Treating obesity is no longer inSURMOUNTable

The SURMOUNT-2 trial was simultaneously presented at the ADA 2023 Scientific Sessions and published in the Lancet, and demonstrated that use of the dual GLP-1/GIP receptor agonist tirzepatide resulted in a mean body weight reduction of up to 14.7% after 72 weeks in people living with type 2 diabetes and comorbid obesity or excess weight. This level of weight loss has previously been associated with type 2 diabetes remission, and was also accompanied by clinically meaningful improvements in a number of cardiometabolic risk factors, including lipids, blood pressure and liver enzymes. With tirzepatide and semaglutide, we now have two compelling evidence-based pharmacological therapies with superior efficacy and safety profiles compared to previous obesity medications. However, there remains uncertainty about durability of effect and impact of withdrawal of treatment on weight loss maintenance. Amid calls to use percentage weight loss as a target biomarker in obesity (like HbA1c in diabetes, LDL-cholesterol in atherosclerotic cardiovascular disease and albuminuria in chronic kidney disease), a seismic shift in how we approach the management of obesity, with significant financial implications for healthcare systems globally, may be required.

Kevin Fernando

GP in North Berwick

Citation: Fernando K (2023) Diabetes Distilled: Treating obesity is no longer inSURMOUNTable. Diabetes & Primary Care 25: [early view publication]

      The SURMOUNT-2 trial was simultaneously presented at the ADA 2023 Scientific Sessions in San Diego and published in the Lancet. The trial demonstrated that use of the dual GLP-1 and GIP receptor agonist tirzepatide resulted in a mean body weight reduction of up to 14.7% after 72  weeks in people living with type 2 diabetes and comorbid obesity or excess weight.

      Moreover, around one third of participants lost over 20% of their baseline body weight. The average weight reduction with tirzepatide after 72 weeks was 14–16 kg, a level that has previously been associated with remission of type 2 diabetes (Lean et al, 2018).

      With respect to glucose-lowering efficacy (a  pre-specified key secondary endpoint of the trial), use of tirzepatide reduced HbA1c by 23  mmol/mol (2.1%) after 72  weeks. The mean HbA1c of trial participants at trial end was 41 mmol/mol (5.9%), reflecting, in other words, normalisation of glucose levels.

      Additional benefits observed included reductions in fasting glucose and insulin levels (indicating a significant increase in insulin sensitivity); improvements in lipid profile, particularly fasting triglyceride and non-HDL cholesterol levels; a reduction in systolic blood pressure of 6–7 mmHg; and reductions in liver enzymes (notably a 35% improvement in ALT) – all clinically meaningful improvements in cardiometabolic risk factors.

      SURMOUNT-2 also explored the safety profile of tirzepatide; reassuringly, the overall rate of serious adverse events was similar between the tirzepatide and placebo groups. Most treatment-emergent adverse effects with tirzepatide were, predictably, gastrointestinal in nature: most commonly nausea, diarrhoea and vomiting. However, these gastrointestinal adverse effects occurred primarily during the dose escalation period, were mostly mild to moderate in severity and decreased over time.

      Importantly, there was no imbalance observed with diabetic retinopathy events, liver and gallbladder events, malignancies (including pancreatic cancer and medullary thyroid cancer) and pancreatitis, which have previously shadowed certain incretin molecules. There were also no cases of severe hypoglycaemia detected, despite the potent glucose-lowering efficacy of tirzepatide. Mean pancreatic enzyme levels were increased but remained within the normal range, which is consistent with other incretin therapies used for obesity, such as semaglutide. Overall, mean pulse rate increased by 1 bpm over 72 weeks; there was an initial rise of 4 bpm observed, which subsequently decreased.

A seismic shift is required

      It is well known that people living with obesity and type 2 diabetes lose less weight than those living with obesity alone, so SURMOUNT-2 is a prodigious advance for the management of obesity and type 2 diabetes. The results of SURMOUNT-2 also surpass the compelling results with semaglutide 2.4 mg in the STEP-2 trial (Davies et al, 2021).

      Obesity is now recognised as a chronic disease with multiple pathophysiological aspects; it involves more than just an increase in body mass. Like other chronic diseases, obesity is relapsing in nature and can lead to a range of complications, including cardiometabolic disease and malignancy.

      Different complications require different amounts of weight loss for treatment; for example, in non-alcoholic fatty liver disease (NAFLD), 3–5% weight loss reduces hepatic steatosis, while ≥5–7% weight loss can lead to resolution of non-alcoholic steatophepatitis and ≥10% weight loss improves hepatic fibrosis (Hannah and Harrison, 2016). The 2022 ADA/EASD Consensus Report suggests that 5–10% weight loss confers metabolic improvement in type 2 diabetes, and weight loss of >10–15% can lead to remission of type 2 diabetes (Davies et al, 2022).

