Managing weight and glycaemic targets in people with type 2 diabetes—How far have we come?

Abstract Introduction As the vast majority of people with type 2 diabetes (T2D) are also overweight or obese, healthcare professionals (HCP) are faced with the task of addressing both weight management and glucose control. In this narrative review, we aim to identify the challenges of reaching and maintaining body weight targets in people with T2D and highlight current and future treatment interventions. Methods A search of the PubMed database was conducted using the search terms “diabetes” and “weight loss.” Results According to emerging evidence, treating obesity may be antecedent to the development and progression of T2D. While clinical benefits typically set in upon achieving a weight loss of 3–5%, these benefits are progressive leading to further health improvements, and weight loss of >15% can have a disease‐modifying effect in people with T2D, an outcome that up to recently could not be achieved with any blood glucose‐lowering pharmacotherapy. However, advanced treatment options with weight‐loss effects currently in development including the dual GIP/GLP‐1 receptor agonists may enable simultaneous achievement of individual glycemic and weight goals. Conclusion Despite considerable therapeutic progress, there is still a large unmet medical need in patients with T2D who miss their individualized glycemic and weight‐loss targets. Nonetheless, it is to be expected that development of future therapies and their use will favourably change the scenario of weight and glucose control in T2D.


| INTRODUC TI ON
Diabetes is a global public health burden, with type 2 diabetes (T2D) accounting for roughly 90% of all cases. This corresponds to approximately 537 million adults globally in 2021, and the number is projected to increase to 643 million by 2030 and to 784 million by 2045. 1 In addition, according to the Centers for Disease Control and Prevention (CDC), almost 90% of individuals with T2D in the United States are also overweight (body mass index [BMI] ≥25 kg/m 2 ) or obese (BMI ≥30 kg/m 2 ). 2 This shows that overweight and obesity are almost invariably associated with T2D.
Glycaemic control represents the primary target for people with T2D, regardless of the individual's body weight. Recent guideline recommendations suggest a glycated haemoglobin A1c (HbA1c) of less than 7% (53 mmol/mol) as a glycaemic target for the majority of adults without significant hypoglycaemia. [3][4][5] However, glycaemic treatment goals should be individualized based on patient preferences and goals, risk of adverse effects of therapy (e.g., hypoglycaemia and weight gain) and patient characteristics, including frailty and comorbidities. 4,5 According to the American Diabetes Association (ADA), more stringent HbA1c targets may be recommended if they can be achieved safely and with acceptable burden of therapy, and less stringent targets (e.g., up to 8% [64 mmol/mol]) may be adequate for patients with limited life expectancy or in cases where the harms of treatment outweigh the potential benefits. 3 Similarly, the shared European Society of Cardiology (ESC) and European Association for the Study of Diabetes (EASD) guideline 6

