A large body of evidence (predominantly largely derived from long-term prospective studies, with limited evidence from randomized controlled trials) is available, examining the associations between certain food groups, dietary composition, and incidence of T2DM. Indeed, the evidence appears to support a common set of dietary approaches for the prevention of T2DM and chronic disease(s), largely underpinned by evidence-based guidance to limit the daily consumption of highly processed foods and carbohydrates, particularly those consisting of rapidly digestible starches and sugars.

These overarching messages were also outlined in an ADA consensus report that stated that macronutrient distribution should be based on individualized assessment of current eating patterns, preferences, and metabolic goals ( Fig. 3.3 ). This may be facilitated through a referral to an intensive lifestyle intervention program. As such, no ideal percentage of calories from carbohydrates, protein, and fat for all people with NDH was promulgated.

Goals of nutrition therapy in the prevention of type 2 diabetes mellitus ( T2DM ).

Adapted from Evert AB, Dennison M, Gardner CD, Garvey WT, Lau KHK, MacLeod J, et al. Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report. Diabetes Care 2019;42(5):731–754.

The overarching recommendations were recently summarized by the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD). These recommendations were preceded by a 2014 narrative review including results of meta-analyses of prospective cohort studies demonstrating that processed and unprocessed red meat, white rice, and sugar-sweetened beverages having a consistent, positive relation with T2DM. Conversely, green leafy vegetables, whole grains, and coffee were inversely associated with T2DM.

More recently, a 2019 umbrella review of systemic reviews and meta-analyses (53 studies; 153 adjusted summary HRs) explored the associations between the incidence of T2DM and dietary behaviors or diet quality indices, food groups, beverages (including alcohol), macronutrients, and micronutrients. Inverse associations were reported for whole grains (adjusted HR per additional 30 g/day = 0.87 [95% CI, 0.82–0.93]), cereal fiber (adjusted HR per additional 10 g/day = 0.75 [95% CI, 0.65–0.86]), and moderate alcohol intake (vs. no alcohol) (adjusted HR per 12–24 g = 0.75 [95% CI, 0.67–0.83]). Conversely, red meat (adjusted HR per additional 100 g/day = 1.17 [95% CI, 1.08–1.26]), processed meat (adjusted HR per additional 50 g/day = 1.37 [95% CI, 1.22–1.54]), and sugar-sweetened beverages (adjusted HR per one serving/day = 1.26 [95% CI, 1.11–1.43]) were associated with a higher incidence of T2DM.

Although the aforementioned findings are consistent with existing guidelines, diet involves a complex combination of foods and nutrients that act synergistically. As such, examining dietary patterns (e.g., Nordic, Mediterranean ) may be more predictive of disease risk than investigations of single foods or nutrients. For instance, a Western diet (typically high in sugar-sweetened soft drinks, refined grains, and processed meat) was associated with a relative risk for T2DM of 1.49 (95% CI, 1.26–1.76) in 69,554 females (aged 38–63 years), when comparing the highest with lowest quintiles.

The potential of plant-based dietary patterns to be used in the prevention of management of chronic disease (including T2DM) has also gained considerable traction over recent years. This dietary pattern places a greater emphasis on foods derived from plants (e.g., nuts, seeds, fruits and vegetables, whole grains) and includes lower consumption of or exclusion of animal products. A systematic review and meta-analysis including nine observational prospective studies ( n = 307,099, cases of incident T2DM = 23,544) demonstrated a significant inverse association between higher adherence to a plant-based dietary pattern and risk of T2DM (RR = 0.77; 95% CI, 0.71–0.84) versus poorer adherence. These associations were strengthened when fruits, vegetables, whole grains, legumes, and nuts were encapsulated within the definition of a plant-based dietary pattern (RR = 0.70; 95% CI, 0.62–0.79). Similarly, a cohort study ( n = 145,299 postmenopausal females, with a mean follow-up of 16 years) demonstrated that adherence to a Portfolio Diet, assessed with a score based on six components (high in plant protein [soy and pulses], nuts, viscous fiber, plant sterols, and monounsaturated fat and low in saturated fat and cholesterol) was prospectively associated with a lower risk of T2DM (HR = 0.77; 95% CI, 0.72–0.82). Interestingly, the level of risk reduction was comparable to that of a Mediterranean diet (HR = 0.78; 95% CI, 0.74–0.83).

