Indication for weight management intervention in older adults should be considered carefully and individually. As discussed previously, the risk arising from further decrease of muscle mass and progression of frailty is present with almost every weight-reducing intervention. Current clinical consensus and guidelines advise against weight reduction in older adults with overweight to prevent loss of muscle mass and functional decline. Instead, it is recommended for overweight older adults to maintain stable body weight to avoid progression to both obesity or sarcopenic obesity [33].

Older adults with obesity and related health complications (i.e. metabolic, cardiovascular, orthopaedic) should be selected for weight loss intervention only after careful individual weighing of risks, benefits and patient’s priorities. Physical exercise should accompany every weight-reducing intervention if possible alongside with proper nutritional support [33].

Nutritional intervention and physical activity should always be in the forefront of every obesity treatment strategy regardless of age. Moderate weight loss (up to 10% of baseline weight over 3–12 months) in conjunction with physical activity may improve physical function, metabolic outcomes and reduce cardiovascular risks. This is, however, often accompanied by reduction of skeletal muscle mass and bone mineral density, possibly worsening sarcopenia further [34]. This effect can be attenuated but not eliminated completely by concomitant exercise [22].

Only mild calorie deficit (approximately 500 kcal/day) from the daily energy requirement is recommended while maintaining a minimum caloric intake of 1000–1200 kcal/day for a sustainable weight loss of 0.25–1 kg/week [33]. Nutritional intervention should also include enough protein intake (1–1.5 g/kg body weight (BW)/day), calcium intake (1000–1200 mg/day) accompanied by micronutrient supplementation, that is, magnesium, vitamin B6, vitamin B12 and selenium [35]. Vitamin D is needed to mitigate unfavourable effect of weight loss on bone mineral density; some evidence also mentions beneficial effect of vitamin D supplementation on muscle strength and function in patients with sarcopenia [11, 36]. Supplementation of essential amino acids, more specifically leucine (minimum 2 g/day) or its metabolite β-hydroxy-β-methylbutyrate (HMB, also 2–3 g/day) is proposed as well [35].

Physical activity should combine strength, endurance, flexibility and balance exercises in older adults. American College of Sports Medicine (ACSM) recommends weekly a minimum of 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity. In addition, two or more days of moderate-intensity strengthening activities, with 8–10 exercises focussing on major muscle groups, is recommended. Patients should strive to perform 2 hours of balance exercises per week and low intensity stretching daily [37]. Training plan of three times a week 90 minute sessions, consisting of 15 minutes of balance training, 15 minutes of flexibility training, 30 minutes of aerobic exercise and 30 minutes of high-intensity resistance training has also been proposed for older adults [35].

Recommended lifestyle interventions for treatment of obesity in older adults are summarized in Fig. 2.

Lifestyle interventions for treatment of obesity in older adults

Bariatric surgery is the most effective treatment of obesity [38] and type 2 diabetes [39]. Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are the most commonly used bariatric procedures worldwide [40].

Despite a similar prevalence of obesity compared with younger age groups, patients older than 65 years of age represent less than 7% of the population undergoing bariatric surgery. This is at least in part due to the fact that recommended age for bariatric surgery was traditionally 18–60 years with a possibility to operate on older patients on an individual basis when benefits outweigh the risks [41].

In a cohort study performed by Iranmanesh et al., significant weight loss and comorbidity improvement were achieved in both groups of 22,981 patients < 65 years of age and 532 patients ≥ 65 years. Overall postoperative complications were similar between patients < 65 and ≥ 65 years 3388/22,981 (14.7%) versus 73/532 (13.7%, p = 0.537) as well [41].

There is, however, mounting evidence that bariatric surgery in older adult patients could be associated with increased in-hospital mortality, complications after surgery and consequently greater healthcare costs. Retrospective study by Mabeza et al. included 351,292 patients undertaking bariatric surgery (elective laparoscopic gastric bypass or sleeve gastrectomy), of which 44,183 (12.6%) belonged to geriatric cohort. This study revealed that patients aged 65 years and more had higher unadjusted rates of in-hospital mortality (0.3% versus 0.04% in non-older adult patients, p < 0.001), and complications, that is, cardiac (0.4 versus 0.2%, p < 0.001), respiratory (1.2 versus 0.5%, p < 0.001), renal (2.6 versus 1.0%, p < 0.001) and thromboembolic (0.2 versus 0.1%, p < 0.001) compared with their younger counterparts. Older adults also experienced prolonged hospitalization more often and had higher associated hospitalization costs [42].

