Mortality Reduction in Diabetics with  PDE5 Inhibitor, Statin, and Testosterone Combination

by Jeffrey Dach MD

While researching nitric oxide and the plant based diet, I came across this 2017 study by Geoffrey Hackett in the World Journal of Diabetes, “Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes.” (22)

Well known complications of Diabetes are peripheral neuropathy,  diabetic renal disease, accelerated coronary artery disease, and erectile dysfunction, all related to nitric oxide deficiency commonly found in diabetics.(1-11)

It is also well known that both testosterone therapy and statin therapy are beneficial for diabetics, providing a reduction in all cause mortality of 20- 60%, depending on the study.

Statin Drugs for Diabetics

The recommendation of prescribing a statin drug for diabetics is regardless of cholesterol levels.  In my opinion, the benefit of a statin drug for diabetics is not due to cholesterol lowering effect of the drug.  The benefit is due to pleomorphic effects, the anti-inflammatory and anti-microbial effects. For example, see this 2007 study by Zhang in which 1-2 years of statin use in diabetics is associated with 24-29% reduced all-cause mortality.(14)  There are many others. (13-16)

Testosterone for Diabetics

The benefits of Testosterone for Diabetics was demonstrated nicely in a 2013 study by Muraleedharan, Vakkat, et al.(12)   “Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.” European J of Endo 169.6 (2013): 725-733.

Here is another more recent study (Hackett, 2019) of Diabetic Men with low testosterone.  For untreated men, mortality was 16.9%.  However when these men were given testosterone then discontinued, mortality was reduced to 6.2%.  If the men were treated continuously with testosterone, mortality over 3.8 years was reduced to ZERO !!  (49)

See: Hackett, Geoffrey, et al. “Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors.” BJU Int 123.3 (2019): 519-529.

Even Greater Benefits For PDE5 Inhibitor Tadalafil (Cialis)

As impressive as the benefits of Testosterone and Statins are for diabetics, the benefit of a PDE5 inhibitor such as Cialis (tadalafil) 5 mg daily, is even greater.  This was demonstrated nicely by Dr Geoffrey Hackett  in the UK who found profound reduction in mortality in diabetics taking Cialis 5 mg daily. (22)

Above Image Fig 3. courtesy of Hackett shows mortality in Untreated Group (A) labeled NONE (black line and arrow) . Upper Right (B) Labeled S , Red line is untreated group. Blue line is Statin treated group with reduced mortality.  Lower Left (C) labeled T.  Low Testosterone patients untreated (Black Line) and Treated with Testosterone (Yellow Line). Lower Right (D) Labeled P for PDE5 inhibitor Cialis.  Untreated Group Black Line. Cialis Treated Group Blue Line. Note Dramatic separation (Blue Arrows) greater than other two treatment charts. (22)

All three treatments together in Combination:

 

Left Chart Courtesy of Hackett (E): Black Line is Mortality of Untreated Group.  Blue Line is Mortality of Treated Group using all three modalities, statin, testosterone and PDE5 inhibitor.  Note dramatic reduction in mortality denoted by Red Arrows in the Blue Treated Group.

What is the Connection to Nitric Oxide, Erectile Dysfunction and PDE5 inhibitors?

Nitric Oxide production declines with age: (see the left chart). This is directly related to erectile dysfunction, endothelial dysfunction and and vascular disease.

Mechanism of Action

In 1998, The Nobel Prize in Medicine was awarded to Robert F. Furchgott, Ferid Murad and Louis Ignarro for work on nitric oxide in smooth muscle vasodilation.  The key messenger molecule producing vasodilatation is cyclic guanosine monophosphate (cGMP), which is downstream to Nitric Oxide.  The PDE5 inhibitors do not directly increase Nitric Oxide.  They prevent degradation of the cyclic guanosine monophosphate (cGMP) induced by Nitric Oxide, thus producing vasodilatation, and relieving erectile dysfunction. (17-19)

PDE5 inhibitors for BPH and Chronic Prostatitis

In addition to their benefit for diabetics, Cialis (tadalafil) 5 mg daily has been found beneficial for Benign Prostatic Hypertrophy (BPH), and Chronic Prostatitis patients. (32-35)  Of the PDE5 inhibitors drugs, tadalafil has the longest duration of action (36 hours) making the drug suitable for daily dosing.(23-24)