Although these dietary approaches show some promise regarding the prevention of T2DM, weight loss is clearly the dominant determinant of the reduced risk of T2DM. Evidence suggests that dietary factors are unlikely to lead to any additional reductions in diabetes risk after accounting for weight loss. This was epitomized by findings from the DPP, where there was no independent effects of decreased percent fat on T2DM risk after adjustment for weight change. Similarly, the effects of replacing saturated fatty acids with monounsaturated fatty acids or high glycemic index foods with low glycemic foods over 24 weeks had little effect on insulin sensitivity when body weight remained stable. Even when weight loss is achieved through dietary manipulation, the methods appear to have similar effects upon insulin resistance. For example, an 8-week comparison between two weight loss diets (low-fat [20% fat, 60% carbohydrate] and low-carbohydrate diets [60% fat, 20% carbohydrate]) in 24 overweight/obese adults resulted in comparable effects on body weight (7.6% and 7.1% reduction in low carb and low fat, respectively) and insulin resistance, independent of macronutrient composition.

These findings question the relative merits of different dietary approaches independent of weight loss. Arguably, the ideal diet is the one that is best adhered to by individuals so that they can stay on the diet as long as possible (i.e., a personalized approach). This recommendation was typified by results from a meta-analysis including 48 randomized controlled trials, showing that both low-carbohydrate and low-fat diets were elicited similar weight loss at 6 (~–8 kg) and 12 months (~–6 kg) when compared with no dietary intervention. Although statistical differences existed among several well-publicized diets, the differences were minimal and unlikely to be important in those seeking to lose weight.

Regular physical activity is recommended for all individuals, unless otherwise contraindicated, with national (The UK Chief Medical Officers [CMO], NICE) and international (ADA, WHO, American College of Sports Medicine [ACSM]) guidelines produced that apply to all age groups. To discuss in detail is beyond the scope of this chapter; therefore we provide an abridged version here within and a summary in Table 3.3 .

Those at a high risk of T2DM are encouraged to undertake a minimum of 150 minutes per week of moderate-intensity physical activity, which is congruent with the general population. Vigorous intensity can be substituted in for moderate in those who are already physically active with a minimum of 75 minutes per week suggested. This should be supplemented with two to three resistance, flexibility, and/or balance training sessions/week. Sedentary behaviors should also be limited (discussed in more detail below). Regardless of subtle differences in their recommendations, each set of physical activity guidelines promulgates the use of a personalized, patient-centered approach to promotion, while considering personal limitations and preferences.

Although individuals are encouraged to work toward the aforementioned recommendations, the absolute targets are to a certain degree, arbitrary, as physiological and psychological benefits can be achieved at levels below and above these thresholds. It should be emphasized that although a higher intensity and duration of activity will elicit a greater range and magnitude of physiological adaptations, any form of increased movement has beneficial effects on overall health. For example, all intensities of physical activity are associated with a substantially lower risk of mortality in a graded association (up to a plateau of ~150 minutes per week of moderate-to-vigorous intensity and ~300 minutes per week for light-intensity physical activity). Importantly, the graded relationship between physical activity achieved and health outcomes is curvilinear, suggesting that the gains of increased physical activity could be especially significant for those currently doing the lowest levels of activity (fewer than 30 minutes per week), as the associations with improvements in health per additional minute of physical activity will be proportionately greater.