      Percentage weight loss should now be used as a target biomarker in obesity (like HbA1c in diabetes, LDL-cholesterol in atherosclerotic cardiovascular disease and albuminuria in chronic kidney disease) to mitigate the specific complications of obesity (Garvey, 2022).

      Much of current thinking for preventing and treating obesity centres around hedonic eating in combination with a sedentary lifestyle; “Eat  less, move more” is commonly delivered advice to people living with obesity. However, while these are contributing factors, it is well known that pathophysiological mechanisms affecting appetite and satiety are pivotal in the development of obesity. Optimising satiety needs to be addressed early in the management of obesity, as calorie restriction alone is unlikely to be a long-term solution if there is ongoing abnormal hunger.

      A seismic shift is required in how we approach the management of obesity, with increased access to weight management services and evidence based pharmacological therapies that directly impact appetite and satiety, such as semaglutide and tirzepatide.

Ongoing questions

      As with all good studies, SURMOUNT-2 raises more questions than answers. What is the durability of effect of tirzepatide after 72 weeks and, crucially, what is the effect of withdrawal of tirzepatide on weight loss maintenance? The STEP-4 weight maintenance trial and STEP-1 off-treatment extension study both demonstrated weight regain after discontinuation of semaglutide, suggesting that incretin therapy is required over the long term for sustained weight loss (Rubino et al, 2021; Wilding et al, 2022). This has significant financial implications for healthcare systems globally. One solution would be a phased approach to the management of obesity, with early phases using highly efficacious obesity drugs such as tirzepatide or semaglutide and then transitioning to lower-efficacy and cheaper obesity drugs for weight maintenance. Several such obesity maintenance drugs are in the early stages of development.

      This approach is analogous to the treatment of rheumatoid arthritis, where often potent targeted biological therapy is used early on to achieve remission of arthritis, followed by a switch to a conventional DMARD for maintenance therapy, for reasons of long-term safety and health economics. Using this approach for obesity management might help the sustainability of healthcare systems.

      Finally, what are the cardiovascular, renal and liver benefits of tirzepatide? These questions will hopefully be answered on completion of the SURPASS-CVOT, SURMOUNT-MMO and SYNERGY-NASH trials, which, unfortunately, are not due to report soon. However, positive results would facilitate targeted use of tirzepatide for people living with obesity and specific co-morbidities such as atherosclerotic cardiovascular disease, chronic kidney disease and NAFLD.

      In conclusion, treatment of obesity is no longer insurmountable, with two compelling evidence-based pharmacological therapies with superior efficacy and safety profiles compared to previous obesity medications. However, there remains uncertainty about durability of effect and impact of withdrawal of treatment on weight loss maintenance. Much-needed real-world data will help resolve some of this uncertainty.

References

1. Davies M, Færch L, Jeppesen OK et al; STEP 2 study group (2021) Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, doubleblind, double-dummy, placebo-controlled, phase 3 trial. Lancet 397: 971–84

2. Davies MJ, Aroda VR, Collins BS et al (2022) Management of hyperglycemia in type 2 diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 45: 2753–86

3. Garvey WT (2022) New horizons. A new paradigm for treating to target with second-generation obesity medications. J Clin Endocrinol Metab 107: e1339–47

4. Hannah WN Jr, Harrison SA (2016) Lifestyle and dietary interventions in the management of nonalcoholic fatty liver disease. Dig Dis Sci 61: 1365–74

5. Lean ME, Leslie WS, Barnes AC et al (2018) Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. Lancet 391: 541–51

6. Rubino D, Abrahamsson N, Davies M et al; STEP 4 investigators (2021) Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomized clinical trial. JAMA 325: 1414–25

7. Wilding JPH, Batterham RL, Davies M et al; STEP 1 study group (2022) Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab 24: 1553–64

This article is excerpted from the Diabetes & Primary Care Vol 25 No 4 2023 by Wound World.

一种皮肤感染性压疮动物模型的构建方法及其应用(12)发明专利申请

(10)申请公布号 CN 115812675 A

(43)申请公布日 2023.03.21

(21)申请号 202211475178 .2

(22)申请日 2022 .11 .23

(71)申请人 南方医科大学

地址 510515 广东省广州市白云区沙太南 路1023号

(72)发明人 张琳 张璐 张敏 王雪儿 卢魁 陈银燕

(74)专利代理机构 广州嘉权专利商标事务所有限公司 44205

专利代理师 齐键

(51)Int .Cl .

A01K 67/027 (2006 .01)

A61K 49/00(2006 .01)

The relevance of skin tones in the diabetic foot

Luxmi Dhoonmoon

      It is important for clinicians to understand the implications of skin tone in diabetic foot ulcers as it can influence various aspects of wound care, including early detection, assessment, management and overall outcomes. Greater awareness and education in dark skin tones is needed and the purpose of this article is to give clinicians the confidence, knowledge and skills required to care for patients with both dark skin tones and diabetic foot.

