FormalPara Key Summary Points

Obesity is a multifactorial, relapsing chronic disease that is a gateway to a plethora of metabolic, cardiovascular, mechanical and mental problems

Obesity is a root cause of type 2 diabetes mellitus

An obesity-centric treatment approach with sustained lost weight is a key intervention in prevention and treatment of type 2 diabetes mellitus

Introduction

Obesity is a multifactorial, relapsing chronic disease that is a gateway to a plethora of metabolic, cardiovascular, mechanical and mental problems [1]. It is not simply a moral issue or one of compromised willpower, but rather a product of complex interplay of environmental, genetic and biologic determinants. In the last few decades, the global prevalence of obesity has almost tripled [2,3,4,5]. According to a report by World Health Organization in 2016, approximately 2 billion adults are overweight, with 650 million considered to suffer from obesity [6]. Projections based on current trends suggest that 2.7 billion adults are overweight, over 1 billion will be affected by obesity, and 177 million will have severe obesity by 2025 [6]. The gravity of obesity becomes even more apparent when its comorbidities, such as type 2 diabetes mellitus (T2DM), cardiovascular disease, degenerative arthritis, respiratory and sleep disorders, and certain cancers, are considered.

Over the past 2 decades, the prevalence of T2DM has increased more than threefold, parallel to the global rise in obesity rates [7]. Currently, there are approximately 537 million patients with T2DM worldwide. Projections for the future are even more disconcerting. If this trend persists, it is anticipated that the number of patients with T2DM will soar to 783 million by 2045 [7]. This alarming projection raises serious concerns about the sustainability of healthcare systems and emphasizes the urgent need for comprehensive strategies to address both T2DM and its associated health complications.

The temporal relationship between obesity and T2DM has led to the term 'syndemic' and fostered efforts to shed light on the chicken-egg dilemma between these two conditions. A large body of evidence has shown that the risk of T2DM increases with even modest weight gain [8,9,10]. We surmise that addressing the root causes of T2DM, promoting healthy lifestyles and implementing effective interventions are critical steps in mitigating the escalating burden of T2DM on a global scale. This article briefly reviews the effect of obesity management on T2DM and its related outcomes.

Role of Obesity in the Pathogenesis of T2DM

A number of mechanisms have been postulated to connect obesity to insulin resistance and the subsequent risk of T2DM. One key factor is the increased secretion of proinflammatory adipokines, such as tumor necrosis factor-alpha and interleukin-6, from adipose tissue. These adipokines can interfere with insulin signaling pathways, leading to insulin resistance [11]. The compensatory hyperinsulinemia further promotes the deposition of “ectopic fat” in liver [12]. The excess accumulation of fat in liver leads to increased fat distribution to various tissues, including the pancreas, which can contribute to a gradual decline in insulin production over time. This intricate interplay of elevated insulin levels and ectopic fat accumulation forms a cycle that results in hyperglycemia and contributes to the pathogenesis of T2DM. Another defect that links obesity to T2DM could be mitochondrial dysfunction, which exerts effects by decreasing insulin sensitivity and compromising beta cell function [13]. Weight loss, on the contrary, may cause a rapid loss of ectopic fat from liver, pancreas and other peripheral tissues and lead to significant improvements in insulin resistance [14,15,16,17]. Decreased body weight also restores pancreatic first-phase insulin secretion, a key factor in pathogenesis of T2DM [18].

Effect of Obesity Management on T2DM Prevention

Dozens of drugs have been developed and introduced in the treatment algorithms of T2DM worldwide [19]. Despite their substantial expense, the effectiveness of these drugs in individuals with T2D is limited, with a 1–2% reduction of glycosylated hemoglobin (HbA1c) at best [20]. Use of these drugs is not straightforward; it is instead tailored by presence of micro- and/or macrovascular complications [21]. Their efficacy can also be curtailed by a range of side effects. Given these challenges and limitations in the treatment of T2DM, it becomes evident that the fundamental paradigm should prioritize prevention over treatment.

Pharmacotherapy has always been an attractive option to prevent or delay the development of T2DM. The ADA recommends considering metformin therapy for T2DM prevention in individuals at high risk such as subjects with BMI ≥ 35 kg/m2, age ≤ 60 years, higher fasting plasma glucose (≥ 110 mg/dl) and higher A1C (≥ 6.0%) [22]. Some studies have also demonstrated promising effects of metformin when used in combination with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors for the prevention of T2DM [23,24,25]. Sodium-glucose co-transporter-2 (SGLT2) inhibitors, currently one of the most used drugs in T2DM treatment, have been shown to be associated with a lower risk of new-onset diabetes [26,27,28,29], especially being more evident in subjects with prediabetes. Improved cardiovascular outcome and modest weight loss are other benefits of these agents. However, enthusiasm about using thiazolidinediones for the prevention of T2DM has faded because of their adverse effects [30, 31].