A meta-analysis summarized the epidemiological evidence examining the independent association of physical activity (after additionally adjusting for body weight) and T2DM incidence. In total, three studies ( n = 261,618 participants and 19,417 events) were included. To aid interpretation and in comparison to the aforementioned binary outcome, the authors derived a single, continuous physical activity metric. Overall, the results demonstrated an RR of 0.74 (95% CI, 0.72–0.77) for T2DM after adjustment for body weight and a similar level of risk when not adjusted for body weight (RR = 0.73; 95% CI, 0.68–0.79). Interestingly, the dose-response curve demonstrated a similar benefit when moving from inactive (0 METs) to 6 METs (RR = 0.77; 95% CI, 0.74–0.80), compared with moving from inactive to the MET h/week synonymous with current physical activity guidelines (11.25 MET h/week) (RR = 0.70; 95% CI, 0.54–0.90). The inverse association between physical activity and T2DM incidence also exists after adjusting for genetic risk. For example, a recent prospective cohort analysis using the UK Biobank demonstrated that when compared to the least-active individuals, a dose-response association was observed for moderate-to-vigorous intensity physical activity (corresponding daily minutes (HRs and 95% CIs): 5.3 to 25.9 minutes/day (0.63 [0.53–0.75]), 26.0 to 68.4 minutes/day (0.41 [0.34–0.51]) and >68.4 minutes/day (0.26 [0.18–0.38]). Interestingly, there was an interaction between moderate to vigorous physical activity (MVPA) and genetic risk score, suggesting larger absolute risk differences amongst those with a higher genetic risk. Inverse associations have also been shown between various physical activity modalities and T2DM incidence. For instance, a meta-analysis including 81 studies reported that the RR for high versus low activity was 0.65 (95% CI, 0.59–0.71). Similar results were also seen across the physical activity continuum with low (RR = 0.68; 95% CI, 0.52–0.90), moderate (RR = 0.66; 95% CI, 0.47–0.94), and vigorous activity (RR = 0.74; 95% CI, 0.70–0.79) all yielding significant inverse associations. More specifically, an RR of 0.85 (95% CI, 0.79–0.91) was also observed for walking. Although the strongest inverse association was seen for cardiorespiratory fitness (RR = 0.45; 95% CI, 0.29–0.70), the favorable associations also extended beyond aerobic activities, with resistance exercise displaying an RR of 0.72 (95% CI, 0.57–0.91) for high versus low resistance exercise.

Several reviews, consensus documents, and meta-analyses have summarized the health benefits of exercise training in T2DM-related outcomes (see Chapter XX), with favorable associations evident across the whole glucose spectrum and encompassing the continuum of human movement (from light activity through to high-intensity interval training [HIIT]). For example, a meta-analysis including both those with normal glucose tolerance and NDH (25 studies [ n = 870]) demonstrated that HIIT effectively reduced postprandial glucose (−0.37; 95% CI, −0.60 to −0.13) and insulin (−0.36; 95% CI, −0.68 to −0.04) levels when compared with a control group. Subanalysis further showed that the results for glucose were only significant in those individuals identified as having NDH at a baseline (5 intervention arms).

Similarly, results from a meta-analysis (15 studies), not including those with T2DM, demonstrated that physical activity interventions were associated with significantly lower HbA _1c (effect size = 0.32; 95% CI, 0.01–0.62) versus control. Interestingly, supervised physical activity programs (effect size = 0.33; 95% CI, 0.14–0.52) had greater magnitude of associations than physical activity counseling (effect size = 0.03; 95% CI, −0.13 to 0.20) and interventions <12 weeks and >150 minutes per week yielded the largest associations with improved glycemic control. This is similar to interventions in those living with T2DM, where a pooled analysis of 23 randomized controlled trials, ranging from 12 to 52 weeks of aerobic, resistance, or combined (aerobic plus resistance) exercise training elicited significant reductions in HbA _1c compared with nonexercise control participants (mean difference–0.73%,–0.57%, and–0.51%, respectively). Interestingly, total duration greater than 150 minutes per week had the greatest effect on average reduction of HbA _1c (–0.89%), but even those below this threshold exhibited on average significant reductions in HbA _1c (–0.36%). These results suggest that any form of sustained physical activity is likely to be beneficial for patients at a high risk of T2DM.

Aerobic exercise interventions are repeatedly found to induce clinically significant benefits on cardiorespiratory fitness (mean improvement in peak oxygen uptake [V·O ₂ peak] ~12%) and glycemic control. The evidence is also clear on a dose-response relationship, whereby activity of greater intensity, duration, or frequency will likely result in greater benefits. Some of these short-term benefits include (but are not limited to): improvements in sleep quality, anxiety/stress management, blood pressure, and insulin sensitivity. Chronic adaptions to sustained physical activity include the lowering of whole-body and ectopic lipid stores, improvements in endothelial function, improvements in cognitive function, reduction of systolic and diastolic blood pressure, promotion of a more favorable circulating lipid profile, reduced risk of cardiovascular morbidity, and all-cause mortality and improvements in glycemic control.