This finding supports the need for careful weighing of risks versus benefit including geriatric assessment while deciding the appropriate treatment modality in older adults. Bariatric surgery is one of the promising strategies in treatment of obesity. More detailed discussion of this treatment modality in older adult individuals is, however, beyond the scope of this publication.

Pharmacotherapy is, in the last couple of years, the fastest developing and promising treatment strategy for obesity and related complications. However, available data focusing on the older adult population, that is, age > 65 years, are still very scarce. Representation of this age group in clinical trials is often very limited or not evaluated separately and more closely or it is excluded completely. Trials evaluating currently available obesity medications often focus mainly on weight reduction endpoints, which is not always the main goal from a geriatric viewpoint. This is especially true when the weight loss is accompanied by significant lean muscle mass reduction, which may aggravate pre-existing sarcopenia and result in frailty with related functional limitations. Other relevant geriatric outcomes such as muscle strength and bone mineral density are usually not part of the endpoint evaluation. We have selected currently approved pharmacotherapy for obesity and reviewed data for its use in the older adult population.

Glucagon-like peptide 1 (GLP-1) receptor agonists were initially used as a therapy for type 2 diabetes, thanks to their incretin role in glucose metabolism. It has been proven that systemic administration of GLP-1 or GLP-1 receptor agonists, in addition to improving glucose control decreases food intake, slows gastric emptying and reduces body weight by central anorexigenic effect [43, 44].

Liraglutide in a maximum dose of 1.8 mg once daily as a subcutaneous injection has been used for the treatment of diabetes since 2009 [45]. It was also approved in 2014 by the Food and Drug Administration (FDA) and in 2015 by the European Medicines Agency (EMA) as a treatment for obesity with maximum dose of 3 mg once daily. It is indicated as an adjunct to a hypocaloric diet and increased physical activity for weight management in adult patients with obesity (BMI of ≥ 30 kg/m2), or overweight (BMI ≥ 27 kg/m2 to < 30 kg/m2) in the presence of at least one weight-related comorbidity such as prediabetes or type 2 diabetes mellitus, hypertension, dyslipidaemia or obstructive sleep apnoea in adults. Treatment with liraglutide should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their baseline body weight [46].

The starting dose of liraglutide is 0.6 mg once daily. The dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least 1-week intervals to prevent/reduce gastrointestinal side effects. Doses higher than 3.0 mg are not recommended. No dose adjustment is necessary in older adults aged 65 years and more, however, therapeutic experience in population in patients ≥ 75 years of age is limited and use in these patients is not recommended due to lack of data [46].

Liraglutide clinical safety and efficacy was evaluated in the SCALE trials. The original SCALE Obesity and Pre-Diabetes trial resulted in a total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group losing at least 5% of their body weight (p < 0.001), and 33.1% versus 10.6% losing more than 10% of their body weight (p < 0.001) [47]. In SCALE Obesity and Prediabetes and SCALE Diabetes randomized control trials, once daily liraglutide 3.0 mg administration, as an adjunct to diet and exercise, showed similar mean and categorical weight loss efficacy in individuals aged ≥ 65 and < 65 years. In both trials, the proportion of individuals reporting adverse events tended to increase with age for each treatment. In SCALE Obesity and Prediabetes trial the serious adverse event rate was 6.1% versus 4.5% for liraglutide 3.0 mg compared with placebo in the < 65 years of age subgroup and 8.8% versus 13.2 % in the ≥ 65 years of age subgroup. In SCALE Diabetes trial the serious adverse event rate was 7.7% versus 5.7% for liraglutide 3.0 mg versus placebo in the < 65 years of age subgroup and 12.9% versus 7.9% in the ≥ 65 years of age subgroup. Hepatobiliary disorders were more common in the < 65 years of age subgroup, gastrointestinal events were more frequent with liraglutide 3.0 mg than placebo in both groups and benign, malignant and unspecified neoplasms were more common in the ≥ 65 years age subgroup [48].