Mounting evidence has suggested the effectiveness of newer therapies like GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists on T2DM prevention. These agents have ability to decrease appetite, increase satiety and augment pancreatic insulin secretion, resulting in weight loss and improved insulin sensitivity. Studies have reported that treatment with exenatide, liraglutide, semaglutide or tirzepatide offer a significantly reduced risk of T2DM compared to placebo [32,33,34,35,36,37]. The reduction of T2DM risk in subjects using GLP-1 receptor agonists appeared to be greater in subjects with prediabetes and cardiometabolic risk factors [37]. However, the extent to which weight loss plays a role in diabetes prevention and the understanding of other potential protective mechanisms of GLP-1 receptor agonists require further exploration. Future randomized prospective studies are needed to determine which subjects may benefit from pharmacotherapy in preventing T2DM.

The hypothesis that lifestyle intervention, including weight management, may prevent T2DM was tested by several observational studies [38,39,40,41]. Although early reports indicated changes in lifestyle might delay the onset of T2DM, their results were not robust because of methodologic drawbacks, i.e., absence of randomization. Finnish Diabetes Prevention Study, which examined the effect of lifestyle interventions on the development of T2DM, randomly assigned 523 overweight subjects with impaired glucose tolerance to either intervention group or control group [41]. The results of this study were promising, demonstrating that even a modest weight loss reduced the risk of T2DM by 58% in high-risk individuals.

Since interventions that decrease the risk of T2DM in some populations might not be consistently beneficial for others, a concern has been raised about the validity of generalizing the results of the Finnish Diabetes Prevention Study. This was partly addressed by the Diabetes Prevention Program (DPP), which was a multicenter, randomized trial in the US that involved > 3000 high-risk subjects with ethnically and culturally diverse backgrounds [42]. This study aimed to explore whether the risk of developing T2DM could be mitigated by intensive lifestyle intervention (ILI) or metformin compared with the risk in those who only received standard recommendations about lifestyle. The results of DPP were in accordance with its Finnish predecessor. Subjects who had overweight or obesity in the ILI arm in DPP had an average weight loss of 5.6 kg at 2.8 years with a 58% relative reduction in the risk of T2DM compared to 31% reduction in the metformin arm. The efficacy of weight loss in reducing T2DM risk was consistent across different racial groups.

The encouraging effects of weight loss on diabetes prevention raised further questions: how long can weight loss be maintained, and how long will the reduced risk of T2DM last? Diabetes Prevention Program Outcomes Study (DPPOS) was designed to cover these issues. Although the participants in the ILI arm approached their baseline weights at 10-year follow-up, cumulative incidence of diabetes was lowest in this group [43]. This highlighted the enduring benefits of the initial weight loss on diabetes risk over an extended period.

The preventive effect of maintenance of lost weight on diabetes achieved through ILI parallels the preventive effect of weight loss due to bariatric/metabolic surgery. In both scenarios, weight management emerges as a key factor in reducing the risk of T2DM. Perhaps some of the most convincing evidence regarding the effect of bariatric/metabolic surgery (BMS) on diabetes prevention emerged from the Swedish Obese Subjects (SOS) study [44]. The SOS study was a prospective non-randomized trial including 4047 subjects where patients with obesity who underwent gastric surgery were simultaneously matched with conventionally treated patients in the control group. The group that underwent BMS exhibited 16% weight loss over the course of 10 years, in contrast to the control group, which showed 1.6% weight gain. More strikingly, the incidence of T2DM in the surgery group was only 7%, while the control group showed a significantly higher incidence of 24%. Another study analyzed the SOS study in which 1658 patients with obesity treated with BMS were matched with 1771 controls with obesity [45]. At 15 years, the incidence rate of T2DM in the control group was approximately four times higher than that in the bariatric surgery group. These findings underpin the profound impact of weight management on prevention of diabetes. Moreover, a target of weight loss of 7–10% in subjects with obesity may prevent or delay the onset of T2DM [46]. Considering these data, the American Diabetes Association (ADA) strongly recommends ILI that support weight loss in high-risk individuals [47].

Role of Obesity Treatment on Glycemic Control and T2DM Remission

A loss of at least 5% of body weight has proven benefits in glycemic regulation [48]. Therefore, an integral component of diabetes self-management education is imparting the principles of healthy living. Nevertheless, traditional healthy living approaches often fall short in providing the weight loss required for remission of diabetes [49]. The apparent need for a structured and professionally supported weight management approach was underpinned by landmark studies: Action for Health in Diabetes (Look AHEAD), Diabetes Remission Clinical Trial (DiRECT), Diabetes Intervention Accentuating Diet and Enhancing Metabolism I (DIADEM-I) and STANDby [50,51,52,53].

