SIRAJ FARID,1 BILAL BASHIR,2,3 ADEEL HAMAD,1 SHAISHAV DHAGE,1,2 JAN HOONG HO,1 HANDREAN SORAN,2,3 SAFWAAN ADAM1,2
1 The Christie NHS Foundation Trust, Manchester, UK
2 Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
3 Manchester University Hospitals NHS Foundation Trust, Manchester, UK
Address for correspondence: Dr Safwaan Adam
The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester, M20 4BX, UK.
E-mail: safwaan.adam1@nhs.net
Br J Diabetes 2024;24(1):6-12
https://doi.org/10.15277/bjd.2024.438
There is increasing evidence that obesity is an independent risk factor for the development of microvascular disease. Addressing modifiable risk factors such as obesity may help prevent and even reverse microvascular complications, including neuropathy, nephropathy and retinopathy.
In this review article, we examine the evidence for the impact of obesity on microvascular disease, as well as the effects of weight loss in individuals with and without type 2 diabetes mellitus (T2DM). Numerous studies have shown obesity to be an independent risk factor for neuropathy and nephropathy in patients with and without T2DM but the association between obesity and retinopathy is less clear. Addressing obesity through weight loss strategies can have beneficial outcomes. Although evidence for medical weight management is limited due to the lack of longitudinal data, there is growing recognition of the positive impact of surgical weight management. Recent studies have shown bariatric surgery to be protective against diabetic neuropathy despite previous concerns from older studies. Similarly, several studies have demonstrated improvements in renal measures after bariatric surgery. Improvements in retinopathy, however, have been less encouraging, with further research required to fully understand the impact of obesity. Overall, managing obesity and implementing weight loss through bariatric surgery has positive outcomes for reducing the burden of microvascular disease.
Key words: microvascular, diabetes, obesity
Microvascular disease carries significant morbidity and mortality, and represents amongst the most serious complications of obesity and type 2 diabetes mellitus (T2DM). The chronic elevation of blood glucose damages the small blood vessels that supply organs and tissues, which most commonly manifests as neuropathy, nephropathy and retinopathy, all of which have significant impact on both quality of life and life expectancy. One of the important modifiable risk factors implicated in microvascular disease is obesity, which is increasingly recognised in patients both with and without T2DM.1 However, it is difficult to segregate and study the impact of obesity and hyperglycaemia on microvascular disease since their co-existence is not uncommon. It is imperative that modifiable elements are addressed to prevent and potentially reverse microvascular complications. In this review article, we aim to share some of the evidence pertaining to the risk conferred by obesity and the subsequent impact of weight loss on microvascular disease in people both with and without T2DM.
Databases including PubMed, MEDLINE and Web of Science were used to locate studies on obesity, diabetic microvascular disease and bariatric surgery. Search terms used included “Obesity”, “Diabetes”, “Nephropathy”, “Neuropathy, “Retinopathy”, “Weight loss”, “Bariatric Surgery”. The search was conducted in two parts: first to understand the impact of obesity on microvascular disease and then to review the impact of bariatric surgery on microvascular parameters.
The relationship between obesity and microvascular disease parameters is summarised in Table 1.