supports individualized
HbA1c targets, with HbA1c targets of 6.0%-6.5% (42-48 mmol/mol) in younger patients with a short diabetes duration and no evidence of cardiovascular disease, if achieved without significant hypoglycaemia. Less-stringent HbA1c goals of up to 9% (75 mmol/mol) may be appropriate for elderly patients with long-standing diabetes, limited life expectancy and frailty with multiple comorbidities. 6 Nonetheless, achieving the individual glycaemic target is and remains even more challenging for overweight and obese patients. There is a positive and statistically significant association between excess body weight and inadequate glycaemic control. 7 Consequently, overweight and obese people with T2D are less likely to meet their glycaemic targets compared to people with normal body weight. 7 In this narrative review, we aim to determine the challenges of reaching and maintaining body weight targets in people with T2D and highlight treatment interventions that may enable simultaneous achievement of individual glycaemic and weight goals.
Overweight and obesity represent not just a frequent concomitant condition but are also amongst the leading causes of T2D, together with hereditary predisposition and lack of exercise. 8,9 Even among individuals with low genetic risk score and favourable lifestyle, obesity was associated with a >8-fold increased risk of T2D compared with normal-weight people. 10 The rising prevalence of obesity worldwide, which increased threefold between 1975 and 2016, 11,12 is a global concern. In its latest report on the topic, the WHO announced that in 2016, more than 1.9 billion adults were overweight, and 650 million were obese, corresponding to 39% and 13% of the world population, respectively. 11 Since overweight and T2D are closely interconnected, it is likely that the increasing global proportion of overweight and obese people will contribute to the increasing prevalence of diabetes in the years ahead. This is even more the case because of the recent COVID-19 pandemic where many people have put on weight due to reduced exercise and overeating during lockdowns. [13][14][15] More worryingly, small changes in body weight in relatively short periods can become permanent and lead to substantial weight gain over time. 16 Targeting excess body weight may aid counteracting the epidemic of diabetes. Fat accumulation, predominantly in the abdominal or visceral region, can induce β-cell dysfunction 17 (also linked to excess fat in the pancreas), as well as excess liver fat and poorly regulated gluconeogenesis leading to the manifestation of hyperglycaemia in T2D. [18][19][20][21] Conversely, weight loss can reverse this process. 22 Consistent evidence shows that obesity management can delay the progression from prediabetes to T2D [22][23][24] and ameliorate hyperglycaemia in T2D. 22 Moreover, in overweight or obese people with T2D, modest and sustained weight reduction reduced the need for glucose-lowering medications. 22 Even a modest intentional body weight reduction of 5% produces some clinically meaningful health benefits, which increase with more prominent weight loss. 25,26 In an analysis of 0.5 million people from a United Kingdom primary care database, individuals in the weight loss cohort had a median 13% weight loss resulting in T2D risk reductions of 41%, assuming a BMI of 40 kg/m 2 before weight reduction. 27 A weight loss of ≥15% can reverse T2D metabolic abnormalities and improve glucose control-an effect unattainable by any currently licensed glucoselowering treatment. 28 Moreover, in the DiRECT clinical trial, intensive lifestyle changes with a low-calorie diet and an average weight loss of about 10 kg led to T2D remission in around 46% of cases within one year 29 and 36% after two years. 30 Similar one year remission rates were seen in the DIADEM-I trial conducted in Qatar. 31

| Difficulty of reaching glycaemic targets
Getting T2D under control by reaching the glycaemic targets proves challenging for many patients. Typically, 40%-60% of people with T2D across several geographic regions and in both low-and higherincome countries have suboptimal glycaemic control. 32 Despite the accelerated rate of introduction of new medicine classes since the mid-1990s, 33 the percentage of people reaching the HbA1c targets of <7% has not substantially increased. 34 Furthermore, reliance on pharmacotherapies only often fails to optimize glycaemic control.
Despite the availability of insulin-based therapies, roughly up to three quarters of patients failed to reach glycaemic targets. 35 Longterm maintenance of initial HbA1c level reduction proved an additional challenge when addressing glycaemic targets likely due to the progressive nature of beta-cell dysfunction over time. 36 Over a 10year period, a very modest improvement of 0.2 percentage points in HbA1c was demonstrated in T2D patients. 37

| Weight loss as a challenge in the context of T2D
Achieving glycaemic control represents just one more challenge for overweight and obese people with T2D that adds to the hurdle of reaching another target-weight loss. Data suggest that people with T2D experience more difficulty in trying to lose excess weight and maintain a healthy weight when compared to overweight people without diabetes regardless of the form of therapy utilized. 38,39 Moreover, one of the first long-term studies comparing conventional therapies in the late 1990s and their effect on weight and glycaemia over a period of 15 years demonstrated weight regain within three years regardless of the applied treatment. 36 Difficulty for overweight people with T2D in attaining both glycaemic targets and weight loss goals becomes even more urgent considering that the typical patient with T2D may have become one BMI unit (kg/m 2 ) heavier over the course of 10 years. 37 This excess weight gain may represent an even greater proportion of fat gain, as most people tend to lose muscle mass in older age, and this process is more accelerated in T2D. 40,41 Many obesity-related risk factors depend mainly on body fat distribution rather than excess weight per se. The visceral fat, that surrounds organs within the abdominal cavity and rib cage, is associated with an increased risk of metabolic diseases. 42 Although the underlying mechanism has not yet been fully understood, it is likely related to functional differences in subtypes of adipose tissue. 21,43 Visceral fat has been associated with higher metabolic activity and extent of inflammation. 44 As a result, more free fatty acids 44 and pro-inflammatory adipokines 45 are thought to be released to the bloodstream but further evidence proving such changes are causally linked to diabetes is needed.