The proliferation and popularity of newly developed wearable devices have streamlined the measurement, quantification, and prescription of habitual physical activity. Daily step counts provide an easy-to-understand metric of ambulation that are common to most (if not all) wearable devices. Moreover, steps can be categorized as light, moderate, or vigorous, providing a range of exertion choice in the context of physical activity monitoring and prescription. This is exemplified by analyses demonstrating that a 5- to 6-minute brisk intensity walk per day (~500 steps in 5 minutes) equates to ~4-year greater life expectancy.

Previous studies have also shown that an increase of as little as 500 steps per day is associated with a 2% to 9% lower risk of cardiovascular morbidity and all-cause mortality, including those with NDH. Ponsonby et al. also estimated that for any average daily step count, an additional 2000 steps was associated with a 25% lower incidence of NDH over 5 years. Concurrent with the findings from the NAVIGATOR studies, the relationship between daily step count and health outcome appears linear. For instance, Kraus et al. analyzed the relationship between baseline steps and the incidence of T2DM in 7118 participants (where 35% subsequently developed T2DM). Results showed that each 2000-step increment in the average number of daily steps up to 10,000 was associated with >6% lower risk of progression toward T2DM. In addition, recent results from the UK Biobank (median follow-up of 7.4 years, n = 162,155, of which 4442 participants developed T2DM), demonstrate that compared with self-reported slow walkers, self-reported brisk walkers have the same diabetes incidence rate 18.6 (females) and 16.0 (males) years later. Moreover, the prospective associations between walking pace and the incidence of T2DM have been observed independent of adiposity, highlighting the potential benefits of combining brisk walking and weight management strategies in the prevention of T2DM.

Physical activity trackers, particularly those that count steps, are effective in supporting physical activity behavior change through enabling goal setting and feedback. For example, results from a meta-analysis of 34 randomized controlled trials ( n = 3793) showed a significant association of wearable tracker use (i.e., pedometers, accelerometers, or fitness trackers) with increased physical activity levels, which is amplified further when combined with health professional consultations.

Despite the impressive results of medication and/or surgery, existing therapeutic approaches (i.e., physical activity) still have a pivotal role to play. For instance, although the dual effects of weight loss and improved glycemic control associated with GLP-1RAs are appealing, a recent review examining the effect of GLP-1RA on changes in body composition demonstrated that the proportion of lean body mass reduction ranged between 20% and 50%, which is consistent with diet-induced weight loss and bariatric surgery. Therefore multimodal (both aerobic and resistance) exercise can be used to help preserve lean mass during weight loss, while acting to increase cardiorespiratory fitness and improve physical function. Muscle mass is critical to maintaining healthy human physiology, fundamentally providing the dynamic biomechanical device needed for locomotion, physical function, and the completion of essential daily activities. It also plays a fundamental role in maintaining cellular homeostasis through contributing to a wide range of physiological processes, including regulating glucose, inflammation, hormonal, and energy balance. Given that T2DM also represents a state of accelerated metabolic aging, some of the additional frailty risk (up to 5 times) may be underpinned by an increased loss of lean body mass and function.

Sedentary behavior has recently become more prominent in current physical activity guidelines (see above and Table 3.3 ). This important step forward is epitomized by the incorporation of new evidence-based recommendations on sedentary behavior within the 2020 WHO guidelines. That said, given the relative infancy of the research, the overarching message for the general population and those at risk of chronic disease remains generic (“sit less”). In comparison, the ADA guidelines stipulate breaking sitting time at least every 30 minutes with light or moderate activity in those with T2DM (see also Chapter XX).

