Patient initiation and maintenance of GLP-1 RAs for treatment of obesity: a narrative review and practical considerations for primary care providers

Figures & data

Table 1. Summary of the benefits of obesity management

Condition	Benefit
Glycemic control & type 2 diabetes	In adults with impaired glucose tolerance, behaviorally mediated weight reductions can prevent diabetes [26] Weight reduction of around 5% to 10% is associated with a reduction in HbA1c of around 0.5% in 1 year [11] AACE guidelines recommend a weight reduction of 5% to ≥15% in individuals with overweight (pre-obesity) or obesity and T2D, in order to reduce their HbA1c and required number/doses of glucose-lowering medications [6]
All-cause mortality	Weight reduction of 5% or more is associated with lowered all-cause mortality [27]
Cardiovascular disease (including hypertension)	Intensive obesity management programs in those with overweight (pre-obesity) or obesity have been shown to reduce the incidence of cardiovascular mortality compared to those without intervention [28] The AACE guidelines recommend a weight reduction of 5% to ≥15% in those with overweight (pre-obesity) or obesity and hypertension, in order reduce SBP and DBP as well as the required number/doses of glucose-lowering medications [6] Weight loss of around 5–10% is associated with a reduction in both SBP and DBP [29]
Dyslipidemia	Sustained 5–10% weight reduction in patients with overweight (pre-obesity) or obesity is associated with reductions in LDL cholesterol, total cholesterol, and triglycerides, and with increased levels of high-density lipoprotein [11] AACE guidelines recommend a weight reduction of 5% to ≥15% in individuals with overweight or obesity and dyslipidemia to lower triglycerides and non-HDL cholesterol levels, and raise HDL cholesterol levels [6]
Nonalcoholic fatty liver disease	Five percent weight reduction over 6 months is associated with a significant reduction in anthropometric markers for liver disease and hepatocellular apoptosis [30] AACE guidelines recommend a weight reduction of ≥5% in patients with overweight and steatosis in order to reduce intrahepatocellular lipid levels, and 10% to 40% in those with steatohepatitis to reduce inflammation and fibrosis [6]
Renal disease	Weight reductions induced by changes in nutritional intake, physical exercise, or bariatric surgery have been shown to be accompanied by an important antiproteinuric effect, which can protect against nephropathy of different etiologies [31]
Obstructive sleep apnea	Weight reductions can result in significant and clinically relevant improvements in obstructive sleep apnea among patients with obesity and T2D [32] AACE guidelines recommend a weight reduction of 7% to 11% or more in those with overweight or obesity and obstructive sleep apnea in order to improve symptomatology and decrease apnea–hypopnea index scores [6]
Female infertility	AACE guidelines recommend a ≥10% weight reduction in women with overweight (pre-obesity) or obesity and fertility issues in order to improve ovulation and chances of pregnancy and live birth [6]
Polycystic ovary syndrome	AACE guidelines recommend a weight reduction of 5% to 15% or more in women with overweight (pre-obesity) or obesity and polycystic ovary syndrome in order to improve ovulation and regularization of menses as well as a reduction in hirsutism and serum androgen levels, and enhanced insulin sensitivity [6]
Health-related quality of life	Patients with overweight (pre-obesity) or with obesity and T2D who receive an intensive lifestyle intervention resulting in significant weight loss have been shown to experience significant improvements in health-related quality of life compared with those who receive diabetes support and education but achieve minimal weight loss [20,33]
Lung function & asthma	AACE guidelines recommend a weight reduction of 7% to 8% or more in patients with overweight (pre-obesity) or obesity and asthma/reactive airway disease in order to improve symptomatology as well as forced expiry volume at 1 second [6]
Osteoarthritis & related disability	Five to ten percent weight reduction is associated with improved physical function and reduced knee pain in patients with obesity aged over 60 years with established osteoarthritis, with a clear dose–response effect [16] AACE guidelines recommend a weight reduction of ≥10% or 5–10% (when coupled with exercise) in order to improve symptomatology and function [6]

AACE, American Association of Clinical Endocrinologists; DBP, diastolic blood pressure; HbA_1c, glycated hemoglobin; HDL, high- density lipoprotein; LDL,low-density lipoprotein; SBP, systolic blood pressure; T2D, type 2 diabetes.