PDE5 Inhibitors for Cognitive Function and Neuropathy

Increases in micro circulation, and blood flow induced by PDE5 inhibitors provides benefit in peripheral neuropathy, cognitive function and neuroprotection.(36-44)

Use as A Repurposed Cancer Drug

A large volume of clinical and pre-clinical studies suggests PDE5 Inhibitors may be repurposed as highly effective anti-cancer drugs. (59-60)

Other Benefits of PDE5 Inhibitors 

Other suggested benefits of PDE5 Inhibitors include Atherosclerotic Heart Disease.  Alzheimer’s Dementia, Duchene Muscular Dystrophy, and of course, the drug is approved for treatment of pulmonary hypertension.(50-58)(66)

Visual and Hearing Adverse Effects of PDE5 inhibitors

Nonarteritic anterior ischemic optic neuropathy (NAION), and hearing loss are some of the most prevalent side effects associated with the use of PDE5 inhibitors.(67)

Retinal toxicity of taldalafil and other PDE5 onhiboitors is related to the key role of cyclic GMP in the retina in the visual cascade.(67-74)

In 2022 Dr Saikia writes:

The presence of a high concentration of PDE6 enzyme in the rods and cones of the retina makes these cells a vulnerable target for PDE5 inhibitors causing altered color vision, particularly by sildenafil, which has a high affinity for blocking both PDE6 and PDE5. (67)

Other Adverse Effects of PDE5 Inhibitors to be Aware of

In 2022 Dr Saikia writes:

Back pain and myalgias are caused by a high concentration of
the PDE11 enzyme in skeletal muscle, which has a strong
cross-reactivity with tadalafil. The FDA issued a warning on
the possibility of hearing loss linked with PDE5I usage due to
the pathophysiology that causes sensorineural hearing loss,
which has been described in a few case studies.64 Additionally,
using nitrates or nitroglycerin alongside PDE5 inhibitors
increases the risk of hypotension. Vardenafil, tadalafil, and
sildenafil have all been linked to longer QT intervals in ECGs,
with vardenafil having the longest QT intervals, tadalafil
having the shortest QT intervals, and sildenafil having
intermediate QT intervals. Patients taking PDE5Is should
wait at least 1–2 days following their last PDE5I dose before
taking nitrates, according to the American College of
Cardiology.63,68 Erythromycin and HIV protease inhibitors
are two examples of medications that interact with PDE5
inhibitors since they share the same metabolic pathway.(67)

Conclusion: The dramatic benefit of PDE5 inhibition with tadalafil in diabetics is even greater when used in combination with testosterone and statin drugs. A 2023 retrospective study by Dr Robert A Kloner showed the benefits od PDE-5 inhibitors extended to non-diabetics with ED.

Addendum: Some authors such as Robert J DuBroff, and Matthew Bouchonville have expressed the opinion that studies showing mortality benefit with statins in diabetics are flawed, and in fact there is no mortality benefit for statins in Diabetics.  See the following:

https://ebm.bmj.com/content/early/2015/07/15/ebmed-2015-110236?versioned=true
DuBroff, Robert J. “The statin diabetes conundrum: short-term gain, long-term risk or inconvenient truth?.” BMJ Evidence-Based Medicine (2015).

Multiple RCTs specifically designed and powered to study the effects of statins in diabetes have demonstrated inconsistent clinical benefits and no mortality benefit.

https://pubmed.ncbi.nlm.nih.gov/28319804/
Bouchonville, Matthew F., et al. “Are diabetes guidelines truly evidence based?.” Diabetes research and clinical practice 127 (2017): 70-79.

Our analysis supports the ADA recommendations regarding a Mediterranean diet, glycemic control, and BP control, but we believe the evidence to support aspirin and statin therapy in diabetes is inconclusive. This discordance may be multi-factorial including the exclusion of some relevant studies and an over-reliance upon subgroup and meta-analysis. Given the lack of mortality benefit and inconsistent clinical benefits of aspirin and statins, it is essential that clinicians individualize treatment decisions while carefully weighing the risks and harms of any intervention.