Multiple meta-analyses have helped to highlight the importance of sedentary behavior by estimating the independent associations on the incidence of chronic disease(s) and markers of health, including those associated with T2DM. Importantly, the strongest and most consistent associations are seen for risk of T2DM (when compared with the increased risk for all-cause and cardiovascular disease [CVD] mortality). For instance, results from a meta-analysis including 11 prospective studies ( n = 1,331,468), demonstrated a graded association between higher levels of TV viewing time with the incidence of T2DM. TV viewing was estimated to be related to 29% (95% CI, 26%–32%) of T2DM incidence (vs. 5% for CVD mortality) with the largest associations with higher risk for T2DM seen <4 hours per day of TV viewing (1.12; 95 CI, 1.08–1.15) versus (1.02; 95% CI, 0.99–1.04) for CVD mortality. A similarly sized graded association meta-analysis ( n = 1,071,967; 13 cohort, 10 cross sectional), demonstrated that the risk of T2DM was 5% higher (total sedentary time) and 8% (TV viewing) for each 1-hour per day higher sedentary time. When examining sitting time only (as opposed to TV viewing), results from a 2019 systematic review and meta-analysis (5 studies, n = 223,871) demonstrated higher risk for CVD (HR = 1.14; 95% CI, 1.04–1.23) and higher risk for incident diabetes (HR = 1.11; 95% CI, 1.01–1.19), independent of physical activity.

Experimental research has complemented these epidemiological findings by examining the postprandial effects of breaking up bouts of prolonged sitting with standing or light-intensity activity. Multiple studies have demonstrated benefits on markers of metabolic health in those at high risk of T2DM. Importantly, this also includes some alternative strategies that do not necessarily involve changes in posture. For example, seated arm ergometry (5 minutes every 30 minutes) has been shown to acutely lower postprandial glucose and insulin levels by 57% and 20%, respectively, when compared with prolonged sitting. This mode of activity offers a viable alternative for those with weight-bearing difficulties or those who are wheelchair bound.

The acute effects of breaking up prolonged sitting on cardiometabolic outcomes in a largely overweight/obese cohort were summarized in a recent meta-analysis (number of randomized crossover trials = 7). The results showed that prolonged sitting punctuated with standing significantly reduced postprandial glucose (mean effect size = 0.31; 95% CI, 0.03–0.60). Similarly, light-intensity walking was also shown to attenuate the postprandial glucose (mean effect size = 0.72; 95% CI, 0.41–1,03) and insulin (mean effect size = 0.83; 95% CI, 0.48–1.18) response when compared with prolonged sitting.

Results from another meta-analysis that included 20 experimental studies demonstrated that when compared with prolonged sitting, short, frequent bouts of light-intensity activity reduced postprandial glucose by 17.5% (95% CI, 8.4–31.7) and insulin levels by 25.1% (95% CI;–18.3 to–31.76). Importantly, the effects on glucose were more pronounced in metabolically impaired individuals (–28.7%; 95% CI,–18.3 to–31.8) versus–20.1; 95% CI,–3.0 to–37.2).

The potential interindividual variability in the response to breaking up prolonged sitting has also been highlighted in a systematic review and meta-analysis, which included 42 studies. Although breaking prolonged sitting with physical activity attenuated the postprandial glucose and insulin response, the greater magnitude of difference in glycemic measures was observed in people with a higher BMI. These findings also corroborate a pooled analysis of four acute, randomized, experimental trials ( n = 129, persons with NDH = 27.1%) examining the postprandial response (glucose and insulin) to three treatment conditions: prolonged sitting (6.5 hours) or prolonged sitting broken up with either standing or light-intensity physical activity (5 minutes every 30 minutes). Reductions in postprandial insulin were modified by ethnicity, gender, and BMI. For instance, the response was more pronounced in South Asians versus White Europeans (–23.5% vs.–9.3%), females versus males (–21.2% vs.–17.6%), or those with a BMI ≥27.2 kg/m ² (–22.9% vs.–18.2%). Glucose responses were also more pronounced in females (–6.8% vs.–1.7%) and those with a BMI ≥27.2 kg/m ² (–6.7% vs.–3.4%).

Exploratory, post-hoc analysis of the Stand and Move at Work intervention, a multilevel intervention targeting reduction in sedentary time, also showed differences in the effect size, determined by glycemic status. Although the intervention yielded reductions in sitting time at 12 months for the whole cohort ( n = 487), the reductions in glucose, HbA _1c , body weight, and body fat were considerably larger and clinically meaningful in those with NDH or T2DM ( n = 95).

Therefore the current evidence suggests that breaking or reducing sedentary behavior is likely to be particularly important in those with NDH or associated risk factors. A reasonable goal may be to first break up sitting time with informal/light-intensity physical activity, which may also be more culturally acceptable to high-risk groups (e.g., South Asian females), before progressing onto higher-intensity activities.