Table 2. Weight loss in randomized, placebo-controlled trials of liraglutide 3.0 mg*

Trial	Key inclusion/exclusion criteria	Duration (weeks)	N†	Change in body weight (%)† Primary analysis		Change in body weight (%)‡ Completer population
				Liraglutide 3.0 mg	Placebo	Liraglutide 3.0 mg	Placebo
SCALE Obesity and Prediabetes [56]	Did not have diabetes, but prediabetes allowed BMI ≥30 kg/m^2 or BMI ≥27 kg/m^2 with complications	56	3731	−8.0	−2.6	−9.2	−3.5
SCALE Obesity and Prediabetes; 160-week extension [57]	Had prediabetes BMI ≥30 kg/m^2 or BMI ≥27 kg/m^2 with complications	160	2254	−6.1	−1.9	−7.1	−2.7
SCALE Diabetes [58]	Had diabetes Taking 0–3 oral hypoglycemic agents BMI ≥27 kg/m^2	56	623	−5.9	−2.0	−6.7	−2.8
SCALE Maintenance [59]	Did not have diabetes BMI ≥30 kg/m^2 or BMI ≥27 kg/m^2 with complications	56	422	−6.2	−0.2	−6.7	−0.1
SCALE Sleep Apnea [60]	Did not have diabetes BMI ≥30 kg/m^2 Apnea–hypopnea index ≥15	32	359	−5.7	−1.6	NR	NR

*Data for liraglutide and placebo are estimated mean changes from baseline. ^†Full analysis set, comprised of patients who underwent randomization, were exposed to at least one treatment dose, and had at least one assessment after baseline. ^‡Same analysis as the primary analysis applied to completers in the full analysis set with a valid (did not significantly violate inclusion, exclusion, or randomization criteria and had a valid assessment at the end of the trial period) non-imputed measurement at the end of the trial. BMI, body mass index; NR, not reported.

Figure 1. Proportion of individuals losing ≥5% (a) and >10% (b) body weight with liraglutide treatment in randomized, placebo-controlled, phase 3 trials

*SCALE Maintenance observed additional weight loss after the run-in period. EOR, estimated odds ratio; ETD, estimated treatment difference; OR, odds ratio. Data from: SCALE Obesity and Prediabetes [56]; SCALE Diabetes [58]; SCALE Maintenance [59]; SCALE Sleep Apnea [60].

Table 3. Gastrointestinal adverse events reported in ≥5% of individuals treated with liraglutide 3.0 mg (and more frequently than placebo)

	Liraglutide 3.0 mg (N = 3384)	Placebo (N = 1941)
Gastrointestinal disorders (%)
Nausea	39.3	13.8
Diarrhea	20.9	9.9
Constipation	19.4	8.5
Vomiting	15.7	3.9
Dyspepsia	9.6	2.7
Abdominal pain	5.4	3.1
Upper abdominal pain	5.1	2.7

Adverse events for trials with treatment period up to 56 weeks, used for the liraglutide 3.0 mg prescribing information [49].

Pooled data included from: Astrup et al. 2012 [66]; SCALE Obesity and Prediabetes [56]; SCALE Diabetes [58]; SCALE Maintenance [59]; SCALE Sleep Apnea [60].

Table 4. Summary of practical recommendations for the initiation and maintenance of liraglutide 3.0 mg treatment in patients with obesity*

