Bariatric surgery reduces diabetes complications
A new study in Diabetologia looks at the impact of bariatric surgery on three different diabetes complications. The findings suggest that surgery could be an effective approach for reducing peripheral neuropathy and stabilising cardiac autonomic neuropathy and retinopathy. Dr Susan Aldridge reports.
Peripheral neuropathy (PN), cardiovascular autonomic neuropathy (CAN) and retinopathy are common complications of type 2 diabetes. Individual risk factors of metabolic syndrome – which often occurs with type 2 diabetes – such as obesity, hypertension, low-HDL cholesterol and high triglycerides are also often associated with PN and CAN, although not consistently so with retinopathy. Given the independent impacts of metabolic risk factors on these three diabetes complications, interventions that can target multiple factors are worth investigating.
Bariatric surgery has the advantage over other treatments of being able to address the above risk factors simultaneously. Recent meta-analyses and systematic reviews have shown that bariatric surgery does improve diabetes complications, including PN and CAN. And a meta-analysis of 14 studies, involving 110,300 participants, found the prevalence of retinopathy was significantly decreased among surgical subjects compared with controls.
However, these earlier studies had a number of limitations, including small sample sizes and/or did not carry out simultaneous assessment of complications in the same population. Therefore, additional evidence is needed to determine whether bariatric surgery can improve outcomes for diabetes complications and how it compares with other interventions, such as weight loss induced by medication. More evidence is also needed on how changes in specific metabolic risk factors are associated with improved outcomes. Therefore, Brian Callaghan and his team at the University of Michigan carried out a new study of the impact of bariatric surgery on PN, CAN and retinopathy in individuals with class II/III obesity (BMI > 35 kg/m2) with and without type 2 diabetes.
A complete baseline metabolic screen was carried out on 127 individuals, who then went on to undergo either sleeve gastrectomy or gastric bypass surgery. Seventy nine of them completed in-person follow-up at two years and another 22 completed a virtual follow-up because of the COVID-19 pandemic. There was a mean weight loss of 31 kg following surgery and all metabolic risk factors significantly improved, save for blood pressure and total cholesterol. However, the number of participants needing anti-hypertensive medication did decrease significantly, while the number on cholesterol or blood glucose-lowering medications remained stable. Meanwhile, the number of participants with diabetes or prediabetes decreased during follow-up – 54.4% improved, 44.3% were stable and only 1.3% worsened.
Changes in peripheral neuropathy
The researchers carried out an exhaustive investigation of PN in the participants at baseline and at two years. The primary outcomes were intra-epidermal nerve fibre density (IENFD) measured in fibres/mm at the distal leg and proximal thigh. These measures are a good diagnostic for small-fibre PN in people with obesity.
Secondary outcomes included nine nerve conduction measures on three different nerves, the Michigan Neuropathy Screening Instrument (MNSI) questionnaire, examination and combined index, the Utah Early Neuropathy Scale, quantitative sensory testing (QST) of vibration and cold detection thresholds, and vibration perception threshold from neurothesiometer testing and monofilament testing.
The IENFD of the proximal thigh improved during follow-up, while the IENFD of the distal leg remained stable. Further analysis showed that the IENFD of the thigh was significantly improved among those with normoglycaemia and prediabetes, but not among those who already had diabetes.
Two of the secondary outcomes – the MNSI questionnaire and combined index – improved, while tibial distal motor latency (from one of the nerve conduction tests), QST vibration and vibration perception from neurothesiometer worsened. All other secondary PN outcomes were stable. In addition, the number of participants with clinical PN, as defined on the Toronto Consensus Definition for probable neuropathy, increased during follow-up – 0% improved, 89.9% stable and 10.1% worsened.
Changes in CAN, retinopathy and patient-reported outcomes
The primary CAN outcome was expiration/inspiration (E/I) ratio and a cardiovascular reflex test, which is considered the gold standard for autonomic testing. The validated Survey of Autonomic Symptoms (SAS) was also used. The secondary outcome was various measures of heart rate variability (HRV). The E/I ratio and the scores on the SAS remained stable during follow-up, but some of the HRV outcomes improved, while others remained stable. The number of participants who actually had CAN was also stable – 12.5% improved, 80.6% remained stable and 6.9% worsened.
Finally, the primary outcome for retinopathy was a change in the mean deviation on frequency doubling technology testing and the secondary outcomes were pattern standard deviation (SD) and foveal sensitivity. All remained stable during follow-up and the number of participants with clinical retinopathy was also stable – 4% improved, 94.7% were stable and 1.3% worsened.
From the participants’ point of view, there were many improvements after bariatric surgery, as assessed by various questionnaires. Pain and overall quality of life improved significantly, as did quality of life related to foot problems and obesity. Significant improvements were also measured in quality of life with respect to social and emotional wellbeing, patient-reported health status, including health status relating to mobility. However, there was no significant change in quality of life in relation to activities of daily living, self-care and self-reported physical activity.
