Mason MM. et al., 2022: Low-intensity extracorporeal shockwave therapy for diabetic men with erectile dysfunction: A systematic scoping review

Monday, 15 August 2022

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Mason MM, Pai RK, Masterson JM, Lokeshwar SD, Chu KY, Ramasamy R.
University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Urology, Yale University School of Medicine, New Haven, Connecticut, USA.
Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

Abstract

Background: Erectile dysfunction (ED) is a very common complication in men with diabetes mellitus (DM). Low-intensity extracorporeal shockwave therapy (Li-ESWT) offers a promising nonsurgical treatment option for ED. A systematic scoping review investigating the outcomes of Li-ESWT in diabetic men with ED has not yet been performed.

Objectives: To systematically review animal and clinical studies related to the use of Li-ESWT for treatment of DM-related ED.

Data sources: PubMed, Embase, The Cochrane Library, Scopus, and Web of Science were searched, unrestricted by dates or study design.

Materials and methods: We included qualitative studies, quantitative studies, primary research studies, meta-analyses, and research letters written in English. Full text reviewing was completed in all animal and human studies discussing Li-ESWT for the treatment of ED in subjects with DM. Data extracted included the journal citation, publication year, country of origin, study design, and a summary of the pertinent findings.

Results: Our search yielded nine clinical studies and 10 animal studies. The results of the clinical studies suggest that Li-ESWT is a safe and effective treatment in men with well-controlled DM and moderate or better ED. However, the benefit is less durable in diabetic men than nondiabetic men. The results of the animal studies suggest that Li-ESWT can significantly improve erectile function in diabetic rat models with ED.

Conclusions: The examined studies present encouraging results for the use of Li-ESWT to treat diabetic men with ED. Future studies, particularly robust randomized controlled trials, are necessary to confirm these findings and provide long-term follow-up.
Andrology. 2022 Jun 1. doi: 10.1111/andr.13197. Online ahead of print. PMID: 35642619

Comments 1

Jens Rassweiler on Monday, 15 August 2022 10:30

Erectile dysfunction (ED) is one the most difficult to treat complications of Diabetes because it impacts microangiopathy as well as neuropathy induced by Diabetes Mellitus (DM). Low-intensity extracorporeal shock wave therapy (Li-ESWT) has recently be shown to improve ED in impotent men due to several factors, such as potential neo- angiogenesis, stem cell/growth factor recruitment, improvement in blood flow, and nerve regeneration. Since there are not many studies focusing on the effect of Li-ESWT on ED in diabetic men, the authors decided to present this systematic scoping review. Most importantly, they also reviewed experimental studies. In summary, 19 of 79 papers met the strict inclusion criteria: nine clinical and 10 animal studies. Results of the clinical studies suggested that Li-ESWT is a safe and effective treatment in men with well-controlled DM and moderate or better ED. However, the benefit is less durable in diabetic men than nondiabetic men. The results of the animal studies suggest that Li-ESWT can significantly improve erectile function in diabetic rat models with ED.

One main problem of this review is the poor data basis, since most of the larger studies just reported the results in diabetic men as a subgroup analysis. Nevertheless, the reader can learn a lot from the detailed presentation of the studies:

1. High variation in the technical parameters of the Li-ESWT-protocol with respect to the applied numbers of shock waves per session (1500 – 6000) as well as the use of energy density (0.09 – 0.20 mJ/mm2) and frequency (2 – 8 Hz).
2. High variation of treatment period (2x 3 weeks to 12 weeks) and follow-up (3 months – 24 months)
3. Some studies used adjuvant taldalafil

Moreover, in most studies, the cases of severe ED and insufficiently treated DM were excluded.

Focusing on the clinical efficacy of Li-ESWT, it becomes clear, that the long-term effect is limited. This could be overcome by a maintenance therapy for responders. The additional use of taldalfil remains unclear, since most of the study patients were failures to PDE-5-inhibitors. However, one goal of the use of ESWT in this difficult to treat population might be to transfer a PDE5-inhibitor non-responder to a responder.

In contrast to the clinical situation, the review of the animal studies shows very promising aspects. Diabetic rats represent a very good model to examine the impact of various treatment options on DM-induced erectile dysfunction. Some of the findings are:

- Erectile function (ICP/MAP) was significantly improved in Li-ESWT+DMED rats compared to DMED rats with maximal efficacy noted in the 300-shock cohort.
- Li-ESWT improved the max length and percentage of elastic fibers in the corpora of diabetic rats as well as the smooth muscle/collagen ratio.
- Li-ESWT significantly improved expression of nNOS compared to DMED rats.
- Li-ESWT significantly improved expression of VEGF compared to DMED rats in a dose related manner.

All these findings are in-line with the clinical observations. However, more interesting seems to be the effect of Li-ESWT on stem cells:

Li-ESWT led to increased survival of transplanted BMSCs in the cavernous bodies, which is likely related to increased stromal cell derived factor-1 expression along with increased angiogenesis in the diabetic cavernous tissue. Combining Li-ESWT and BMSC transplantation led to improved erectile function in DMED rats compared to either Li-ESWT or BMSC transplantation alone.

Since, we discuss the impact of Li-ESWT on local stem cells in various clinically important indications, such as wound healing or urinary sphincter insufficiency, such findings are very important for future studies.