| Existing burdens in obesity management
Why does the challenge of achieving the respective targets persist?
Potential explanations are likely to be multifactorial and linked to a number of patient-, physician-and treatment-related factors.

| Maintaining weight reduction, avoiding body weight variability
An existing burden is the frequent failure to maintain body weight reduction over time with obesity interventions, typically resulting in rapid weight loss followed by gradual regain. 46,47 A meta-analysis of 29 long-term weight loss studies found that just 23% of initial weight lost was maintained after 4 or 5 years. 48 In the long term, obesity prevention and treatment strategies proved effective to a limited extent with, speculatively, hormonal, metabolic and neurochemical adaptations defending against weight loss and promoting weight regain. 49 The failure to maintain weight loss may be partially explained by metabolic adaptation. Metabolic adaptation is a survival mechanism which acts to counteract weight loss and is thought to contribute to weight regain. 50,51 Since overweight and obese people typically burn more calories than normal-weight individuals, their total energy expenditure significantly declines as people lose weight. 52 The reduction in energy expenditure as well as the increased levels of hunger hormones and reduction in satiety hormones represent examples of metabolic adaptations in response to weight loss. 53 Nonetheless, the effect of metabolic adaptation remains a controversial topic with recent studies showing that metabolic adaptation does not predict weight regain at up to two years of follow-up. 54,55 The body weight variability (BWV) after weight loss should also be addressed since it is associated with greater cardiovascular risk in people with T2D, as shown in post hoc analyses of clinical trials. 56,57 In a real-world study with Asian patients with T2D, BWV was associated with higher risks of myocardial infarction, stroke and all-cause mortality. 58 A recent study 59 using data from the Swedish National Diabetes Register of 100,576 people with T2D and without prevalent cardiovascular diseases at baseline evaluated the link between visit-to-visit BWV and the risk of cardiovascular complications in a Caucasian population. High BWV predicted the development of cardiovascular complications such as non-fatal myocardial infarction, non-fatal stroke and all-cause mortality in T2D. 59 These studies further suggest that any weight loss strategy in people with T2D should be aimed at maintaining the reduction in the long term and avoiding body weight oscillations.

| Lack of education and clinical inertia
A lack of diabetes-related education may contribute to the failure to achieve patient's treatment goals. 32 For instance, 20% of the healthcare professionals (HCP) surveyed in the DAWN2 study reported that they had received no formal postgraduate education regarding diabetes. 60 A survey indicated knowledge gaps in 46% of primary care physicians in Australia regarding the medical management of T2D. 61 Underestimating the health consequences of obesity, which is yet not ubiquitously considered as a disease amongst HCPs but instead regarded simply as a failure to commit to a healthy lifestyle, 62 may also represent an educational gap. A popular misconception is that a temporary change to better diet and more physical activity will reverse obesity, suggesting a common failure to recognize modern concepts in regulation of energy metabolism and body weight management. 62 As a result, initially successful weight loss is frequently followed by a phase of weight regain. [63][64][65][66] Up to half of people with T2D appear to be inadequately treated due to clinical inertia and other reasons for underuse of intervention by their healthcare providers. 32,67,68 Extended periods of 'mild' hyperglycaemia are often accepted by HCP. 32 As a result, T2D patients often continue in poor glycaemic control without appropriate changes in therapy. 32,69,70 Early exposure to inadequate glycaemic control in people with T2D can result in a significantly increased risk of myocardial infarction, heart failure, stroke or composite cardiovascular events. 71 Substantial delays of a median of 1.6-2.9 years or 6.9-7.2 years in intensifying treatment by adding a second or third oral agent or insulin, respectively, were reported despite persistently high glycaemic levels. 72 Early clinical inertia and delays in achieving a desired level of glycaemic control have been associated with increased probability of the patient failing to achieve their glycaemic targets later in the disease process. 69,73 The opposite has also been reported-treatment modification in patients with elevated HbA1c after 6 months reduced therapeutic inertia and was predictive of better long-term glycaemic control. 74 Clinical inertia is also a barrier to effective weight management.
It presents a failure to start or intensify treatment and a missed opportunity to prevent complications at early stages (i.e., the progression from prediabetes to T2D) or reduce the risk of long-term complications (i.e., cardiovascular events). 75 Much of the inertia in addressing obesity can be attributed to the prevailing and persistent framing of obesity as matter of personal responsibility. 62,76 The causes of clinical inertia are multifactorial and occurring at the level of the practitioner, patient and/or healthcare system. 77 Regardless of the cause, there is a pressing need to address clinical inertia. Multidisciplinary teams, a coordinated chronic care model, including self-management and decision support, delivery system design, clinical information systems, community resources and policies, may counteract clinical inertia by promoting interaction between more empowered patients and better prepared HCP. 4,5 In addition to these multiple factors leading to a reduced likelihood of achieving individualized targets, one of the most important factors may be underestimating the interconnection of T2D and obesity. A current hypothesis is that treating obesity may be antecedent to the development and progression of T2D, such that weight loss may result in better glycaemic control also prospectively. 28 If this hypothesis were correct, this would imply that obesity is often neglected in T2D when it should be the first priority for intervention.