Peripheral neuropathy
Peripheral neuropathy is an established microvascular complication of diabetes; examining the evidence suggests that obesity is an independent risk factor (with or without a history of diabetes mellitus). A large population-based study showed that although hyperglycaemia had the strongest association with peripheral neuropathy, obesity was an important metabolic determinant.2 In this study, patients without T2DM had a higher risk of distal symmetrical neuropathy in the presence of components of the metabolic syndrome such as obesity.2 Similarly, in patients with diabetes the risk of peripheral neuropathy is compounded by obesity. These findings support similar observations in a large prospective cohort study where central obesity, high triglycerides and low HDL-cholesterol were found to be independently associated with peripheral neuropathy in individuals with and without diabetes.3 In another population- based cohort study, Hanewinckel et al also concluded that increased waist circumference was a risk factor for the development of peripheral neuropathy, after controlling for age, sex and hyperglycaemia.4 The association with peripheral neuropathy was stronger with more components of metabolic syndrome.4 We previously assessed neuropathy markers in obese patients without diabetes compared to a control group and showed that participants with obesity had a significantly higher neuropathy symptom profile.5
Retinopathy
Diabetic retinopathy
Although several studies have shown that elevated body mass index (BMI) and central obesity are risk factors for the development and progression of diabetic retinopathy, establishing direct causality remains a challenge.6-11 Revisiting data from the Diabetes Control and Complications Trial (DCCT) revealed an interesting finding regarding the impact of BMI on the progression of retinopathy in patients with both ideal and suboptimal glycaemic measures in type 1 diabetes mellitus (T1DM).6 The study found that despite good glycaemic control, with glycated haemoglobin A1c (HbA1c) of <53 mmol/mol (7%), 10% of participants developed diabetic retinopathy. In contrast, in patients with an HbA1c >75 mmol/mol (9%), 43% did not develop retinopathy. In addition to diabetes duration, BMI was found to have made a significant contribution to this paradoxical observation.6 There was further supporting evidence from the Diabetes Incidence Study in Sweden, which showed that higher BMI was associated with increased severity and a shortened time to onset of incident retinopathy.7
Retinopathy in people without diabetes
Few studies have specifically examined the presence of retinopathy in obese persons without diabetes; most studies have focused on individuals with pre-existing diabetes and have employed statistical models to elucidate the independent effect of obesity on retinopathy. The Los Angeles Latino Eye Study found an independent association between higher BMI (>30 kg/m2) and an increased prevalence of retinopathy in a cross-sectional analysis of people without diabetes.8 Gray et al reported a positive associations between obesity, T2DM and retinopathy, with a progressive increase in the risk of retinopathy with higher BMI, based on data from the Medicare Current Beneficiary Survey.9 The Hoorn study also found a positive trend between diabetic retinopathy and increasing BMI in patients both with and without known diabetes].10 Additionally, Dirani et al demonstrated that a BMI >30 kg/m2 was three and six times more likely to be associated with proliferative diabetic retinopathy respectively, with significant positive association also observed for greater waist and neck circumference and development of retinopathy.11 These findings support the role of obesity in the development of retinopathy, independent of glycaemic control. It is important, however, to note that other factors such as hypertension and dyslipidaemia (particularly hypertriglyceridaemia), being frequent accompaniments of obesity, may also contribute to the development and progression of retinopathy.
Nephropathy
As with neuropathy, there is increasing evidence to demonstrate the independent impact of obesity on adverse renal measures, both in those with and without diabetes mellitus. The relationship between obesity and the development of nephropathy in individuals with diabetes and hypertension has been contentious, on balance supporting adverse renal outcomes in people with “diabesity”. Some studies argue that obesity is an independent risk factor for the development or progression of nephropathy,12 while others suggest otherwise.13 However, a substantial body of evidence supports the notion that obesity is associated with worse renal outcomes, including end-stage renal disease (ESRD),14 chronic kidney disease (CKD),15 renal stones,16 renal cancer,17 and post- transplant graft rejection.18
While ESRD and CKD are often used as a surrogate markers for nephropathy, it is important to consider the broader implications of obesity on renal health. In a large retrospective nationwide population-based analysis, Vivante et al examined the association between BMI and the risk of all-cause ESRD in a cohort of 1.2 million individuals over a 25-year follow-up period. The findings revealed that overweight and obese subjects were three and seven times more likely, respectively, to develop all- cause ESRD compared to those with normal BMI in patients with and without diabetes.19 Moreover, the risk of diabetic ESRD was six and 19 times higher in overweight and obese subjects, respectively. Another study by Hsu et al which included 842 cases of ESRD demonstrated similar trends, with increasing risk of developing ESRD with increasing BMI.20 A 20-year follow-up study of the HUNT I cohort revealed that individuals with pre- hypertension were not at an increased risk of ESRD if they were not obese (BMI <30 kg/m2). However, the risk of ESRD doubled with a BMI above 30 kg/m2 and increased six-fold with a BMI above 35 kg/m2.21 While most studies have focused on incidence or progression of renal failure, early nephropathy was examined in two cross-sectional epidemiological studies in the UK: there was increasing prevalence of microalbuminuria with increasing BMI in subjects without diabetes (3.1% in BMI <25 kg/m2, 12.1% in BMI 25–30 kg/m2 and 27.2% in BMI >30 kg/m2). Similar results were noted in normoglycaemic individuals of South Asian descent, where adiposity was an independent predictor of albuminuria.22
Several studies have utilised statistical modelling techniques to investigate the influence of obesity on the incidence and progression of CKD and ESRD, revealing an independent association between obesity and renal outcomes.15,23 These findings underscore the significant impact of obesity on renal health and the increased risks it poses for the development and progression of nephropathy. The evidence highlights the importance of addressing obesity as a modifiable risk factor in efforts to prevent and manage renal complications.