Update Jan 1 2023 Tadalafil / Hydroxychloroquine combination in Diabetics:

Kukreja, Rakesh C., et al. “Treating diabetes with combination of phosphodiesterase 5 inhibitors and hydroxychloroquine-a possible prevention strategy for COVID-19?.” Molecular and cellular biochemistry.

Update Jan 23, 2023   Benefits of PDE-5 Inhibitors in General Population of Males with ED

Kloner, Robert A., et al. “Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data.” The Journal of Sexual Medicine (2023).

Retrospective study of 70,000 men with ED. According to the findings of this large-population study, men who took PDE-5 inhibitors, Viagra, Cialis, Levitra etc. for erectile dysfunction (ED.  Thos in PDE-5 inhibitors had lower rates of MACE, major adverse cardiovascular events, lower rates of CHF  and cardiovascular mortality compared to men with ED not taking PDE-5 inhibitors.

Among the men who took PDE-5 inhibitors for ED compared to men with ED who did not take these drugs, Kloner’s study identified: 39% lower rate of death due to heart disease, 22% lower rate of unstable angina, 17% lower rate of heart failure, 15% lower rate in the need for revascularization procedures such as angioplasty, stenting and bypass surgery, 13% lower rate of MACE, and 25% lower rate of all cause mortality.

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, FL 33314
954-792-4663
www.jeffreydachmd.com

Articles with Related Interest

Testosterone Found Beneficial for Diabetics

Testosterone Reduces Mortality

Testosterone prolongs Life and Reduces Mortality

Low Testosterone Associated with Increased Mortality

Statin Drugs Pleomorphic Anti Inflammatory Effects

Statin Drugs Reduce Peri-Operative Mortality

Links and References

Nitric Oxide Reduced in AODM – Impaired NOS Activity

1)  Kashyap, Sangeeta R., et al. “Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects.” The Journal of Clinical Endocrinology & Metabolism 90.2 (2005): 1100-1105.

Type 2 diabetes is an insulin-resistant state characterized by hyperinsulinemia and accelerated atherosclerosis. In vitro and in vivo studies in rodents have suggested that nitric oxide generation plays an important role in glucose transport and insulin action. We determined nitric oxide synthase (NOS) activity in skeletal muscle of 10 type 2 diabetic (hemoglobin A(1C) = 6.8 +/- 0.1%) and 11 control subjects under basal conditions and during an 80 mU/m(2).min euglycemic insulin clamp performed with vastus lateralis muscle biopsies before and after 4 h of insulin. In diabetics, insulin-stimulated glucose disposal (Rd) was reduced by 50%, compared with controls (5.4 +/- 0.3 vs. 10.4 +/- 0.5 mg/kg.min, P < 0.01). Basal NOS activity was markedly reduced in the diabetic group (101 +/- 33 vs. 457 +/- 164 pmol/min.mg protein, P < 0.05). In response to insulin, NOS activity increased 2.5-fold in controls after 4 h (934 +/- 282 pmol/min.mg protein, P < 0.05 vs. basal), whereas insulin failed to stimulate NOS activity in diabetics (86 +/- 28 pmol/min.mg protein, P = NS from basal). Basal NOS protein content in muscle was similar in controls and diabetics and did not change following insulin. In controls, insulin-stimulated NOS activity correlated inversely with fasting plasma insulin concentration (r = -0.58, P = 0.05) and positively with Rd (r = 0.71, P = 0.03). In control and diabetic groups collectively, Rd correlated with insulin-stimulated NOS activity (r = 0.52, P = 0.02). We conclude that basal and insulin-stimulated muscle NOS activity is impaired in well-controlled type 2 diabetic subjects, and the defect in insulin-stimulated NOS activity correlates closely with the severity of insulin resistance. These results suggest that impaired NOS activity may play an important role in the insulin resistance in type 2 diabetic individuals.

2) Tessari, Paolo, et al. “Nitric oxide synthesis is reduced in subjects with type 2 diabetes and nephropathy.” Diabetes 59.9 (2010): 2152-2159.
In type 2 diabetic patients with nephropathy, intravascular NOx synthesis from arginine is decreased under both basal and hyperinsulinemic states. This defect extends the concept of insulin resistance to NO metabolism.

Nitric Oxide Protects Beta Cells in Type One Diabetes, Oseoporosis, Vascular function

3)   Jeddi, Sajad, et al. “Role of nitric oxide in type 1 diabetes-induced osteoporosis.” Biochemical pharmacology (2021): 114888.