In the Look AHEAD study, 5145 subjects who had overweight/obesity and T2DM were randomly assigned to ILI and usual care to investigate the effects of intentional weight loss on cardiovascular morbidity and mortality [50]. Although it was not originally designed to assess the effect of weight loss on T2DM remission, patients in ILI group had a higher likelihood of achieving diabetes remission compared to the usual care. The prevalence rates of diabetes remission in the first 4 years were 11.5% and 7.3% in the ILI group and 2.0% in the usual care group at each time point. DiRECT was a randomized trial conducted in UK that included 306 patients with T2DM having a BMI of 27–45 kg/m2 [51]. A structured weight management program, which included total meal replacement with a diet of 825–853 kcal/day followed by gradual food reintroduction, was administered to one group, and the other group received usual care. The percentage of weight loss ≥ 15 kg was 11% in the weight management program group and 2% in the usual care group. In the weight management program group, 36% of patients with T2DM underwent remission compared to 3.4% in the usual care group. The 2-year results of DiRECT support the notion that intensive lifestyle intervention for weight loss can lead to sustained remission in early-stage T2DM. Since DiRECT primarily included European patients, the STANDby study aimed to assess the effectiveness of the total meal replacement strategy in South Asian patients with diabetes [52]. The STANDby study provided promising data to show that weight loss achieved through a diet program with an initial 850 kcal/day can lead to remission of T2DM in South Asians. DIADEM-I was a randomized trial that included patients in the Middle East and North Africa, showing the efficacy of intensive lifestyle interventions with total meal replacement on T2DM management [53]. All these studies collectively provide evidence that intentional weight loss achieved through a hypocaloric diet can lead to diabetes remission across various ethnic groups.

Use of anti-obesity medications (AOMs), combined with lifestyle interventions, is useful in sustained weight loss over an extended duration [47, 54]. This weight loss through AOMs not only contributes to improved glycemic control but also allows for the de-escalation of glucose-lowering medications. Obesity management often leads to favorable outcomes such as lowered blood pressure and improved lipid profiles [55,56,57]. The ADA now recognizes the potential of AOMs as effective adjuncts to a healthy eating plan, physical activity and behavioral counseling, particularly for individuals with T2DM and a BMI ≥ 27 kg/m2 [47]. An ideal drug-treatment strategy for attaining diabetes remission hinges on two crucial factors. First, the risk of hypoglycemia should be low, as frequent hypoglycemia will limit the use of drugs in sufficient dosages to achieve normoglycemia. Second, pharmacologic therapies should lead to weight loss. Glucagon-like peptide receptor agonists (GLP-1 RAs) are a promising drug type that fulfills both criteria [58]. Liraglutide and semaglutide have proven effective not only in lowering glucose levels but also in promoting weight loss via multiple mechanisms, and both were approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for obesity treatment [58,59,60,61]. Almost half of the patients who received semaglutide 2.4 mg achieved a weight loss of ≥ 10%, and > 60% patients attained remission of T2DM at 68 weeks [59].

Recently, a dual agonist called tirzepatide was approved by FDA for treatment of obesity. Tirzepatide, a novel glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 agonist, demonstrated remarkable outcomes in individuals with obesity and T2DM [62]. GIP promotes insulin secretion in a glucose-dependent manner. GIP also signals satiety through hypothalamic receptors, leading to weight loss [63]. SURPASS trials were planned to investigate the effectiveness and safety of tirzepatide in patients with T2DM. In the SURPASS-I study, patients using tirzepatide 15 mg showed a 2% reduction in HbA1c and weight loss of approximately 10 kg. Furthermore, > 80% of patients using tirzepatide 15 mg achieved target glycemic values, and around half of the patients lost weight by > 10% [62]. These data suggest that tirzepatide could be a promising agent for both glycemic control and obesity management.

Effect of Obesity Treatment in Micro- and Macrovascular Complications of T2DM

With the aging population and an increasing incidence of T2DM, diabetic retinopathy and nephropathy have become leading causes of blindness and end-stage renal disease, respectively. Since microvascular complications cause major morbidity and mortality and comprise a significant portion of the total costs associated with diabetes, addressing and treating microvascular complications are of paramount significance [64, 65]. Diabetes induces an inflammatory environment, which plays a crucial role in the pathogenesis of microvascular complications. Obesity, being a potent stimulator of the inflammatory cascade, further complicates this scenario [66].

A study from the Nationwide Diabetes Report of the National Program for Prevention and Control of Diabetes, including > 100,000 patients with T2DM, reported that obesity was independently associated with microvascular complications [67]. The European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study suggested a positive linear association between pre-diagnosis BMI and risk of microvascular complications [68]. This study indicated that for every 5 kg/m2 increase in BMI, there was a 21% rise in the incidence of total microvascular complications. Conversely, a BMI loss of > 1% was associated with a 38% decrease in the incidence of microvascular complications compared to individuals with a stable weight. In addition to increasing the risk of microvascular complications, obesity was also associated with worsening of these complications [69, 70].