A small trial by Perna et al. demonstrated that 24 weeks treatment with 3.0 mg of liraglutide was associated with reduction of fat mass and preserved skeletal muscle mass in nine individuals with both overweight or obesity and type 2 diabetes with mean age of 68.22 ± 3.86 years with baseline lack of physical activity and sedentary lifestyle [49]. The median fat mass reduction was − 1498 g and preserved skeletal muscle mass index (SMI) of + 0.03 kg/m2 median. Importantly, none of the tested subjects progressed into sarcopenia; in one individual the treatment showed anabolic effect with augmentation of fat free mass by + 1134 g. No protein supplementation or enhancement of physical activity was part of the intervention. Physical activity was assessed by physical activity scale for the elderly (PASE) questionnaire, with median change of − 11.60 points at 24 weeks. The recent data show, however, that when assessing skeletal muscle mass in obese and overweight individuals, adjustment of muscle mass to BMI or body weight is more accurate in revealing sarcopenia compared with adjustment to height2, which might underdiagnose sarcopenia in obese individuals [50]. This fact might be a confounding factor in this or similar studies.

Possible muscle preserving effect as mentioned above is in accordance with findings of Xiang et al., who examined effect of GLP-1 agonists liraglutide and semaglutide on muscle mass and muscular atrophy in murine models of obesity. In this study both GLP1-RA attenuated fat mass gain induced by high-fat diet (HFD) fed mice and preserved muscle strength normally reduced by HFD via activation of sirtuin-1 associated pathways, which is a key player in the ageing processes as well [51].

Liraglutide was also evaluated in terms of efficacy and safety in older adult patients with type 2 diabetes with insulin therapy [52]. The treatment with doses up to 0.9 mg after for 6 months in combination with insulin regimen improved blood glucose variability HbA1c levels and decreased insulin doses and body weight (60.0; 55.4–72.8 kg baseline to 56.7; 52.2–70.5 kg, p = 0.006, post-treatment). The safety profile of liraglutide remained favourable throughout the trial, with only 2 of 20 participants experiencing nausea or diarrhoea, and were able to continue after liraglutide dose reduction. No other adverse effects were reported.

Effect of liraglutide on cardiovascular events was favourable in patients aged both 60–74 and 75 + years, respectively, with type 2 diabetes at high risk of cardiovascular disease, showing reduction of major adverse cardiovascular events (MACEs) by 13% in the entire population of the LEADER trial [53]. Patients aged 75 years or older had a 34% and 29% risk reduction in the frequency of MACEs and expanded MACE outcomes, respectively, comparing liraglutide versus placebo. The risk reduction in all-cause mortality with liraglutide versus placebo was 35% in patients aged 75 years or older versus 6% in patients aged 60–74 years showing interesting advantages in the older age group. Overall, 63.5% and 61.7% of patients aged 75 years or older reported serious adverse events and non-serious medical events of special interest, respectively, versus 49.5% and 49.8% of patients aged 60–74 years. The most common adverse events were neoplasms (10.3% in patients aged 60–74 years compared with 14.2% patients 75 years or older) and gastrointestinal disorders (diarrhoea, nausea and vomiting in 1.2%, 2.4% and 1.1% of patients aged 60–74 years and 2.8%, 2.9% and 1.2% in those aged 75 years or older, respectively). In the liraglutide group versus the placebo group, more patients had gastrointestinal adverse events (46.6% versus 33.0%) and the incidence of acute gallstone disease was higher (10.0% versus 6.3%), regardless of age. The overall benefits seemed more pronounced in the older age group including the influence on cardiovascular outcomes. Obesity, weight loss and muscle preservation were not among the evaluated endpoints of this post hoc analysis [53].

There is also growing evidence that liraglutide may have a positive effect on progression of dementia in older adult patients with type 2 diabetes [54]. Recently, beneficial effect of liraglutide on impaired associative learning in individuals with obesity was also reported by Hanssen et al. [55]. More thorough research is necessary, however, a positive effect on cognition would be another argument for use of liraglutide in obese older adult population.

