDF:

Abstract: Importance: Weight loss of 5% to 10% can improve type 2 diabetes and related comorbidities. Few safe, effective weight-management drugs are currently available. Objective:  To investigate efficacy and safety of liraglutide vs placebo for weight management in adults with overweight or obesity and type 2 diabetes. Design, Setting, and Participants:  Fifty-six–week randomized (2:1:1), double-blind, placebo-controlled, parallel-group trial with 12-week observational off-drug follow-up period. The study was conducted at 126 sites in 9 countries between June 2011 and January 2013. Of 1361 participants assessed for eligibility, 846 were randomized. Inclusion criteria were body mass index of 27.0 or greater, age 18 years or older, taking 0 to 3 oral hypoglycemic agents (metformin, thiazolidinedione, sulfonylurea) with stable body weight, and glycated hemoglobin level 7.0% to 10.0%. Interventions:  Once-daily, subcutaneous liraglutide (3.0 mg) (n = 423), liraglutide (1.8 mg) (n = 211), or placebo (n = 212), all as adjunct to 500 kcal/d dietary deficit and increased physical activity (≥150 min/wk). Main Outcomes and Measures:  Three coprimary end points: relative change in weight, proportion of participants losing 5% or more, or more than 10%, of baseline weight at week 56. Results:  Baseline weight was 105.7 kg with liraglutide (3.0-mg dose), 105.8 kg with liraglutide (1.8-mg dose), and 106.5 kg with placebo. Weight loss was 6.0% (6.4 kg) with liraglutide (3.0-mg dose), 4.7% (5.0 kg) with liraglutide (1.8-mg dose), and 2.0% (2.2 kg) with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, −4.00% [95% CI, −5.10% to −2.90%]; liraglutide [1.8 mg] vs placebo, −2.71% [95% CI, −4.00% to −1.42%]; P < .001 for both). Weight loss of 5% or greater occurred in 54.3% with liraglutide (3.0 mg) and 40.4% with liraglutide (1.8 mg) vs 21.4% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 32.9% [95% CI, 24.6% to 41.2%]; for liraglutide [1.8 mg] vs placebo, 19.0% [95% CI, 9.1% to 28.8%]; P < .001 for both). Weight loss greater than 10% occurred in 25.2% with liraglutide (3.0 mg) and 15.9% with liraglutide (1.8 mg) vs 6.7% with placebo (estimated difference for liraglutide [3.0 mg] vs placebo, 18.5% [95% CI, 12.7% to 24.4%], P < .001; for liraglutide [1.8 mg] vs placebo, 9.3% [95% CI, 2.7% to 15.8%], P = .006). More gastrointestinal disorders were reported with liraglutide (3.0 mg) vs liraglutide (1.8 mg) and placebo. No pancreatitis was reported. Conclusions and Relevance:  Among overweight and obese participants with type 2 diabetes, use of subcutaneous liraglutide (3.0 mg) daily, compared with placebo, resulted in weight loss over 56 weeks. Further studies are needed to evaluate longer-term efficacy and safety.

Article 5:

Link: https://pubmed.ncbi.nlm.nih.gov/27981757/ PDF:

Abstract: Aims: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. Materials and Methods: We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analyzed using a mixed-treatment comparison meta-analysis. Results: A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from −0.55% and −0.73 mmol/L, respectively, for lixisenatide to −1.21% and −1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycemia risk. Albiglutide had the lowest risk of nausea and diarrhea and once weekly exenatide the lowest risk of vomiting. Conclusions: The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once weekly exenatide had the lowest risk of vomiting. These results, along with patient’s preferences and individualized targets, should be considered when selecting a GLP-1RA.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc.)	Outcome(s) studied	Key Findings	Limitations and Biases
Faerch, D., Jeppsen, O., Pakseresht, A., Pedersen, S., Perreau, L., Rosenstock, J., Shimomura, I., Viljoen, A., Wadden, T., Lingvay, I.  (2021).	Randomized Controlled Trial	– Double-blind, placebo-controlled RCT – Study took place at 149 outpatient clinics in 12 countries including North America – Patients 18 and older were included – A total of 1,200 patients were included. – Inclusion criteria: At least one unsuccessful dietary effort to lose weight, BMI over 27 kg/m2, hemoglobin A1c of 7-10% and diagnosed with T2DM at least 180 days before screening – Exclusion criteria: self-reported changes in bodyweight more than 5kg within 90 days of screening, previous/planned obesity treatment with surgery or device – Patients were either managed by diet/exercise only or metformin, sulfonylureas, SGLT2 inhibitors or TZDs at least 90 days before screening – Patients received 2.4 mg semaglutide, 1.0 mg semaglutide or placebo once a week for 68 weeks along with a lifestyle intervention such as counseling on diet and physical activity. – Height, bodyweight, waist circumference, vital signs, A1c, fasting glucose were measured at baseline and repeated at multiple weeks.	– Primary outcomes: percentage of bodyweight from baseline to week 68, loss of at least 5% of baseline weight at 68 weeks – Secondary outcomes: 10-15% bodyweight reductions at week 68, change in waist circumference/A1c/systolic blood pressure at the end of the study	– Mean weight was -9.6% with semaglutide 2.4mg versus -3.4% for placebo and -7.0% for semaglutide 1.0mg at week 68 – Patients were more likely to have at least 5% weight reduction at week 68 with 2.4 mg semaglutide than placebo or semaglutide 1.0 mg. – More patients had 10-20% weight reduction with semaglutide 2.4 mg than the other two groups. – Semaglutide 2.4 mg had a decrease in waist circumference and systolic blood pressure in comparison to placebo. – Hemoglobin A1c improved in all groups, but improved by -1.6 points with semaglutide 2.4 mg, -1.5 points with semaglutide 1.0 mg and -0.4 points with placebo. – Adverse events were highest 87.6% with semaglutide 2.4mg, 81.8% with semaglutide 1.0mg and 76.9% with placebo. – Gastrointestinal complaints such as nausea, vomiting and diarrhea were most often reported. – Severe adverse events were 9.9% in semaglutide 2.4mg, 7.7% in semaglutide 1.0mg and 9.2% in placebo. – Ultimately, once weekly semaglutide 2.4 mg with lifestyle intervention had a 6.2% greater body weight loss in comparison to placebo and 2.7% greater than semaglutide 1.0mg.	– Patients who were on insulin were excluded from this trial – All patients had lifestyle intervention in addition to the semaglutide or placebo, which can make it difficult to attribute the weight loss solely to the medication alone. – This study only evaluated two doses of semaglutide and its effect on obesity in type two diabetics
Ji, Q. (2017).	Systematic review	– Searched for articles in PubMed and Embase evaluating the effects of GLP-1 receptor agonist with type 2 diabetes and obesity. – Also evaluated the safety and cardiovascular complications of GLP-1 receptor agonists for these patients. – Articles in English were included and there was no time restriction on the articles used.	– Primary outcome: most of the articles primary endpoint was time to first occurrence of multiple factors such as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke. – Secondary outcomes: endpoint of cardiovascular death, nonfatal MI or stroke, hemoglobin A1c etc. – The studies evaluated in this review had anywhere from 3,330 to 9,300 patients.	– GLP-1 receptor agonists had the second-best decrease in hemoglobin A1c and blood glucose. – The best reduction was seen with insulin. – GLP-1 receptor agonists had the greatest effect on weight reduction alongside SGLT2 inhibitors. – Other benefits found of GLP-1 receptor agonist was a decrease in lipid levels and systolic blood pressure. – Exenatide, in comparison to insulin glargine, had a significantly lower weight at the end of the treatment in multiple studies ranging from 16 weeks to 1 year. – In one meta-analysis that evaluated fifty-one randomized controlled trials, GLP-1 receptor agonists (either exenatide 10 mg twice daily, liraglutide 1.8 mg once daily or exenatide once weekly) patients had a higher weight reduction in comparison to other oral antidiabetic medications. – LEADER study reported a decrease in cardiovascular events in patients on GLP-1 receptor agonists (reduction of 13%) in comparison to placebo. – Side effects of GLP-1 receptor agonists included gastrointestinal symptoms such as nausea and vomiting, as well as upper respiratory infections. However, hypoglycemia incidence was low.	– One limitation is that there was no time limit on the articles chosen for this review, therefore if any of the articles were older than five years this could be included – however the articles included ended up being from 2015 and later. – This review’s primary focus was safety and cardiovascular complications, which was not the focus of the question, however it did provide adequate evidence on GLP-1 receptor agonist in weight loss for T2DM and obesity.