| Enhancing weight loss with current therapeutic options
As discussed above, weight management emerges as another important target as glycaemic control for a majority of people with T2D. Various treatments aid achieving glycaemic targets and enhancing body weight loss to a different extent. Here, lifestyle interventions, weight loss medications, anti-diabetes pharmacotherapies and bariatric surgery will be discussed as well as their effects on both targets.

| Diet, physical activity and behavioural intervention
Lifestyle modifications such as diet and increased physical activity have been established as a cornerstone of the treatment of T2D and obesity. Moreover, it has been recommended as a first-line strategy by guidelines for management of both diabetes and obesity. 4,5,22,78,79 The aim is management and reversal of excess weight that can lead to better glycaemic control. The approach should be a high-quality hypocaloric diet, which promotes patient's adherence accompanied by a minimum of 150 min of moderate activity per week. 80 The feasibility of these recommendations was demonstrated in the Look AHEAD clinical trial. 81 In that study, intensive lifestyle intervention resulted in clinically meaningful weight loss (≥5%) in 50% of people with T2D, and approximately 26% maintained a body weight loss of ≥10% at year 8. 81 Moreover, intensive dietary interventions with low-29,30 and very-low-calorie diets 82,83 have been shown to achieve substantial reduction of HbA1c and sustained T2D remission in obese people with T2D. However, according to the ADA, such structured, low-calorie diets should be prescribed only for carefully selected patients by well-trained and experienced practitioners with close monitoring. 22 For the vast majority of obese people with T2D, significant weight loss is feasible with lifestyle programs that achieve a 500-750 kcal/day energy deficit, 22 somewhat regardless of macronutrient composition. 84,85 Accordingly, dietary choice should be individually tailored to the patient's preferences and nutritional needs. 22,86 Besides energy intake in the form of calories, energy expenditure is the other important determinant in the body's energy balance.
Thus, weight loss can be attained by selective increase of energy expenditure utilizing physical activity, 87 although most people would need to exercise for several hours per week to achieve such weight loss which is unfeasible for most. Moreover, regular exercises could present a physical burden on people with T2D due to their often low physical performance threshold. 88 Exercise or increasing activity is, however, a very effective intervention to help prevent or minimize weight (re)gain in adults. 89 Weekly moderate to vigorous physical activity is recommended for T2D management. 4,5,90 Encouraging high levels of physical activity (200-300 min/week) after achieving short-term weight loss goals is also recommended, 22 although hard to achieve for many. For the large proportion of people with T2D who are ageing, currently sedentary, overweight or obese, deconditioned or unable to embark upon structured exercise, 'sitting less' may prove an alternative behavioural strategy. In a recent experimental study in postmenopausal women, a significant improvement in peripheral insulin sensitivity in the sitting less (~13%) and the exercise regimen (~20%) has been reported, compared with the sitting regimen. 91 Encouragingly, these results confirmed earlier findings in which breaking sitting with standing and light-intensity walking effectively improved 24 h glucose levels and insulin sensitivity in elderly people with T2D. 92 Therefore, people should be encouraged to find some physical activity that they enjoy and are likely to sustain or to vary physical activities to have more tools to help maintain higher habitual activity levels. Yet, physical activity represents just one component of long-term (≥1 year) weight-maintenance programs, which additionally provide regular contact and support. 22 Moreover, combining dietary interventions and physical exercise improves hyperglycaemia and reduces cardiovascular risk factors more than diet or physical activity alone. 84