Liraglutide is effective medication for weight loss with years of clinical practice and robust evidence. More data on muscle mass preservation is necessary as with other weight reducing drugs. Adverse effects (mainly gastrointestinal) tend to be more pronounced in older population, increasing risk of dehydration, malnutrition and consequently, sarcopenia and frailty and should be kept in mind when prescribing liraglutide.

Semaglutide is another GLP-1-receptor agonist approved for use in patients with type 2 diabetes and/or obesity.

OZEMPIC (injectable form) and RYBELSUS (oral form) were both approved by EMA and FDA for the treatment of type 2 diabetes mellitus in adults as an adjunct to hypocaloric diet and exercise in monotherapy when metformin is considered inappropriate or in addition to other medications for the treatment of diabetes. Semaglutide is licenced for 1 mg once-weekly subcutaneous injection or in dose of 14 mg once daily in the oral form [56].

WEGOVY (injectable form), on the contrary, is indicated as an adjunct to a hypocaloric diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with BMI of ≥ 30 kg/m2 (obesity) or ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity, for example, prediabetes or type 2 diabetes mellitus, hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease [56].

The therapy is escalated over 16-week period to reach the maximum maintenance dose of 2.4 mg of subcutaneous semaglutide once weekly, starting with a dose of 0.25 mg once weekly to reduce the risk of gastrointestinal adverse events. The therapy escalation should be delayed if there are significant gastrointestinal symptoms present, until their subsidence. Weekly doses higher than 2.4 mg are currently not recommended, however, there is an ongoing trial testing the doses up to 7.2 mg once weekly. No dose adjustment is recommended in the older adult population, however, data in patients 75 years of age and older are limited [56].

Efficacy and safety of once-weekly semaglutide was evaluated in the SUSTAIN series trials in which adults with type 2 diabetes were randomized to semaglutide 0.5 mg and semaglutide 1.0 mg and comparator (placebo, sitagliptin, insulin glargine, other GLP-1 agonists) medical treatments with primary endpoint being reduction of glycated haemoglobin and secondary endpoint being weight loss. The post hoc analysis [57] of SUSTAIN 1–5 trials included 854 (21.9% of total) older adult subjects with mean age of 69–70 years. Semaglutide reduced bodyweight comparably between non-older adult and older adult age group, with 0.5 mg semaglutide weekly, body weight reductions ranged from − 3.3 to − 4.3 kg in non-older adult patients and − 3.6 to − 4.6 kg in older adult patients, and from − 4.6 to − 6.4 kg in non-older adults and − 4.1 to − 6.7 kg in older adults with semaglutide 1.0 mg weekly. Glycated haemoglobin reduction was also comparable in both groups [58].

Adverse events were compared as well, with severity of AE being similar in both age groups, more patients from the older adult group reported gastrointestinal adverse events. More older adult subjects discontinued the treatment prematurely compared with non-older adult group due to adverse events [57].

In the SUSTAIN 7 trial, semaglutide and dulaglutide were compared head-to-head in subjects on background treatment with metformin. Interestingly, proportion of older adult versus non-older adult subjects achieving glycaemic targets and weight loss response of ≥ 5% was consistently higher with both semaglutide and dulaglutide despite older adult subjects having a lower baseline HbA1c and BMI than non-older adult subjects. Proportions of subjects achieving ≥ 10% weight loss were comparable between the two age subgroups for both treatment arms [59]. However, evaluation of body weight reduction did not take into account body composition changes, that is, fat mass and its distribution versus lean mass decrease, an important factor in evaluating obesity treatment in the older adult population. Adverse events were reported in more than a half of subjects in SUSTAIN 7 trial regardless of age category, with gastrointestinal AE being the most frequent issue.

Once-weekly injectable semaglutide was also evaluated as a weight loss medication in the series of STEP randomized controlled trials. STEP 1 trial showed 14.9% reduction in body weight during 68 weeks of treatment with 2.4 mg of semaglutide combined with lifestyle intervention compared with 2.4% body weight reduction in the placebo plus lifestyle intervention group [60]. A subgroup of 140 participants underwent a DXA measurement, with result being a total fat mass and regional visceral mass reduction from baseline with treatment with semaglutide. Total lean body mass also decreased in absolute terms; the proportion of lean body mass relative to total body mass increased after treatment with semaglutide [60]. STEP 8 trial also showed superior bodyweight reduction in patients treated with once-weekly 2.4 mg semaglutide compared with daily 3.0 mg liraglutide. At week 68, the estimated mean change in body weight was – 15.8% with semaglutide and – 6.4% with liraglutide [61]. The differences between older adult and non-older adult populations, however, were not part of STEP trials analyses, as age-group-specific data were not evaluated separately.