Metformin may be pivotal in diabetes prevention, as indicated by NICE prevention guidelines, where benefits appear to be the strongest in adults at a higher risk of incident T2DM. For example, metformin has been shown to be more effective in younger (<60 years), obese individuals (BMI >35 kg/m ² ) and in females with a history of gestational diabetes. Metformin may also have favorable effects beyond its ability to improve insulin sensitivity (i.e., weight loss/maintenance). The largest study to show the weight benefits of metformin in those with NDH is the DPP. As previously discussed, the metformin arm of the DPP reduced the incidence of diabetes by 31% in a 3-year period, but participants also experienced a mean weight loss of 2.1 kg. Unsurprisingly, the degree of weight loss was strongly associated with adherence, where those participants displaying high levels of adherence over 2 years of follow-up demonstrated an average 3.5% reduction in body mass, compared with weight neural status in the low adherence group. Importantly, this weight loss persisted in the extended follow-up period over 10 years for the highly adherent group.

The addition of metformin to a dietary intervention has also been shown to result in the maintenance of diet-induced weight loss in overweight and obese females with normoglycemia and hyperinsulinemia. Results from a meta-analysis of randomized controlled trials also demonstrated that metformin does not increase body weight and may prevent weight gain from other glucose-lowering medications or induce small amounts of weight loss (−1.1 kg).

However, due to the modest effects of weight loss (particularly when compared with other pharmacological options mentioned below), metformin is not approved as a weight loss agent. That said, it is frequently utilized in patients at high risk for metabolic complications and who do not tolerate other interventions. Furthermore, it can be combined with other glucose-lowering medications, including GLP-1RAs and dual agonists that may result in additional weight loss or weight maintenance.

In addition to increasing insulin secretion and synthesis, GLP-1RAs suppress glucagon secretion, slow gastric emptying, promote β -cell proliferation, and reduce food intake via the reduction of appetite and enhancement of satiety. Liraglutide, a GLP-1RA, was initially approved as an adjunct therapy to diet and exercise for management of hyperglycemia of T2DM. Subsequently, its influence upon body weight has been investigated in multiple phase III and IV clinical trials. With particular relevance to diabetes prevention, The Satiety and Clinical Adiposity—Liraglutide Evidence (SCALE) Obesity and Prediabetes trial assessed the efficacy and safety of daily liraglutide injections (3 mg) versus placebo injections. After 56 weeks, the obesity and prediabetes cohort ( n = 2487 participants; 61.2% with NDH) demonstrated 8% weight loss (vs. 2.6% in the placebo arm). Of these, 63.2% reached the clinically significant threshold for weight loss (≥5%) and 33.1% achieved ≥10%. The combination of weight loss and improved glycemic control (HbA _1c [− 0.30% ± 0.28]) also likely contributed to the observed reductions in the prevalence of prediabetes (OR for NDH at 56 weeks = 0.30; 95% CI, 0.21–0.42) and the lower odds for incident T2DM (OR = 0.12; 95% CI, 0.04–0.38). These promising results persisted at 3 years, where the time to onset of T2DM over 160 weeks was 2·7 times longer with liraglutide than with the placebo, yielding a HR of 0.21 (95% CI, 0.13–0.34). Liraglutide also induced greater weight loss at 160 weeks (vs. placebo) (–6.1% vs.–1.9%).

Semaglutide is another example of a GLP-1RA used in the management of hyperglycemia of T2DM (1.0 or 2 mg per week, via subcutaneous injection), with the capability of inducing significant weight loss, particularly when considered in the context of other available weight loss medications. For example, orlistat and the aforementioned liraglutide each induce ~4% to 8% weight reductions on average when compared with the placebo. However, semaglutide more than doubles this weight loss. Indeed, findings from the Semaglutide Treatment Effect in People With Obesity (STEP) 8 trial, an open-label randomized controlled trial conducted in 338 participants, showed that after 68 weeks, those adults living with obesity achieved–15.8% weight loss with semaglutide (2.4 mg, n = 126) versus 6.4% with liraglutide (3.0 mg, n = 127). The STEP 1 trial, a double-blind randomized controlled trial in 1961 in overweight/obese individuals, also demonstrated specific benefits in those with NDH. In those randomized to once-weekly subcutaneous semaglutide (2.4 mg), 84.1% of those with NDH at baseline returned to normoglycemia after 68 weeks (vs. 47.8% in the placebo, plus lifestyle intervention arm). This offers great potential for clinical improvement for those living with obesity and NDH. Table 3.4 describes the weight loss observed with semaglutide in the related phase III trials in more detail.