Babenko, A., Savitskaya, D., Kononova, Y., Trofimova, A., Simanenkova, A., Vasilyeva, E., Shlyakhto, E. (2019).	Prospective cohort study	– 40 patients were included in this study. – Inclusion criteria: age 18-75 years old with established T2DM, 30 kg/m2 BMI or more, treated with antidiabetic for at least 3 months prior to study – Exclusion criteria: uncontrolled hypothyroidism, severe cardiovascular disease, severe hepatic or kidney disease, acute infectious disease etc. – 12 men and 28 women with 12 on exenatide and 28 on liraglutide. – Participants were evaluated at baseline and at 28 weeks	– Primary outcomes: predictors of GLP-1 receptor agonist on weight reduction, hemoglobin A1c and lipid profile – Secondary outcomes: change in blood pressure and hormone levels.	– BMI decreased by 2.4 kg/m2 and waist circumference by 6.6 cm after 24 weeks on the GLP-1 receptor agonists. – Hemoglobin A1c decreased by 1.0% and fasting plasma glucose decreased by 2 mmol/l. – An effective body weight loss, which was defined as 5% or more loss from baseline, was seen in 51.5% of patients. – There was no significant association between duration of diabetes diagnosis, age, sex, or initial BMI with weight reduction on GLP-1 receptor agonists. – There was no difference in BMI or hemoglobin A1c between the two GLP-1 receptor agonist groups, exenatide and liraglutide. – Ghrelin level two hours after breakfast were lower in patients with weight reduction over 5% at 2.2 in comparison to 11.8, thus identifying ghrelin as a potential weight predictor.	– Small sample size of only 40 participants. – Prospective cohort study, not a randomized controlled study therefore there was no placebo for control and the participants/those administering the medication knew which medication each participant received. This study was conducted in a medical practice, which is why there was no randomization. – Patients received either exenatide or liraglutide, which compares two GLP-1 receptor agonists but does not compare to no treatment or a placebo.
Davies, M., Bergenstal, R., Bode, B. (2015).	Randomized Controlled Trial	– Randomized, double-blind, and placebo-controlled – Trial took place at 126 sites in nine countries including the United States – Study was 56 weeks, with an additional 12 weeks off-drug follow-up – Inclusion criteria: BMI over 27 kg/m2, age over 18 years old, stable body weight, TD2M with hemoglobin 7-10% – Participants were randomly assigned to 3.0 mg liraglutide, 1.8 mg liraglutide or placebo.	– Primary outcomes: change in bodyweight after 56 weeks, proportion of participants losing 5% or more of baseline weight, proportion of participants losing 10% or more of baseline weight – Secondary outcomes: waist circumference at the end of 56 weeks, BMI, hemoglobin A1c, prandial glucose, fasting glucose, lipid level, blood pressure, patient-reported outcome on weight quality of life.	– A mean baseline body weight of 105.7 kg for liraglutide 3 mg, 105.8 kg for liraglutide 1.8 mg and 106.5 kg for placebo resulted in mean weight losses of 6%, 4.7% and 2.0% respectively. – Weight loss was greater for the two groups of liraglutide in comparison to placebo in change in body weight and proportion of 5 or 10% in weight reduction. – Significant decreases in BMI and waist circumference were found in both liraglutide groups in comparison to placebo. – Liraglutide, both groups, had higher rates of adverse events, mainly gastrointestinal related. These include nausea, vomiting and diarrhea. There was a greater incidence in the higher dosage of liraglutide group. – Rates of serious adverse events was 8.8% in liraglutide 3 mg, 8.6% in liraglutide 1.8 mg and 6.1% in the placebo group. – Liraglutide 3 mg was statistically significant for improvement on weight in comparison to liraglutide 1.8 mg, while also reducing hemoglobin A1c and reducing patients’ use of oral hypoglycemic agents. – Patients who stopped liraglutide after the trial regained weight and reductions in systolic blood pressure and fasting plasma glucose levels were also reversed.	– Study only completed a 12-week observational study on weight change after being taken off the GLP-1 receptor agonist. Therefore, the effects of weight after discontinuation of the medication needs to be further studied. – More studies are needed on the effects of liraglutide 3.0 mg in the long term. – Conclusions about safety were not able to be adequately drawn due to the power of the study.
Hitke, Z., Zaccardi, F., Papamargaritis, D., Webb, D., Khunti, K., Davies, M. (2017).	Systematic review	– Searched PubMed, ISI Web of Science and Cochrane for RCTs published from inception to 2016 comparing GLP-1 receptor agonist with placebo or another GLP-1. – 34 trials with 14,464 participants met inclusion criteria for this review.	– Primary outcome: Assess the safety and efficacy of GLP-1 receptor agonist. Data to be collected on efficacy included reduction in hemoglobin A1c, fasting plasma glucose, weight loss, cholesterol, triglycerides, and blood pressure.	– GLP-1 receptor agonists, in comparison to placebo, had significant weight loss. – Greatest weight loss was seen with liraglutide, followed by twice a day exenatide and then dulaglutide. – GLP-1 receptor agonist improved hemoglobin A1c and fasting plasma glucose in comparison to placebo. Reduction in hemoglobin A1c ranged from 0.55% to 1.21%, with dulaglutide providing the most reduction followed by liraglutide. – Hypoglycemic events were reported in 12,761 participants. GLP-1 receptor agonist significantly increased the risk of hypoglycemia in comparison to placebo. – GLP-1 receptor agonist had a higher association with gastrointestinal side effects such as nausea, vomiting and diarrhea.	– Despite the large sample size of this review, there are still relatively few studies comparing safety and efficacy of different GLP-1 receptor agonist – While the bias was recorded as low for the RCTs, it is possible that the studies did not fully report their biases. – This review did include multiple studies that were published prior to 2015, making them not within the last five years.  – Only evaluated if the patients were type 2 diabetics and did not directly include obesity, however many patients with type 2 diabetes are also overweight or obese.