Citation: Dhoonmoon L (2023) The relevance of skin tones in the diabetic foot. The Diabetic Foot Journal 26(1): 16–9

Key words

- Dark skin tone

- Diabetic Foot

- Foot care

Article points

1. Incorrect use of assessment tools in people with dark skin tones has to led to discrepancies in wound care.

2. A validated classification tool, such as the skin tone tool, needs to be used to determine an individual’s skin tone at baseline.

3. It is easy to miss erythema in patients with dark skin tones, so clinicians should make full use of the senses and assess for cardinal signs other than redness.

4. Clinicians need to use inclusive, person-first language, and they shouldn’t be afraid to ask if they are unsure of something.

Authors

Luxmi Dhoonmoon is Tissue Viability Nurse Consultant, London North West University Healthcare NHS Trust, UK

The power of the digital flexor tenotomy: a case study

Krishna Gohil and Helen Milnes

In May 2023, the International Working Group on the Diabetic Foot (IWGDF) updated the offloading guidelines to support surgical offloading interventions. The evidence for digital tenotomy of the flexor tendon is strong, with the desirable effects reported to be moderate. This case study describes a patient with a 5-year history of apical toe ulcerations and a history of apical osteomyelitis, which were healed within 2 weeks following digital tenotomies performed in an outpatient setting. Considering the new offloading guideline, we must consider how clinicians can optimise patient care and offer this valuable treatment option to patients.

Citation: Gohil K, Milnes H (2023) The power of the digital flexor tenotomy: a case study. The Diabetic Foot Journal 26(1): 6–10

Key words

- Diabetes Related foot ulceration

- Digital flexor tenotomy

- Healing

- Surgical offloading

- WIfI

Article points

1. The International Working Group on the Diabetic Foot 2023 guidelines support digital flexor tenotomies in individuals with diabetes and callus to prevent development of ulceration or recurrent foot ulceration.

2. The cost of flexor tenotomies is low in comparison to ongoing dressings, ongoing antibiotics and potential hospital admission for infection management

3. Surgical offloading should be considered when conservative non-operative treatments have been unsuccessful.

Authors

Krishna Gohil is Senior Lecturer Podiatry/Prescribing, University of Northampton, UK; Helen Milnes is Consultant Podiatric Surgeon, University Hosptital Birmingham, UK

Pharmacological treatment of painful neuropathy in adults with diabetes

Helen O’Neil

Diabetic neuropathy is one of the most prevalent chronic complications in people living with diabetes and painful diabetic neuropathy is difficult to manage clinically. Guidelines recommend offering a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain. It is recommended that pharmacotherapy is offered in a stepwise approach to ensure tolerability and effectiveness of individual medications. Patients often do not respond to monotherapy and, therefore, combination pharmacotherapy may be required. The aim of treatment is to improve quality of life for patients living with painful diabetic neuropathy by reducing pain and promoting increased participation in all aspects of daily living.

Citation: O’Neil (2023) Pharmacological treatment of painful neuropathy in adults with diabetes. The Diabetic Foot Journal 26(1): 20–3

Key words

- Diabetic neuroarthropathy

- Neuropathic pain

- Pharmacological therapy

Article points

1. Painful diabetic neuropathy is common in people with diabetes and is difficult to manage clinically.

2. Guidelines recommend amitriptyline, duloxetine, gabapentin or pregabalin as initial pain management options.

3. Patients often do not respond to monotherapy, so combination pharmacotherapy may be required.

Author

Helen O’Neil is Senior Medicines Optimisation Pharmacist, South Tyneside and Sunderland NHS Foundation Trust, UK

Imaging in osteomyelitis and Charcot neuroarthropathy: can infrared thermography aid in diagnosis?

Gillian Harkin

Differential diagnosis between active Charcot neuroarthropathy and infection in the presence of neuropathic ulceration presents a significant challenge to the clinician. Both conditions may present as a red, hot, swollen foot with an absence of pain. Although additional tests may aid in developing a clear diagnosis these can be invasive (blood testing), carry exposure to ionising radiation (X-ray) or be difficult to access rapidly (MRI). The following case study demonstrates how infrared thermography may prove useful within the clinical environment as a diagnostic test as well as a useful educational tool to guide treatment planning in collaboration with an individual with diabetes. 

Citation: Harkin G (2023) Imaging in osteomyelitis and Charcot neuroarthropathy: can infrared thermography aid in diagnosis?. The Diabetic Foot Journal 26(1): 24–8

Key words

- Charcot neuroarthropathy

- Differential diagnosis

- Osteomyelitis

- Thermal imaging

- Ulceration

Article points

1. It can be difficult to differentiate between Charcot neuroarthropathy and osteomyelitis due to similar clinical presentations.

2. Thermal images can be used to inform discussions as part of realistic medicine

3. Thermal imaging may be helpful in identifying the origin of heat within the foot, aiding diagnosis.

Author

Gillian Harkin is Lead Clinical Podiatrist. NHS Greater Glasgow & Clyde, Glasgow, UK.