Once-daily oral semaglutide as a glucose-lowering medication was evaluated in series of PIONEER trials. A subgroup analysis of the PIONEER 9 and 10 Japan trials showed dose-dependent body weight reduction without consistent pattern in both age groups of < 65 years of age and > 65 years of age. Adverse events occurred in larger proportions of older adult patients compared with the non-older adult population. The frequency of serious AEs was low in patients receiving oral semaglutide in PIONEER 9 and 10 and was similar in both age groups. Gastrointestinal adverse events were the most common AEs in both groups [62]. Body composition changes were not a part of the PIONEER trial evaluation, similarly to the STEP or SUSTAIN trials.

Muscle-preserving and at the same time fat-reducing properties of oral semaglutide were observed in 25 patients with type 2 diabetes aged 20–78 years (54.1 ± 2.7, mean ± standard error) in a study performed by Uchiyama et al., who used bioimpedance electrical analysis (BIA) to analyse body composition [63]. This 24-week trial by an individually adjusted dose by tolerability (3.0 mg minimal dose at 24 weeks, 14 mg maximal dose at 24 weeks) of oral semaglutide was accompanied by a decrease of both BMI and whole-body fat. BMI was 29.3 ± 0.68 kg/m2 at baseline, 28.5 ± 0.72 kg/m2 at 12 weeks (p < 0.01) and 28.0 ± 0.71 kg/m2 at 24 weeks (p < 0.001 versus baseline). Whole-body fat decreased from 28.3 ± 1.52 kg at baseline to 26.8 ± 1.59 kg at 12 weeks (p < 0.01) and 25.5 ± 1.57 kg at 24 weeks (p < 0.001 versus baseline). Muscle mass preservation was estimated by whole-body lean mass and skeletal muscle index (SMI), which was defined as appendicular skeletal muscle mass adjusted for height2. Baseline muscle mass was 48.1 ± 1.92 kg, 47.7 ± 1.93 at 12 weeks and 47.6 ± 1.89 kg at 24 weeks. SMI was 8.1 ± 0.20 kg/m2 at baseline, 8.1 ± 0.20 kg/m2 at 12 weeks and 8.1 ± 0.20 kg/m2 at 24 weeks. There was no subgroup analysis of older adult participants, however, the authors did not observe any significant correlations between age and changes in body composition at 24 weeks, suggesting effects of semaglutide being independent on age [63]. As discussed previously, using skeletal muscle mass adjusted for body weight or BMI would be more appropriate to assess muscle mass preservation in obese individuals.

Semaglutide is a promising effective agent in the treatment of obesity in both non-older adult and older adult populations, however, the effect on muscle mass preservation needs to be evaluated further to assure its position in treatment of older adults with sarcopenic obesity. The age group of subjects aged 75 years and older were also poorly represented in all performed trials, which has to be taken into account when deciding about safety for older adult population. As with other GLP-1 agonists, gastrointestinal adverse effects (i.e. nausea, diarrhoea, constipation) should be considered in older adult population as it may aggravate pre-existing health conditions, including sarcopenia.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist. It has a comparable GIP receptor binding affinity to native GIP and five times lower GLP-1 receptor affinity than that of native GLP-1 [64].

Tirzepatide (MOUNJARO) was approved in 2022 by both EMA and FDA for treatment of type 2 diabetes mellitus, and recently, in November 2023, FDA approved and EMA recommended change of the marketing authorisation for the use of tirzepatide for treatment of obesity and overweight in adults with BMI > 27kg/m2 or greater with presence of comorbidities, similarly to liraglutide and subcutaneous semaglutide [65, 66].