Type 1 diabetes (T1D)-induced osteoporosis is characterized by decreased bone mineral density, bone quality, rate of bone healing, bone formation, and increased bone resorption. Patients with T1D have a 2–7-fold higher risk of osteoporotic fracture. The mechanisms leading to increased risk of osteoporotic fracture in T1D include insulin deficiency, hyperglycemia, insulin resistance, lower insulin-like growth factor-1, hyperglycemia-induced oxidative stress, and inflammation. In addition, a higher probability of falling, kidney dysfunction, weakened vision, and neuropathy indirectly increase the risk of osteoporotic fracture in T1D patients. Decreased nitric oxide (NO) bioavailability contributes to the pathophysiology of T1D-induced osteoporotic fracture. This review discusses the role of NO in osteoblast-mediated bone formation and osteoclast-mediated bone resorption in T1D. In addition, the mechanisms involved in reduced NO bioavailability and activity in type 1 diabetic bones as well as NO-based therapy for T1D-induced osteoporosis are summarized. Available data indicates that lower NO bioavailability in diabetic bones is due to disruption of phosphatidylinositol 3‑kinase/protein kinase B/endothelial NO synthases and NO/cyclic guanosine monophosphate/protein kinase G signaling pathways. Thus, NO bioavailability may be boosted directly or indirectly by NO donors. As NO donors with NO-like effects in the bone, inorganic nitrate and nitrite can potentially be used as novel therapeutic agents for T1D-induced osteoporosis. Inorganic nitrites and nitrates can decrease the risk for osteoporotic fracture probably directly by decreasing osteoclast activity, decreasing fat accumulation in the marrow cavity, increasing osteoblast activity, and increasing bone perfusion or indirectly, by improving hyperglycemia, insulin resistance, and reducing body weight.

4)   Jahn, Linda A., et al. “Nitric oxide-dependent micro-and macrovascular dysfunction occurs early in adolescents with type 1 diabetes.” American Journal of Physiology-Endocrinology and Metabolism 322.2 (2022): E101-E108.
This is the first study to show that type 1 diabetes impairs multiple nitric oxide-dependent vascular functions.

5)  Oleson, Bryndon J., and John A. Corbett. “Dual role of nitric oxide in regulating the response of β cells to DNA damage.” Antioxidants & redox signaling 29.14 (2018): 1432-1445.

Protective actions of nitric oxide in β cells
These findings suggest that nitric oxide functions to enhance protective pathways leading to restoration of metabolic function and insulin secretion, while at the same time opposing apoptotic signaling to delay and attenuate β cell death during cytokine exposure.

Nitric Oxide Rx Heals Foot Ulcers in AODM

6) Edmonds, Michael E., et al. “Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes—ProNOx1 study.” Wound Repair and Regeneration 26.2 (2018): 228-237.

7) Malone‐Povolny, Maggie J., Sara E. Maloney, and Mark H. Schoenfisch. “Nitric oxide therapy for diabetic wound healing.” Advanced healthcare materials 8.12 (2019): 1801210.

Copper releases NO for Wound Healing

8) Zhang, Pengju, et al. “Copper-based metal–organic framework as a controllable nitric oxide-releasing vehicle for enhanced diabetic wound healing.” ACS Applied Materials & Interfaces 12.16 (2020): 18319-18331.

These results suggest that such a copper-based metal–organic framework material as a controllable NO-releasing vehicle is a highly efficient therapy for diabetic wounds.

Activating eNOS protects against Diabetic Nephropathy in Mice

9) Fan, Yuyan, et al. “Astragaloside IV protects against diabetic nephropathy via activating eNOS in streptozotocin diabetes-induced rats.” BMC Complementary and Alternative Medicine 19.1 (2019): 1-10.

Lemon Balm Increases NOS in Mice improves BDNF in Hippocampus

10) Naseri, Mohsen, et al. “The effect of Melissa officinalis L. extract on learning and memory: Involvement of hippocampal expression of nitric oxide synthase and brain-derived neurotrophic factor in diabetic rats.” Journal of Ethnopharmacology 276 (2021): 114210.