Conclusions:

Article 1: Faerch et al., concluded that in patients with obesity and type 2 diabetes, semaglutide had the greatest reduction in weight in comparison to placebo, with greater reductions seen in the higher dose (2.4 mg in comparison to 1.0 mg). These were in conjunction with lifestyle interventions. They also found reductions in hemoglobin A1c and fasting plasma glucose with minimal side effects.

Article 2: Ji concluded that GLP-1 receptor agonist is associated with significant weight loss, which is beneficial in the management of patients with T2DM and obesity. In one study, participants on exenatide, a GLP-1 receptor agonist, had significantly lower weight in comparison to insulin. Additionally, another study found that multiple GLP-1 receptor agonists had more patients with weight loss in comparison to other antidiabetic medications.

Article 3: Babenko et al. concluded that GLP-1 receptor agonist resulted in a decrease in BMI and waist circumference in patients with T2DM and obesity. Additional results that the article found included that ghrelin level two hours after breakfast predicts bodyweight reduction in these patients, which can help determine which patients may have the best outcomes from GLP-1 receptor agonist.  

Article 4: Davies et al. concluded that in patients with TD2M and who were overweight or obese, subcutaneous 3.0 mg liraglutide (which is a higher dose of liraglutide) resulted in weight loss from baseline to 56 weeks in comparison to placebo.

Article 5: Hitke et al., concluded that GLP-1 receptor agonists are effective in the reduction of bodyweight in patients with type 2 diabetes, especially in comparison to placebo. There were no clinically meaningful differences between bodyweight reduction when comparing one GLP-1 receptor agonist to another.

Clinical Bottom Line:

Weight of evidence:

I weighed the fifth article by Hitke et al. the most because it was a systematic review with a large sample of participants. It evaluated thirty-four trials, all randomized controlled trials, that compared GLP-1 receptor agonist to another GLP-1 receptor agonist or placebo. The authors found that GLP-1 receptor agonists had significant weight loss in comparison to placebo, and that out of the GLP-1’s that were evaluated, liraglutide had the greatest weight loss. Even though this systematic review did not directly evaluate RCTs that assess diabetics who are overweight or obese, a large proportion of diabetics are overweight/obese and since it was not a specific exclusion criterion, I believe this review is still valid for inclusion.

Articles one and four were weighed next because each were randomized controlled trials evaluating weight loss in patients with diabetes and obesity on GLP-1 receptor agonist. Both trials included placebos. I weighed article four more than article one, because article one also included a lifestyle intervention. Even though all groups received the lifestyle intervention, this could have contributed to the results of the GLP-1 receptor agonist. Both used two different doses of the GLP-1, in addition to placebo, which allowed for greater understanding regarding dose and response to treatment.

The second article was weighed fourth because it was a systematic review that evaluated the effects of GLP-1 receptor agonist on type 2 diabetics and obesity. However, it mainly assessed the safety profile and cardiovascular effects of such medication. While these are other important outcomes that need to be evaluated prior to starting a patient on a new regimen, it was not the main assessment of the question.   

The last article weighed was article three because it was a prospective cohort study with only forty participants. Participants were evaluated for 28 weeks, which may not have been enough time to evaluate the full effects of the medication. However, I still included this article in analysis as it was directly related to the outcome and evaluated two different GLP-1 receptor agonists for weight loss in the population.