Finally, no changes in metabolic risk factors were associated with the changes relating to PN or CAN. However, reductions in fasting glucose were related to an improvement in the primary retinopathy outcome.
Assessing the impact of bariatric surgery
This is the largest study to assess IENFD before and after bariatric surgery. Two other small studies also found improved PN after surgery by assessing IENFD and corneal nerve fibre density. Taken together, these three sets of findings suggest that bariatric surgery may enable regeneration of peripheral nerves and may be a worthwhile therapy for people with obesity.
However, in this new study, the IENFD of the distal leg was stable after bariatric surgery, which indicates that reversing damage to the more severely affected distal nerves may be more difficult and/or may require longer follow-up.
The study also adds to growing evidence that bariatric surgery improves PN symptoms. At the same time, some measures – like vibration perception threshold – worsened, while more participants met the Toronto Consensus Definition for PN. One possible explanation for these conflicting findings is that bariatric surgery improves small-fibre nerves but does not prevent worsening in large-fibre nerves. Another possibility is that bariatric surgery improves neuropathy by improving the metabolic profile, but worsens neuropathy in some patients through nutritional deficiencies – of vitamin B12 for instance. Further research is needed to tease out the different effects of surgery on outcomes, but it’s important to note that all patient outcomes related to PN improved after surgery.
The primary CAN and retinopathy outcomes were stable after surgery, in contrast to previous studies. It may be that for those who have long-term metabolic impairment, the improvements noted here are insufficient to reverse even mild pre-existing autonomic and retinal nerve damage. Or it may be that a two-year follow-up is not long enough to detect any improvements in CAN or retinopathy. Therefore, studies with longer follow-up are needed.
A meta-analysis has found that bariatric surgery can actually result in short-term progression of retinopathy in those who already have proliferative retinopathy. So the stability in retinopathy outcomes seen here might actually be a period of progression followed by improvement, which might have been detected if outcomes had been measured throughout follow-up rather than just at the end.
Four HRV measures improved in this study and improvements in two of them have been seen in other studies. These measures may therefore be sensitive or early indicators of CAN improvement. And, given that these measures are associated with a greater risk of mortality, these outcomes are clinically relevant. Further research should focus on whether HRV improvement does reduce the risk of silent myocardial infarction and death.
Simultaneous measurement of changes in PN, CAN and retinopathy allowed the authors to determine whether changes in specific metabolic factors can exert differential effects on diabetes complications. Improvements in fasting glucose did lead to an improved in retinopathy outcome and this adds to the growing body of evidence that, for retinopathy, controlling hyperglycaemia is probably even more important than controlling obesity. However, for PN and CAN, it is important to control both.
Comparison with medical weight loss
Of course, bariatric surgery is costly and not without risk. New weight loss drugs have come onto the market recently, so it is relevant to consider how bariatric surgery might compare with medical weight loss (MWL) when it comes to improving metabolic risk factors and diabetes complications.
In an earlier study, the authors did compare the two and found 10.3% weight loss with MWL and 23.8% with bariatric surgery, and a more modest improvement in metabolic profile for MWL compared with surgery. Medical weight loss stabilised IENFD outcomes, while surgery improved the IENFD of the proximal thigh, while both approaches found an improvement in PN symptoms. Primary CAN outcomes were stable after both interventions, but only surgery improved HRV outcomes.
Since surgery led to greater weight loss and a better metabolic profile than MWL, improvements in PN and CAN may be attributed to a direct effect via a dose-response relationship. However, there are also effects of bariatric surgery that are not related to weight loss, such as increased levels of gut satiety hormones and improved hunger-related behaviour, that may impact diabetes complications. And other changes that influence glucose control, such as increased gastric emptying, modulated bile acids and changes to the gut microbiota, might improve PN and CAN to a greater extent than is possible with MWL.
Therefore, in conclusion, two years after bariatric surgery and the resulting improvements in metabolic risk factors, one of two primary measures of PN, plus pain and quality of life, improved and CAN and retinopathy were stable. This shows that bariatric surgery may be an effective approach to reverse PN in people with obesity. Given the natural history of worsening of CAN and retinopathy, stability in these complications probably indicates a successful result. However, randomised controlled trials are now needed to confirm these findings. For retinopathy, a specific reduction in hyperglycaemia following bariatric surgery is probably required to reverse this complication.
To read this paper, go to: Reynolds EL, Watanabe M, Banerjee M, Chant E, Villegas-Umana E, Elafros MA, Gardner TW, Pop-Busui R, Pennathur S, Feldman EL, Callaghan BC. The effect of surgical weight loss on diabetes complications in individuals with class II/III obesity, Diabetologia 14 March 2023. https://doi.org/10.1007/s00125-023-05899-3
To learn more, enrol on the EASD e-Learning course ‘Metabolic surgery’: https://easd-elearning.org/courses/metabolic-surgery/
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.