Metformin Increases NO

11)  Sambe, Takehiko, et al. “Metformin treatment decreases nitroxidative stress, restores nitric oxide bioavailability and endothelial function beyond glucose control.” Biomedicine & pharmacotherapy 98 (2018): 149-156.

12)  Testosterone Reduces Mortality in Diabetics

Muraleedharan, Vakkat, et al. “Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes.” European Journal of Endocrinology 169.6 (2013): 725-733.

Statins Reduce Mortality in Diabetics

13)   Maqbool, Mudasir, and Imran Gani. “Utilization of Statins in Reducing Comorbidities of Diabetes Mellitus: A Systematic Review.” Journal of Pharmacy Practice and Community Medicine 4.4 (2018).  Conclusion: An overwhelming amount of data that confirm the morbidity and mortality benefit of statin therapy in diabetes mellitus have been reported, both in primary and secondary prevention settings.

14) Zhang, Quanwu, et al. “Short-term statin exposure is associated with reduced all-cause mortality in persons with diabetes.” Medical care (2007): 308-314.  Conclusions: One to 2-year statin exposure is associated with a 25% to 29% risk reduction in all-cause mortality of the subsequent year in a high-risk diabetes cohort.

15) Fung, Colman Siu Cheung, et al. “Statin use reduces cardiovascular events and all-cause mortality amongst Chinese patients with type 2 diabetes mellitus: a 5-year cohort study.” BMC cardiovascular disorders 17.1 (2017): 1-9.

PDE5 for Peripheral neuropathy

54) HACKETT, G. “PDE5 inhibitors in diabetic peripheral neuropathy.” International journal of clinical practice 60.9 (2006): 1123-1126.

Peripheral neuropathy is the most common complication of diabetes. This paper reviews the case histories of five patients with diabetic peripheral neuropathy or severe peripheral vascular disease who reported improvement in their symptoms when treated with regular or daily dosing with phosphodiesterase type 5 inhibitors (PDE5Is). These patients had been previously treated with PDE5Is for erectile dysfunction (ED) and not responded to on-demand therapy with a PDE5I at maximal recommended dose. This improvement is likely to be due to the known benefit of these drugs on endothelial dysfunction via an improvement of blood supply to the vasa nervorum. These cases suggest that further research is indicated to evaluate the potential use of PDE5Is in the treatment and prevention of diabetic peripheral neuropathy, particularly as these drugs are already licensed to treat ED, which occurs in around 50% of male diabetics.

PDE5 for Duchenne muscular dystrophy

55) Percival, Justin M., et al. “Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy.” The Journal of pathology 228.1 (2012): 77-87.

56) Nelson, Michael D., et al. “PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.” Neurology 82.23 (2014): 2085-2091.

PDE5 Mechanism of Action

63) Stief, Christian G., et al. “Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue.” Urology 55.1 (2000): 146-150.

64) Corbin, J. D. “Mechanisms of action of PDE5 inhibition in erectile dysfunction.” International journal of impotence research 16.1 (2004): S4-S7.

Mechanism of Action of Sildenafil

65) The mechanism of action of sildenafil involves the protection of cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum. Nitric oxide (NO) in the corpus cavernosum of the penis binds to guanylate cyclase receptors, which results in increased levels of cGMP, leading to smooth muscle relaxation (vasodilation) of the intimal cushions of the helicine arteries. This smooth muscle relaxation leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection. Robert F. Furchgott, Ferid Murad and Louis Ignarro won the Nobel Prize in Physiology or Medicine in 1998 for their independent study of the metabolic pathway of nitric oxide in smooth muscle vasodilation.

Sildenafil is a potent and selective inhibitor of cGMP-specific phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections.

PDE5 Approved for Pulmonary Hypertension

66) Ghofrani, Hossein A., Ian H. Osterloh, and Friedrich Grimminger. “Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond.” Nature reviews Drug discovery 5.8 (2006): 689-702.

67)  Saikia, Queen, Ajit Hazarika, and Ritu Mishra. “A Review on the Pharmacological Importance of PDE5 and Its Inhibition to Manage Biomedical Conditions.” Journal of Pharmacology and Pharmacotherapeutics (2022): 0976500X221129008.

68) Coscas, Florence, et al. “Optical coherence tomography in tadalafil-associated retinal toxicity.” European Journal of Ophthalmology 22.5 (2012): 853-856.