While both articles two and three are not the highest sources of evidence for the question in this mini-CAT, I continued to evaluate and include them in this assessment as they closely aligned with my research question. Article two was a systematic review with a large sample size and article three was a prospective cohort study, however I still included each as they evaluated the GLP-1 receptor agonists for weight loss in type two diabetics and obesity

The use of multiple GLP-1 receptor agonists was both beneficial and a weakness when evaluating these studies. It was beneficial as it allowed for evaluation of the entire class of GLP-1 receptor agonist, however it can be considered a weakness as it did not allow for direct comparison of one GLP-1 to placebo on weight loss. Another weakness of all studies was difficulty generalizing to larger populations, as the articles excluded individuals who had uncontrolled hypothyroidism, severe cardiac disease etc.

Magnitude of effects:

Article 1: This article found mean weight change was -9.6% (SE 0.4) with semaglutide 2.4 mg. In comparison, semaglutide 1.0 mg was -7.0% (SE 0.4) and placebo treatment difference was -3.4% (0.4). Estimated treatment difference for semaglutide 2.4 mg versus semaglutide 1.0 mg was -2.7% (95% CI -3.7 to -1.6 p<0.0001). An achievement of at least 5% reduction in bodyweight at the end of the trial was seen more with semaglutide 2.4 mg than placebo (267 or 68.8% versus 107 or 28.5%, odds ratio 4.88 95% CI 3.58-6.64, p<0.0001).

Article 2: A randomized controlled trial found that there was a statistically significant difference in weight when comparing exenatide and insulin aspart. Another trial found a significant decrease in body, visceral and subcutaneous fat with exenatide (−3.45 [0.98] kg or −10.5%; P = 0.0015), (−389 [475] mL or −6.8%; P = 0.42), (−964 [773] mL or −10.6%; P = 0.22). 

Article 3: This study found that 51.5% of participants had a bodyweight reduction, 5% or more from initial, when treated with GLP-1 receptor agonist. There was no significant association of age, length of diabetes diagnosis, initial BMI, or sex with weight loss. Ghrelin level two hours after breakfast was lower in patients with bodyweight reduction over 5%, 2.2 (1.3; 2.7) vs. 11.8 (4.8; 14.5), p = 0.011.

Article 4: This article found that 3.0 mg liraglutide was statistically significantly better than 1.8 mg liraglutide in weight loss of both 5% and more than 10%. 3.0 mg liraglutide had a mean weight loss of 6% (6.4 kg), liraglutide 1.8 mg was 4.7% (5.0 kg) and placebo was 2.0% (2.2 kg).

Article 5: The review found that in comparison to placebo, GLP-1 receptor agonists had significantly more weight loss. The greatest weight loss was seen with liraglutide (1.96 kg; 95% CI 1.25, 2.67) then twice a day exenatide (1.67 kg; 95% CI 1.05, 2.29), dulaglutide (1.57kg; 95% CI 0.66, 2.48), taspoglutide (1.54 kg; 95% CI 0.66, 2.41), once weekly exenatide (1.49 kg; 95% CI 0.40, 2.58), and lixisenatide (0.78 kg; 95% CI 0.09, 1.48)

Clinical Significance:

The results found above are clinically significant as each article found that GLP-1 receptor agonists did improve weight loss, especially when compared to a placebo. While not all articles found statistical significance in this, it still shows that there is an effect when using GLP-1’s in patients with type 2 diabetes who are overweight/obese. In the studies that evaluated differing dosages of GLP-1, they found that the higher doses did result in an increase weight loss. Also, in the articles evaluating other effects, additional positive effects of these medications included a decrease in hemoglobin A1c, decrease in fasting plasma glucose and a decrease in blood pressure. As is the case with many antidiabetic medications, several of the studies found more hypoglycemic events with the GLP-1 in comparison to the placebo, which is to be expected. Additionally, all the studies found adverse effects with the GLP-1 receptor agonist, mainly gastrointestinal symptoms, however there were minimal severe side effects. The risks of these additional side effects must be weighed against the benefit of weight loss in this population. The weight loss may also bring further improvement in quality of life and activities of daily living, which should also be considered. Thus, it is reasonable to use GLP-1 receptor agonists in patients with type 2 diabetes and obesity to treat both the patient’s diabetes and aid in weight loss.

Other Considerations:

Additional research is needed with larger population sizes and longer treatment duration to assess the long-term benefit of GLP-1 receptor agonists. Longer studies can also assess whether there is a plateau in weight loss after a certain number of weeks or years. Evaluating which GLP-1 agonists. what doses are most effective and formulation (PO versus SC) also needs to be evaluated further. Although the side effects are minimal, assessing compliance in the setting of gastrointestinal symptoms should also be studied long-term. Lastly, as seen in one of the studies, observational studies after the GLP-1 agonists are removed should be examined, to determine whether the weight is immediately, gradually, or never regained after the medication is removed.