Aspect of treatment	Practical recommendations
Gradual dose titration	Utilize the 10 ‘micro-clicks’ between daily doses to help titrate slowly
Managing GI AEs	If nausea develops, reduce liraglutide to a lower tolerated dose for a sustained period Remind patients that most GI AEs tend to be transient and mild in nature and do not lead to discontinuation of treatment Inform patients that dietary modifications may minimize GI AEs, and that anti-emetics may be prescribed if necessary Discuss reflux precautions (eating smaller meals, not eating 2 hours before bedtime) Recommend a fiber supplement to help prevent constipation Suggest a magnesium supplement to help relieve GI symptoms Recommend that patients increase their water consumption or use over-the-counter oral rehydration treatments, to maintain hydration if they experience GI symptoms
Administration	Discuss the steps to follow in the event of missed doses, as per prescribing information, with the patient Explain that the pen does not need to be refrigerated while they are using it for the month Recommend that patients store their pen in a place that they will remember to take it, and that they set a reminder alarm on their phone Provide training on using pens, especially if the individual is new to using a treatment that requires injections Remind the patient that it is only an injection because the medication cannot be delivered orally Illustrate the small size of the needle compared to a phlebotomy needle, and explain that only a small amount of solution is injected, meaning that administration is virtually painless If you as the treating healthcare provider do not have time to undertake all these steps with your patient, consider training another member of your team to do so
Maintaining adherence	Remind patients that weight-reduction pharmacotherapies are not a ‘quick fix’ but a long-term option for managing obesity Explain that a 5–10% reduction in weight and management of obesity have many health benefits Discuss the benefits of liraglutide beyond weight reduction, such as the improvement of cardiovascular-associated risk factors and cardio-renal benefits
Managing weight reduction expectations	Remind patients of their success and celebrate their accomplishments Show patients a graph of their weight reduction over time and improvement in metabolic markers Remind individuals that when medication is stopped, most patients regain weight over time Explain that all weight reduction reaches a plateau eventually, due to metabolic adaptation, and that further interventions can then be considered

*Recommendations are based on the clinical experiences of the authors, and do not form part of the prescribing information for liraglutide.

AE, adverse event; GI, gastrointestinal.

Feldman AL, Griffin SJ, Ahern AL, et al. Impact of weight maintenance and loss on diabetes risk and burden: a population-based study in 33,184 participants. BMC Public Health. 2017;17:170.

 PubMed Web of Science ®Google Scholar

Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481–1486.

 PubMed Web of Science ®Google Scholar

Garvey WT, Mechanick JI, Brett EM, et al. AACE/ACE comprehensive clinical practice guidelines for medical care of patients with obesity: executive summary. Endocr Pract. 2016;22:842–884.

 PubMed Web of Science ®Google Scholar

Kritchevsky SB, Beavers KM, Miller ME, et al. Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials. PLoS One. 2015;10:e0121993.

 PubMed Web of Science ®Google Scholar

Li G, Zhang P, Wang J, et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing diabetes prevention study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2014;2:474–480.

 PubMed Web of Science ®Google Scholar

Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47:296–308.

 PubMed Web of Science ®Google Scholar

Ghaemi A, Taleban FA, Hekmatdoost A, et al. How much weight loss is effective on nonalcoholic fatty liver disease? Hepat Mon. 2013;13:e15227.

 PubMed Web of Science ®Google Scholar

Morales E, Praga M. The effect of weight loss in obesity and chronic kidney disease. Curr Hypertens Rep. 2012;14:170–176.

 PubMed Web of Science ®Google Scholar

Kuna ST, Reboussin DM, Borradaile KE, et al. Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes. Sleep. 2013;36:641–649A.

 PubMed Web of Science ®Google Scholar

Wright F, Boyle S, Baxter K, et al. Understanding the relationship between weight loss, emotional well-being and health-related quality of life in patients attending a specialist obesity weight management service. J Health Psychol. 2013;18:574–586.

 PubMed Web of Science ®Google Scholar

Williamson DA, Rejeski J, Lang W, et al. Impact of a weight management program on health-related quality of life in overweight adults with type 2 diabetes. Arch Intern Med. 2009;169:163–171.

 PubMedGoogle Scholar

Messier SP, Resnik AE, Beavers DP, et al. Intentional weight loss in overweight and obese patients with knee osteoarthritis: is more better? Arthritis Care Res (Hoboken). 2018;70:1569–1575.

 PubMed Web of Science ®Google Scholar

Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22.

 PubMed Web of Science ®Google Scholar

le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399–1409.

 PubMed Web of Science ®Google Scholar

Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the scale diabetes randomized clinical trial. JAMA. 2015;314:687–699.

 PubMed Web of Science ®Google Scholar

Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013;37:1443–1451.

 PubMed Web of Science ®Google Scholar

Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial. Int J Obes (Lond). 2016;40:1310–1319.

 PubMed Web of Science ®Google Scholar

Novo Nordisk. SAXENDA® (liraglutide) injection, for subcutaneous use. 2018. [cited 2020 Oct]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206321s007lbl.pdf.

 Google Scholar

Astrup A, Carraro R, Finer N, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–854.

 PubMed Web of Science ®Google Scholar