69) Moschos, Marilita M., and Eirini Nitoda. “Pathophysiology of visual disorders induced by phosphodiesterase inhibitors in the treatment of erectile dysfunction.” Drug design, development and therapy 10 (2016): 3407.

70) Stryer, Lubert. “Cyclic GMP cascade of vision.” Annual review of neuroscience 9.1 (1986): 87-119.

71) Lolley, Richard N., and Rehwa H. Lee. “Cyclic GMP and photoreceptor function.” The FASEB journal 4.12 (1990): 3001-3008.

72) Coscas, Florence, et al. “Optical coherence tomography in tadalafil-associated retinal toxicity.” European Journal of Ophthalmology 22.5 (2012): 853-856.

73) Moschos, Marilita M., and Eirini Nitoda. “Pathophysiology of visual disorders induced by phosphodiesterase inhibitors in the treatment of erectile dysfunction.” Drug design, development and therapy 10 (2016): 3407.

74) Stryer, Lubert. “Cyclic GMP cascade of vision.” Annual review of neuroscience 9.1 (1986): 87-119.

75) Kloner, Robert A., et al. “Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data.” The Journal of Sexual Medicine (2023).

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How I reversed my Levaquin-induced neuropathy with PDE5 Inhibitors

In 2015, I developed a horrible, nearly 2 year-long status of being clinically disabled due to only 2x pills of Levaquin which started a chain reaction in my body. Since that time, I developed abnormal sweating in my feet/hands, episodic pain and more, which got worse after my doctor told me my fasting blood glucose was borderline pre-diabetic; Levaquin, like other FQs, appears to cause significant dysglycemia (Friedrich and Dougherty 2004, Singh and Jacob 2008, Kelesidis and Canseco 2009) Dysglycemia is a broad term that refers to an abnormality in blood sugar stability, which is what I had, post-Levaquin. According to Telfer (2014), Fluoroquinolones seem to induce intracellular magnesium deficiency, as the 3-carboxyquinolone substructure of FQs is metal-cleating, and 6-fluoro substituent on the pharmacophore gives rise to sufficient lipophilicity that the drugs can dissolve in and penetrate cell membranes. It has also been suggested that intracellular fluoroquinolones can exist as a magnesium complex! Cellular Diffusion and/or Active Transport of such a complex would deplete Magnesium from the cells. (Lecomte et al., 1994; Bensikaddour, 2008) The effects of fluoroquinolones on intracellular magnesium levels might be considered to be almost cumulative, and slow to reverse overall. (Jahnen-Dechent and M. Ketteler, 2012) . Magnesium affects blood sugar stability, so there was the cause.

Neurological workup was initially unremarkable, but followups showed reduced Nerve Velocity in my feet, reduced nerve density and more. The pain started getting worse, with being unable to tolerate clothing or heat. The doctor wanted to prescribe me the usual cocktails of medications to ‘hide’ the pain. No thanks – I’ll use my scientific background to see about alternative treatments.

Hello ED medications! (PDE5s)

PDE5 Inhibitors, like Viagra, improve neuropathy in human studies, as well as animal studies. (Wang et al., 2017; 2016; 2015; 2011; Mostafa, 2008; Peixoto et al., 2015; Vlachopoulos et al., 2009; Hackett, 2006; Mehmet Fatih Korkmaz et al., 2016; etc) This behavior was described as early as 2002 (Sairam and McNicholas, 2002).

PN symptoms in Fluroquoinoline Patients are more or less the same in Diabetic Patients, as PN initially manifests itself as mitochondrial dysfunction.

PDE5I’s are showing other benefits, such as increased antioxidant status in humans, cardioprotection, and more.

According to Hackett (2006), 5 patients who were prescribed different PDE5Is showed dramatic results within 90 days, with some of the patients showing a nearly complete reversal of neuropathic pain. However, their T2D was quite advanced, so keep that in mind.

The mechanisms behind PDE5I treatments are well documented; Tadalafil treatment improves motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity, increased myelin thickness, enhances Nerve Growth Factor, regional blood flow in Sciatic Nerve Tissue, and more. (Wang, et al., 2016; 2017). Daily dosages of Tadalafil for a period of 90 days will likely reverse early-to-moderate stages of Neuropathy.