Tirzepatide is administered subcutaneously once weekly with a starting dose of 2.5 mg with escalation over 4–20 weeks to achieve the target dosage of 5.0 mg, 10.0 mg and 15.0 mg. In contrast to semaglutide where higher doses are used for the weight loss indication, the dosing of tirzepatide is the same for antidiabetic and weight loss indications [65].

In ZEPBOUND clinical trials (tirzepatide for treatment of obesity), 226 (9%) tirzepatide-treated patients were 65 years of age or older, and 13 (0.5%) tirzepatide-treated patients were 75 years of age or older at baseline; no overall differences in safety or effectiveness have been observed between patients > 65 years of age and younger patients. Similarly, in the pool of seven MOUNJARO clinical trials, 1539 (30.1%) patients treated with tirzepatide were 65 years of age or older, and 212 (4.1%) tirzepatide-treated patients were 75 years of age or older at baseline. No significant differences in efficacy and safety were observed across different age groups [67]. This is in accordance with recommendations of EMA for tirzepatide, which recommends no dose adjustment on the basis of age, sex, race, ethnicity or body weight [68]. It is important to mention that older adult participants of these studies probably do not reflect the heterogenous older adult population with all possible comorbidities and complications. Exclusion criteria often include prior cardiovascular, endocrine, renal and hepatogastric disorders which are very prevalent in the older adult population, favouring healthier individuals.

Tirzepatide was evaluated in the series of SURPASS trials, where effect on diabetes compensation and weight loss was thus far most effective of the available glucose lowering agents. SURPASS 1 trial showed significant weight reduction at 40 weeks. Body weight reduction was progressive and dose dependent, − 7.0 kg with tirzepatide 5 mg, − 7.8 kg with tirzepatide 10 mg and − 9.5 kg with tirzepatide 15 mg, versus − 0.7 kg in the placebo group. A greater proportion of participants had bodyweight reductions of 5% or greater (67–78%), 10% or greater (31–47%) and 15% or greater (13–27%) with tirzepatide versus 14%, 1% and 0% with placebo. BMI and waist circumference were reduced significantly as well [69]. The marked effect was also seen on diabetes compensation, with 87–92% of participants reaching HbA1c concentration of less than 7.0% (< 53 mmol/mol) after treatment with tirzepatide compared with 19% with placebo [69].

Pooled post hoc analysis of SURPASS 1-5 trials compared effects of treatment with tirzepatide in patients aged 60 years and more with their younger counterparts. In both age groups, tirzepatide reduced body weight versus comparator group. With tirzepatide 5 mg, the reduction in body weight ranged from ≥ – 7 kg to ≤ – 7.6 kg in the younger group and ≥ – 5.4 kg to ≤ – 7.1 kg in the older adult group. Similarly, tirzepatide 10 mg reduced weight from ≥ – 7.8 kg to ≤ – 10.7 kg in the younger group and from ≥ – 7.5 kg to ≤ – 9.5 kg in the older adult group, and tirzepatide 15 mg from ≥ – 9.5 kg to ≤ 12.9 kg in the younger group and ≥ – 8.8 kg to ≤ – 11.7 kg in the older adult group. In comparison, the comparator group lost from ≥ – 0.7 kg to ≤ + 2.3 kg of body weight. The baseline age for all tirzepatide doses had no significant effect on body weight reduction effect (for tirzepatide 5 mg: p = 0.198, tirzepatide 10 mg: p = 0.600 and tirzepatide 15 mg: p = 0.608) [70]. Unfortunately, this post hoc analysis did not include age specific adverse event reports or body composition assessment before and after intervention, both very important in the older adult group.

The most frequent adverse events with tirzepatide in SURPASS trials were mild-to-moderate gastrointestinal events, including nausea (12–18% versus 6%), diarrhoea (12–14% versus 8%), and vomiting (2–6% versus 2%) compared with participants who received placebo. Most reports of nausea, vomiting, and diarrhoea were mild to moderate in severity and decreased over time in all groups [69].