When considering the demonstrated relationship between obesity and microvascular disease, it is plausible that weight reduction might have favourable effects. Many studies analysing associations between microvascular disease and weight loss have been short term, and it is therefore difficult to assess the long-term impact of weight loss intervention. Evaluation of the influence of weight loss may be best observed through longitudinal data analysis, and the EPIC-Potsdam study is an example where impact of lifestyle factors on various chronic disease outcomes, including microvascular disease, was assessed over a 12-year duration.24 In this study, patients with a higher BMI at the start of the study were found to be at higher risk of developing microvascular disease, and patients who gained weight from time of diagnosis were also more likely to develop microvascular disease. Conversely, the risk of incident microvascular disease was lower in patients who lost weight from time of diagnosis. The two classes of anti-diabetic medication most associated with weight loss were sodium- glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA).
Few studies have focused on the effect of these drugs on microvascular outcomes as there are limited data for the impact on neuropathy and retinopathy. Despite this, some large studies have shown the beneficial effects of SGLT2 inhibitors on nephropathy.25-29 Similarly, GLP-1 RA have also shown renal benefits.30,31 None of these studies showed a direct or independent relationship to pharmacologically-induced weight loss. However, these medications have a multimodal mechanism of action which includes weight loss and therefore it remains a possibility that this is conferring a mechanistic advantage. Secondary end-point analysis in the early tirzepatide (a combined glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist) trials have shown potential renoprotective effects of the drug although studies exclusively examining the impact of tirzepatide on microvascular disease are yet to be reported.32
The role of bariatric surgery
Bariatric surgery has been shown to reduce microvascular disease burden. The incidence of new microvascular disease after bariatric surgery has been shown to be markedly reduced across studies.33-35 Coleman et al examined long-term microvascular disease outcomes in patients with T2DM who underwent bariatric surgery. After surgery patients who experienced remission of their T2DM had a 29% lower risk of developing microvascular disease than those in whom diabetes persisted (post-surgical follow up period of up to seven years).33 The study also found that the beneficial effects of bariatric surgery persisted even in the event of relapses following surgery, therefore supporting the notion of a “legacy effect” of bariatric surgery in relation to microvascular disease prevention. Furthermore, O’Brien et al, using diagnostic medical record ‘read codes’, demonstrated in a large cohort that bariatric surgery markedly reduced the incidence of microvascular disease (similar post-operative follow-up period of up to seven years).34 We have summarised their findings by demonstrating percentage reduction in microvascular disease incidence risk (compared to usual medical care) in Figure 1. The findings were further corroborated in the Swedish Obese Subjects (SOS) cohort, where bariatric surgery reduced the incidence of microvascular disease (risk reduction 44%) and was especially marked in those with prediabetes.35 Smaller studies have also added granularity to those data and established that bariatric surgery may reverse early manifestations of microvascular complications.36 Table 2 contains a summary of studies demonstrating the impact of bariatric surgery on microvascular disease parameters and outcomes.