Going over the Pharmacodynamics of the PDE5is, Sildenafil (Viagra) has a biological half-life of 4 hours, which is likely /too/ short for effective treatment. Tadalafil has a biological half-life of 17 hours, with a great safety profile. However, Tadalafil, unlike Sildenafil, has no absorption issues when combined with food, etc. (Nichols, Muirhead and Harness, 2002), so Tadalafil is likely a better medication for treatment.

I started taking Tadalafil every 48 hours for about a month. Within the first week, my feet were feeling much better, 2 weeks later, my feet were able to sweat like normal. The pain was reduced by at least 60% on week 2. However, I had to start taking antiacids because the Tadalafil was giving me horrible acid reflux. I continued to take it for about 2 months.

A few months later, I visited my neurologist and demanded another full panel. Nerve Conduction Velocity had improved so much that is was within the ‘normal’ range for my peripheral nerves. Punch biopsy showed increased density as well. I was no longer in any pain, really, except for the occasional pins-and-needles feeling when my feet are just too cold for being outside in the winter.

If you are a male and have neuropathy from Diabetes or something else, you could ask your doctor to write you a prescription for a PDE5 and see if it helps you. I don’t know if women could take PDE5s.

Citations;

– Sairam K, McNicholas T. Sildenafil in diabetic peripheral neuropathy. Br J Diabetes Vasc Dis 2002

– Korkmaz MF, Parlakpinar H, Ceylan MF, et al. The Effect of Sildenafil on Recuperation from Sciatic Nerve Injury in Rats. Balkan Med J. 2016;33(2):204–211.

– Wang L, Chopp M, Szalad A, Lu X, Jia L, Lu M, Zhang RL, Zhang ZG. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice. PLoS One. 2016

– Wang L, Chopp M, Szalad A, Liu Z, Bolz M, Alvarez FM, Lu M, Zhang L, Cui Y, Zhang RL, Zhang ZG. Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. Neuroscience. 2011

– L. Wang, M. Chopp, A. Szalad, Z. Liu, M. Bolz, F.M. Ãlvarez, M. Lu, L. Zhang, Y. Cui, R.L. Zhang, and Z.G. Zhang, Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice, Neuroscience, 193, (399), (2011).

– Lei Wang, Michael Chopp, and ZhengGang Zhang, PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice, Neural Regeneration Research, 12, 2, (218), (2017).

– Christina Alves Peixoto, Ana Karolina Santana Nunes, and Ana Garcia-Osta, Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition, Mediators of Inflammation, 10.1155/2015/940207, 2015, (1-17), (2015).

– Lei Wang, Michael Chopp, Alexandra Szalad, LongFei Jia, XueRong Lu, Mei Lu, Li Zhang, Yi Zhang, RuiLan Zhang, Zheng Gang Zhang and Julie A. Chowen, Sildenafil Ameliorates Long Term Peripheral Neuropathy in Type II Diabetic Mice, PLOS ONE, 10, 2, (e0118134), (2015).

– Taymour Mostafa, Oral Phosphodiesterase Type 5 Inhibitors: Nonerectogenic Beneficial Uses, The Journal of Sexual Medicine, 5, 11, (2502-2518), (2008).

– C. Vlachopoulos, D. Terentes-Printzios, N. Ioakeimidis, K. Rokkas, and C. Stefanadis, “ PDE5 Inhibitors in Non-Urological Conditions”, Current Pharmaceutical Design (2009) 15: 3521. https://doi.org/10.2174/138161209789206980

– Duranti G, Ceci R, Sgrò P, Sabatini S, Di Luigi L. Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells. Cell Stress Chaperones. 2017;22(3):389–396. doi:10.1007/s12192-017-0778-9

– The phosphodiesterase 5 inhibitor sildenafil stimulates angiogenesis through a protein kinase G/MAPK pathway. Pyriochou A, Zhou Z, Koika V, Petrou C, Cordopatis P, Sessa WC, Papapetropoulos A. J Cell Physiol. 2007 Apr;211(1):197-204.

– Pauls MM, Moynihan B, Barrick TR, Kruuse C, Madigan JB, Hainsworth AH, Isaacs JD. The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review. J Cereb Blood Flow Metab. 2018 Feb;38(2):189-203.

Last updated on January 22nd, 2023 by Jeffrey Dach MD