| Weight loss medications
Obesity pharmacotherapy is a valuable option in patients with a BMI  Table 1). Among them are orlistat, phentermine/topiramate extended release (ER), naltrexone (ER)/bupropion (ER) and the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide 3 mg and semaglutide 2.4 mg. 94 All of them result in clinically meaningful weight loss and improve glycaemic control with data in patients completing at least one year of drug treatment. 93 The most recently approved treatment, semaglutide 2.4 mg, has been associated with the greatest weight loss compared with the other approved agents. 95 Semaglutide has been tested within the STEP clinical trials to promote weight loss in overweight or obese subjects without 95 and with T2D. 96 Notably, both GLP-1 RAs are diabetes medications explicitly approved for weight management in non-diabetic patients by appetite suppression. 95,97 Another treatment approach for weight management is the longacting amylin analogue cagrilintide. A phase 2 trial with cagrilintide 0.3-4.5 mg studied its effect on weight loss in people with overweight and obesity compared to liraglutide 3.0 mg, and to placebo.

| Glucose-lowering pharmacotherapies with weight loss effects
In addition to pharmacotherapies addressing obesity directly, there are anti-diabetes medications that promote weight loss. Glucoselowering medications that are weight-neutral or promote weight loss are recommended when treating people with T2D and overweight or obesity. 4,5,22,79 The therapies associated with varying degrees of weight reduction include metformin, α-glucosidase inhibitors (AGI), amylin mimetics, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and GLP-1 RAs. 22 In the following section, the drug classes associated with weight loss will be reviewed.

Metformin
Metformin remains the initial pharmacologic agent of choice for the treatment of patients with T2D unless there are contraindications. 4,5,79,99 Predominantly prescribed as a monotherapy in combination with lifestyle modifications, metformin may be combined with other agents in the presence of cardiovascular or minor renal complications, or when it is necessary to improve glycaemic control or promote weight loss. 99 Metformin belongs to the biguanides family and has the ability to decrease hepatic glucose production and intestinal absorption of glucose, as well as to exert insulin-like effects by increasing peripheral glucose uptake and utilization. 100   daily. 107 The most commonly reported adverse events were nausea of any severity and hypoglycaemia in people randomized to pramlintide vs. control. 105,106 Reports of nausea occurred predominantly in the early weeks of therapy, were mild-to-moderate intensity, were dose-dependent, and subsided over time. 108 With regard to hypoglycaemia, adding pramlintide to an insulin therapy carried the risk of severe hypoglycaemia in people with T2D vs. placebo (0.9 vs. 0.3 events/patient-year in the first 4 weeks of combination treatment) if concomitant insulin use was not proactively reduced. 109 These findings indicated that side effects can be managed by gradual titration program at pramlintide initiation. 108 However, due to its side effects, frequent dosing schedule of daily injections as well as the comparatively modest effect on glycaemic control and body weight, pramlintide clinical uptake has been limited.

SGLT2i
Other glucose-lowering agents introduced subcutaneously are the sodium-glucose cotransporter 2 inhibitors (SGLT2i), that is, canagliflozin, dapagliflozin, empagliflozin and ertugliflozin. This class prevents glucose reabsorption in the kidneys, resulting in an increased glucose excretion. 110 In turn, renal glucose excretion is thought to facilitate weight loss, both through caloric deficit and fluid loss due to increased osmotic diuresis. 111