The 15-year follow-up of DPP demonstrated that individuals who remained diabetes-free had a 28% lower prevalence of microvascular complications compared to those who developed diabetes [71]. Another study assessing the long-term impact of BMS on microvascular complications revealed that individuals who did not develop diabetes had notably fewer microvascular events over the 15-year follow-up [72]. In a smaller cohort study, the maintenance of a weight loss of at least 7% at 1 year was linked to a 68% reduction in the risk of developing nephropathy for up to 10 years compared to those who maintained < 7% weight loss [73]. Beyond its preventive effects on diabetes and microvascular complications, weight loss achieved through BMS may have additional positive impacts; therefore, it could potentially improve existing peripheral neuropathy and slow the progression of retinopathy in individuals with diabetes [74].

The relationship of weight loss with macrovascular complications of T2DM is less clear. The results of the EPIC-Potsdam study indicated that initial BMI of subjects and the BMI change observed were not associated with macrovascular complications such as myocardial infarction and stroke [68]. Another study found no difference in incidence of macrovascular complications between patients who maintained weight loss at 10 years and those who did not [73]. DPPOS also found no reduced major cardiovascular events over 21 years despite long-term prevention of diabetes [75]. In the Look AHEAD trial, although weight loss achieved through lifestyle changes did not decrease the risk of cardiovascular disease in patients with T2DM, it provided some beneficial effects on cardiometabolic risk factors [76]. This trend was supported by other studies reporting improvements in cardiovascular risk factors with weight loss [77, 78]. In the SELECT trial, however, weekly semaglutide at a dose of 2.4 was shown to decrease the incidence of death from nonfatal myocardial infarction and stroke in patients with preexisting cardiovascular disease and overweight or obesity [79]. There is also evidence suggesting the benefit of weight loss on reduction of macrovascular complications through BMS or lifestyle intervention [80, 81].

SURMOUNT-1 trial has shown that tirzepatide significantly reduces the 10-year predicted risk of cardiovascular disease compared to placebo in patients had overweight or obesity without diabetes [82]. Further evidence from prospective randomized trials is needed to fully determine the effect of weight loss on macrovascular complications.

Obesity and T2DM are significant risk factors for the development of heart failure, a major cause of mortality, morbidity and impaired quality of life [83, 84]. More than half of heart failure who come to clinical attention have preserved ejection fraction, and > 80% of these patients have either overweight or obesity [85, 86]. A body of evidence from clinical trials suggests that weight loss through BMS may reduce the risk of developing heart failure [87,88,89]. Additionally, a recent systematic review has concluded that weight loss may increase exercise capacity, decrease the symptom burden and improve quality of life of the patients with heart failure [90]. Notably, drugs developed for treatment of T2DM have potential effects in treating both obesity and heart failure. GLP-1 agonists, at least liraglutide, and SGLT2 inhibitors have proven effective in weight loss and reducing hospitalization for heart failure as well as cardiovascular death [79, 91,92,93,94]. These drugs offer a promising avenue for managing both diabetes-related complications and obesity while improving cardiovascular outcomes.

Another complication that can be precipitated by both T2DM and obesity is renal failure. Weight loss in patients with obesity and renal failure leads to reduction of proteinuria and improvement in glomerular filtration rate [95]. Some drugs approved for treatment of obesity may slow the progression of renal failure. The results of the LEADER, SUSTAIN 6 and REWIND studies showed that subjects using liraglutide, semaglutide or dulaglutide respectively had lower risk of major adverse cardiovascular events and lower occurrence of a composite kidney disease outcome compared with those receiving placebo [94, 96, 97]. In SURPASS-4 trial, patients on tirzepatide experienced lower occurrence of composite kidney endpoint compared to placebo [98]. Although not an AOM, SGLT2 inhibitors promote 5% weight loss and have been shown to slow the progression of diabetic renal disease [99]. The nephroprotective effects of AOMs and SGLT2 inhibitors should be strongly considered in the management of patients with obesity, T2DM and renal failure. As with AOMs, BMS can prevent the decline in renal function by reducing proteinuria and albuminuria while improving glomerular hyperfiltration in patients with obesity and impaired renal function [100, 101].

Conclusion

Obesity is a multifactorial chronic, relapsing progressive disease. It is a root cause of T2DM and harbors increased risk for diabetes-related complications. An obesity-centric treatment approach with sustained weigh loss helps target a key driver of T2DM much earlier in the disease course. Obesity management may also serve as a useful intervention in already established diabetes and its complications. Finally, obesity should be prevented or treated to prevent or treat type 2 diabetes and its complications.