Tirzepatide was and still is being evaluated in people with obesity (BMI 30 kg/m2 or more, or a BMI of 27 kg/m2 or more and at least one weight-related complication (e.g. hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease) in the SURMOUNT trials. In the SURMOUNT-1 trial including patients with obesity (BMI > 30 kg/m2 , or BMI > 27 kg/m2 and at least one weight-related complication), the mean change in body weight at week 72 was − 15.0 % (95% CI − 15.9 to − 14.2%) with a 5.0 mg weekly dose of tirzepatide, − 19.5% (95% CI − 20.4 to − 18.5%) with a 10.0 mg dose and − 20.9% (95% CI − 21.8 to − 19.9%) with a 15.0 mg dose and − 3.1% (95% CI − 4.3 to − 1.9%) with placebo, respectively. SURMOUNT-1 evaluation also included a subgroup of 160 participants who underwent DXA to analyse body composition changes with mean reduction in total body fat mass of 33.9% with tirzepatide, compared with 8.2% with placebo. The ratio of total fat mass to total lean mass decreased more with tirzepatide (from 0.93 at baseline to 0.70 at week 72) compared with placebo (from 0.95 to 0.88) [71]. Detailed and weight/BMI adjusted lean muscle mass data would provide more accurate insight into the effect of tirzepatide on muscle mass preservation, however, they were not part of the original evaluation.

An age group post hoc analysis of SURMOUNT-1 trial [72] evaluated effect on body composition changes in subpopulations undertaking DXA scan within age subgroups under 50 years (n = 99), 50–64.9 years (n = 41) and 65 years and older (n = 20). Fat mass was reduced 33–36% and lean mass 10–11% depending upon age group, which resulted in improvement of body composition. Across all the age groups, the change was almost identical, indicating no evidence of excess lean mass loss in older age groups [72].

Overall, 78.9–81.8% of participants treated with tirzepatide reported at least one adverse event during the treatment compared with 72.0% of participants in the placebo group. The most frequently reported adverse events were gastrointestinal (nausea, diarrhoea and constipation). Serious adverse events were reported by 6.3% of participants, however, approximately 21% of these serious adverse events were considered to be attributable to coronavirus disease 2019 (COVID-19) infection, which affected patients in all treatment groups.

Safety and efficacy were also evaluated across age and BMI subgroups in East-Asia SURPASS programme. Compared with populations of European descent, East Asian patients with diabetes tend to present with lower BMI, but proportionally higher abdominal adiposity, and at any given BMI. In this trial, participants were treated with tirzepatide 5.0 mg, 10.0 mg or 15.0 mg and evaluated to assess the safety and efficacy of tirzepatide in people of East Asian descent (94% from Japan) on the basis of age (< 65 and ≥ 65 years) and BMI (< 25 and ≥ 25 kg/m2). At week 52, tirzepatide induced a similar dose-dependent reduction in glycated haemoglobin, waist circumference and BMI across all sub-groups, with similar safety profile in both age groups; only treatment discontinuation was higher in the group 65 years of age and older due to adverse events [73].

Tirzepatide is a very effective anti-obesity drug with great weight reduction effect and acceptable safety profile, however, in the older adult population, this significant and rapid weight loss may not be always beneficial. Even though there is a major fat mass reduction with body composition improvements, the lean mass loss, even though much lower than fat loss, can’t be overlooked in the frailest and sarcopenic population. Similarly to GLP-1 receptor agonists, gastrointestinal adverse effects may also lead to dehydration and pronounce malnutrition in fragile older adult population. More data on therapy in older adults and patients with sarcopenic obesity are needed to determine the role of tirzepatide in treatment.

Naltrexone/bupropion is a fixed combination treatment option for management of overweight and obesity in addition to exercise and hypocaloric diet sold under names MYSIMBA (EU) and CONTRAVE (USA) [74]. It has been approved for use in 2014 by both the FDA and the EMA for adult patients with obesity defined as BMI > 30 kg/m2 or BMI > 27 kg/m2 with presence of one or more complications such as type 2 diabetes, dyslipidaemia or hypertension [75].

Naltrexone/bupropion is taken orally twice per day (total daily dose: 32 mg naltrexone hydrochloride and 360 mg bupropion hydrochloride) after a previous 4-week escalation dosing scheme starting from 8 mg/90 mg, with a weekly increase by 8 mg/90 mg. The treatment efficacy should be evaluated after 16 weeks of regular use.

Bupropion is a dopamine/norepinephrine