GLP-1RAs
As discussed above, agents of the glucagon-like peptide-1 receptor  Currently, bariatric surgery is considered the gold standard treatment for severe obesity (BMI ≥40 kg/m 2 ) due to its high efficacy in terms of weight loss, duration of effectiveness and improvement of T2D. 22 It is also recommended by the ADA for patients with a BMI 35.0-39.9 kg/m 2 with inadequately controlled hyperglycaemia despite optimal medical therapy. 22 Almost 70% of patients experience complete T2D remission within 5 years following surgery, with a median duration of remission of 8.3 years. 130 In recent studies, significantly more obese patients with uncontrolled T2D achieved glycaemic control after a year of medical therapy plus bariatric surgery. 131 Another trial 132 confirmed that severely obese patients (BMI ≥35 kg/m²) with T2D achieved better glycaemic control after bariatric surgery than with medical therapy. At
biliopancreatic diversion group. A significant difference in extent of weight loss between the surgical and medical therapy groups was also observed, with no significant difference between the two surgical groups. 132 Further, the 10-year follow-up data indicated that 25% of patients in the gastric bypass group and 50% in the biliopancreatic diversion group remained in remission. 133 Unfortunately, about one third of patients in remission relapsed (defined as restarting diabetes medication and/or one or more HbA1c measures ≥6.5%) within 5 years of initial remission. This suggests that surgery is associated with durable remission of T2D in many but not all people with diabetes living with severe obesity. 130 For multiple reasons, including cost, limited access to care and concerns about adverse events, bariatric surgery has been limited to a small proportion of those eligible for the procedure. 87

| Potential future therapeutic options
In addition to the available therapies, multiple others are in development. Since it appears that a combination therapy was superior to monotherapy in newly diagnosed T2D, 134 one of the preferred combination partner for next-generation therapies could be the GLP-1

RAs due to its established robust improvement in glycaemic control
and weight loss and its cardioprotective effects. 135  which refers to the observation of a twofold to threefold increase in insulin secretion following oral glucose ingestion compared with a corresponding intravenous glucose administration (Figure 1). 143 Both GIP and GLP-1 secretion are stimulated mainly by the ingestion and absorption of carbohydrates and triglycerides or their digestion products and, to a lesser extent, by proteins or amino acids.
In people with T2D, plasma concentrations of GIP are higher after an oral glucose load or after a meal than in control subjects without diabetes. 144

Insulinsecretionandtheincretineffect
In healthy humans, both GIP and GLP-1 stimulate insulin secretion in a glucose-dependent manner, such that plasma glucose concentrations determine the degree of the insulin secretagogue effect in individuals exposed to GIP and/or GLP-1. 145 The incretin effect contributes significantly to important mechanisms required for the maintenance of normal glucose tolerance. A reduction in the incretin effect is usually associated with impaired oral glucose tolerance, and it is reduced in people with T2D due to defects in GLP-1/GIP levels and/or action. 146 Proposed mechanisms for the loss of the incretin effect include, first, a reduced response of incretin hormones to nutrients and, second, a reduction in the insulinotropic effect on pancreatic beta cells.
The severely impaired insulinotropic effect of GIP is the main reason  F I G U R E 2 Physiological effects of GLP-1 RAs, GCGR agonists and dual GLP-1 R/GCGR agonists on different organs and tissues (pancreas, liver, brain, brown adipose tissue, muscle, adipose tissue and circulation system). FAO, fatty acid oxidation; GSIS, glucose-stimulated insulin secretion). Adapted from 157 The aim of the study was to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of this drug combination.
It has been shown that concomitant treatment with once-weekly subcutaneous cagrilintide and once-weekly subcutaneous semaglutide 2.4 mg was well tolerated with an acceptable safety profile.
As expected with a GLP-1 RA, the majority of treatment-related adverse events were GI disorders. Moreover, the combination therapy Thus, T2D treatment needs to consider multiple goals simultaneously in addition to glucose control, specifically weight management, cardiovascular and renal risk reduction and improved adherence.
However, if we accept the validity of the emerging evidence, that obesity is upstream of T2D in vast majority of patients, 28 then we believe that an early weight-centric approach to T2D treatment would inevitably result in an effective and holistic approach to T2D with benefits in terms of the multiple T2D treatment goals simultaneously. In this sense, the available new therapeutic interventions can make a difference for our patients when broadly deployed.
Advanced treatment options as the widely available GLP-1 RAs have been shown to support holistic goals by lowering HbA1c without weight gain and hypoglycaemia, and importantly with great potential for reducing hard endpoints such as cardiovascular and kidney outcomes. The results of the combination therapies of GLP-1RAs with SGLT2i, as well as those of the GLP-1/GIP and GLP-1/GCGR co-agonists look increasingly promising, and it is to be expected that further development and use of these therapies will favourably change the scenario of weight and glucose control in T2D.