Impact of bariatric surgery on neuropathy
An increasing body of evidence shows the protective effects of bariatric surgery in patients with and without an underlying diagnosis of T2DM. In a prospective cohort study (n=26), our group investigated how bariatric surgery affects microvascular complications in patients with T2DM, using detailed phenotyping.37 Our cohort consisted of patients with a relatively recent diagnosis of T2DM who underwent bariatric surgery. The key finding was that there were improvements in corneal nerve morphology (using corneal confocal microscopy), which suggested early reversibility of subclinical disease after bariatric surgery. The improvement in corneal nerve fibre length was associated with a reduction in serum triglycerides. Although there was an improvement in glomerular hyperfiltration, another early microvascular pathological manifestation, the retinal parameters were unchanged. Our findings were corroborated by Reynolds et al who, in a larger cohort (n=79), showed that bariatric surgery improved intraepidermal nerve fibre density of the thigh;38 like our study, it showed reversal of neuropathic markers. The study also found subjective improvement in established neuropathy- related patient-reported outcome measures. The improvements in neuropathy markers were greater than in a matched cohort who underwent non-surgical weight management and, notably, the average amount of weight loss in the surgical cohort was 2.5 times greater. The authors also demonstrated stability in retinopathy although they did show a worsening of estimated glomerular filtration rate (eGFR) (from 98 to 94.6 ml/min per 1.73 m2).39,40
In patients without diabetes mellitus we previously demonstrated that, compared to a control cohort, patients with obesity had impairment of a range of clinical and corneal nerve morphological markers of peripheral neuropathy, including non- structural proteins (NSP), vibration perception threshold (VPT), warm temperature perception (WPT), deep breathing heart rate variability (DB-HRV), peroneal and sural nerve amplitudes, corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fibre length (CNFL). Subsequently, after bariatric surgery, there were improvements in corneal markers CNFD, CNBD and CNFL, in parallel with clinical improvement based on NSP. Similar to patients with diabetes, there was an association with improvement in corneal nerve morphology and reduction in serum triglycerides.
Impact of bariatric surgery on nephropathy
Several studies have demonstrated significant improvements in renal measures following bariatric surgery.41-43 Renal risk factor measures such as hyperfiltration exhibit a risk ratio and risk reduction of almost half, while albuminuria and proteinuria are both reduced to less than half and less than a third, respectively. Longitudinal studies, including the SOS study with a 10-year follow-up and the Longitudinal Assessment of Bariatric Surgery 2 study with a 7-year follow-up, have reported a much lower risk of progression to stage 4 and 5 CKD and eGFR improvement (associated with weight loss) after bariatric surgery, with a number needed to treat of 4.35,44 In further support of the benefit of bariatric surgery on renal outcomes, we recently reviewed the findings of 26 studies: there were improvements in renal parameters in 25 of the 26 studies.1 Li et al also reported improvements in glomerular hyperfiltration (RR 0.46), albuminuria (RR 0.42) and proteinuria (RR 0.31) in a pooled meta-analysis of 30 studies.42 The potential mechanisms leading to improvement in renal parameters after bariatric surgery on nephropathy were elegantly reviewed by Docherty and Le Roux,41 who postulated that improvements in visceral fat mass, adipose tissue function, incretin effects, hyperinsulinaemia, insulin resistance, dyslipidaemia leptin levels and renin-angiotensin activity all contributed to the observed improvements in renal function.
Impact of bariatric surgery on retinopathy
In contrast with neuropathy and nephropathy, improvements in retinopathy after bariatric surgery are less encouraging. Evidence from 11 studies suggests that the net effect of bariatric surgery is stability, with a possible tendency towards progression in those with advanced retinopathy.1,39 Similar to the established observation in pregnancy, a rapid reduction in hyperglycaemia can worsen pre-existing diabetic retinopathy, and patients need to be counselled and screened closely for that possibility.40
Obesity is an independent risk factor for diabetic and non- diabetic microvascular disease, particularly for nephropathy and neuropathy. The evidence pertaining to medical weight management is limited due to sparse longitudinal outcomes. In contrast, bariatric surgery has demonstrated consistent improvements and reductions in incidence of both nephropathy and neuropathy, in people with and without diabetes. Although multimodal metabolic risk factor reduction is key, weight loss is likely to contribute to positive outcomes.
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