Jens Rassweiler

One main problem of this review is the poor data basis, since most of the larger studies just reported the results in diabetic men as a subgroup analysis. Nevertheless, the reader can learn a lot from the detailed presentation of the studies:

1.	High variation in the technical parameters of the Li-ESWT-protocol with respect to the applied numbers of shock waves per session (1500 – 6000) as well as the use of energy density (0.09 – 0.20 mJ/mm2) and frequency (2 – 8 Hz).
2.	High variation of treatment period (2x 3 weeks to 12 weeks) and follow-up (3 months – 24 months)
3.	Some studies used adjuvant taldalafil

Moreover, in most studies, the cases of severe ED and insufficiently treated DM were excluded.

Focusing on the clinical efficacy of Li-ESWT, it becomes clear, that the long-term effect is limited. This could be overcome by a maintenance therapy for responders. The additional use of taldalfil remains unclear, since most of the study patients were failures to PDE-5-inhibitors. However, one goal of the use of ESWT in this difficult to treat population might be to transfer a PDE5-inhibitor non-responder to a responder.

In contrast to the clinical situation, the review of the animal studies shows very promising aspects. Diabetic rats represent a very good model to examine the impact of various treatment options on DM-induced erectile dysfunction. Some of the findings are:

-	Erectile function (ICP/MAP) was significantly improved in Li-ESWT+DMED rats compared to DMED rats with maximal efficacy noted in the 300-shock cohort. 
-	Li-ESWT improved the max length and percentage of elastic fibers in the corpora of diabetic rats as well as the smooth muscle/collagen ratio. 
-	Li-ESWT significantly improved expression of nNOS compared to DMED rats. 
-	Li-ESWT significantly improved expression of VEGF compared to DMED rats in a dose related manner.

All these findings are in-line with the clinical observations. However, more interesting seems to be the effect of Li-ESWT on stem cells:

Li-ESWT led to increased survival of transplanted BMSCs in the cavernous bodies, which is likely related to increased stromal cell derived factor-1 expression along with increased angiogenesis in the diabetic cavernous tissue. Combining Li-ESWT and BMSC transplantation led to improved erectile function in DMED rats compared to either Li-ESWT or BMSC transplantation alone.

Since, we discuss the impact of Li-ESWT on local stem cells in various clinically important indications, such as wound healing or urinary sphincter insufficiency, such findings are very important for future studies.

Jens Rassweiler

Erectile dysfunction (ED) is one the most difficult to treat complications of Diabetes because it impacts microangiopathy as well as neuropathy induced by Diabetes Mellitus (DM). Low-intensity extracorporeal shock wave therapy (Li-ESWT) has recently be shown to improve ED in impotent men due to several factors, such as potential neo- angiogenesis, stem cell/growth factor recruitment, improvement in blood flow, and nerve regeneration. Since there are not many studies focusing on the effect of Li-ESWT on ED in diabetic men, the authors decided to present this systematic scoping review. Most importantly, they also reviewed experimental studies. In summary, 19 of 79 papers met the strict inclusion criteria: nine clinical and 10 animal studies. Results of the clinical studies suggested that Li-ESWT is a safe and effective treatment in men with well-controlled DM and moderate or better ED. However, the benefit is less durable in diabetic men than nondiabetic men. The results of the animal studies suggest that Li-ESWT can significantly improve erectile function in diabetic rat models with ED. One main problem of this review is the poor data basis, since most of the larger studies just reported the results in diabetic men as a subgroup analysis. Nevertheless, the reader can learn a lot from the detailed presentation of the studies: 1. High variation in the technical parameters of the Li-ESWT-protocol with respect to the applied numbers of shock waves per session (1500 – 6000) as well as the use of energy density (0.09 – 0.20 mJ/mm2) and frequency (2 – 8 Hz). 2. High variation of treatment period (2x 3 weeks to 12 weeks) and follow-up (3 months – 24 months) 3. Some studies used adjuvant taldalafil Moreover, in most studies, the cases of severe ED and insufficiently treated DM were excluded. Focusing on the clinical efficacy of Li-ESWT, it becomes clear, that the long-term effect is limited. This could be overcome by a maintenance therapy for responders. The additional use of taldalfil remains unclear, since most of the study patients were failures to PDE-5-inhibitors. However, one goal of the use of ESWT in this difficult to treat population might be to transfer a PDE5-inhibitor non-responder to a responder. In contrast to the clinical situation, the review of the animal studies shows very promising aspects. Diabetic rats represent a very good model to examine the impact of various treatment options on DM-induced erectile dysfunction. Some of the findings are: - Erectile function (ICP/MAP) was significantly improved in Li-ESWT+DMED rats compared to DMED rats with maximal efficacy noted in the 300-shock cohort. - Li-ESWT improved the max length and percentage of elastic fibers in the corpora of diabetic rats as well as the smooth muscle/collagen ratio. - Li-ESWT significantly improved expression of nNOS compared to DMED rats. - Li-ESWT significantly improved expression of VEGF compared to DMED rats in a dose related manner. All these findings are in-line with the clinical observations. However, more interesting seems to be the effect of Li-ESWT on stem cells: Li-ESWT led to increased survival of transplanted BMSCs in the cavernous bodies, which is likely related to increased stromal cell derived factor-1 expression along with increased angiogenesis in the diabetic cavernous tissue. Combining Li-ESWT and BMSC transplantation led to improved erectile function in DMED rats compared to either Li-ESWT or BMSC transplantation alone. Since, we discuss the impact of Li-ESWT on local stem cells in various clinically important indications, such as wound healing or urinary sphincter insufficiency, such findings are very important for future studies. Jens Rassweiler

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