The benefits may also extend beyond weight loss, where the ability of 2.4 mg weekly doses of semaglutide to reduce the risk of cardiovascular events in overweight/obesity (BMI = ≥27 kg/m ² ) has recently been demonstrated in the SELECT trial. Indeed, alongside 10.2% weight loss at a 4-year follow-up (208 weeks), semaglutide was also shown to be superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (HR: 0.80; 95% CI, 0.72–0.90) with a mean follow-up of 39.8 months.

It is important to note that high-dose GLP-1RAs are only one of several promising new drug classes in development for obesity, and the results to date merely represent the start of a promising future. For instance, although the therapeutic benefits of GLP-1RAs have been well publicized, trials are now underway, assessing combinations of glycometabolic hormone receptor agonism and antagonism coupled with GLP-1 RA, most notably targeting receptors for glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon. A previous trial using a once-weekly GLP-1R/GIPR dual agonist (tirzepatide; SURMOUNT-1 trial) demonstrated that 72 weeks of therapy in overweight/obese individuals induced weight loss of–15% (95% CI, −15.9 to −14.2),–19.5% (95% CI,–20.4 to–18.5), and–20.9% (–21.8 to–19.9) with 5, 10, and 15 mg doses, respectively. The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82–89) (5 mg), 89% (95% CI, 86–92) (10 mg), and 91% (95% CI, 88–94) (15 mg). Over 50% of participants taking either the 10- or 15-mg doses achieved >20% weight loss. Emerging evidence also highlights their seemingly favorable impact on cardiovascular biomarkers. Other combinations, including cagrisema (GLP-1/amylin receptor agonist) and the triple agonist retatrutide (GLP-1/GIP/glucagon receptor agonist), have now progressed to phase III trials, with preliminary data suggesting that they may induce even greater weight loss than tirzepatide. As such, these GLP-1 R/GIPR dual (and tri) agonists may become appealing pharmacologic agents of choice for those with NDH in the future.

The potential of bariatric surgery in preventing the incidence of T2DM in obese (defined as ≥34 kg/m ² for males and ≥38 kg/m ² for females) patients has been investigated in the seminal Swedish Obese Subjects study. This was the first long-term, prospective study providing information about the associations between surgically induced weight loss using laparoscopic adjustable gastric banding and the incidence of T2DM. In total, 1658 individuals were followed for 15 years postbariatric surgery and compared with matched control patients with obesity who did not receive surgery. Bariatric surgery was associated with a lower risk of developing T2DM by 96%, 84%, and 78% after 2, 10, and 15 years, respectively.

Similarly, a 23-year follow-up ( n = 385; 52 with T2DM), undertaken retrospectively as part of the LAGB10 study group (a network of physicians and surgeons working with bariatric surgery in Italy), also demonstrated a favorable association between surgery and the incidence of T2DM. When compared with controls (medical treatment of obesity, albeit in less effective pharmacological options than currently available), gastric banding was associated with a lower incidence of T2DM (HR = 0.34; 95% CI, 0.20–0.48) as well as being associated with lower mortality (HR = 0.52; 95% CI, 0.33–0.80), particularly in those with preexisting T2DM (HR = 0.46; 95% CI, 0.22–0.94).

These observational findings demonstrate that bariatric surgery is associated with positive metabolic alterations, likely through numerous mechanisms (including but not limited to weight loss, improved insulin sensitivity, inflammatory cytokines) to reduce the risk of T2DM. However, caveats include the practicality of bariatric surgery as a preventative strategy and even with substantial improvements in the safety and efficacy of gastric procedures, the risk of major surgery and the dietary changes that follow should not be considered lightly. Furthermore, the amount of weight loss needed in those with NDH to prevent T2DM is achievable (for most) without surgery through diet and/or pharmacotherapy. This, coupled with the fact that the long-term outcomes of bariatric surgery are largely unknown and the studies are often subject to bias and confounding, means that NDH alone is not one of the indicators for bariatric surgery in professional guidelines.