Mortality Reduction in Diabetics with PDE5 Inhibitor Statin Testosterone Combo

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.”

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.

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. This recommendation of prescribing a statin drug for diabetics is regardless of cholesterol levels.  In my opinion, this 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. See this study by Zhang:

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.

Benefits of Testosterone for Diabetics

was demonstrated nicely in this study by 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.

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 !!

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.

Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%)

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.

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.

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.

The key messenger molecule producing vasodilatation is 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 inducing vasodilatation, and relieving erectile dysfunction.

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. Endquote reference link

PDE5 inhibitors for BPH and Chronic Prostatitis

In addition to their benefit for diabetics, Cialis (tadalafil) 5 mg daily has been found beneficial for BPH Benign Prostatic Hypertrophy and Chronic Prostatitis patients.

PDE5 Inhibitors for Cognitive Function and Neuropathy

Increases in micro circulation, blood flow induced by PDE5 inhibitors provides benefit in peripheral neuropathy and cognitive function.

Conclusion: The dramatic benefit of PDE5 inhibition with tadalafil in diabetes is even greater when used in combination with testosterone and statin drugs.

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.

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

Articles with Related Interest

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

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.

Low Testosterone Associated with Increased Mortality

Testosterone Found Beneficial for Diabetics

Testosterone Reduces Mortality

Statins Reduce Mortality in Diabetics

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.

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.

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.

Chen, Po-Hsun, et al. “Effects of statins on all-cause mortality at different low-density-lipoprotein cholesterol levels in Asian patients with type 2 diabetes.” Current medical research and opinion 34.11 (2018): 1885-1892.

PDE5 Mechanism of action

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

Kass, David A., et al. “Phosphodiesterase regulation of nitric oxide signaling.” Cardiovascular research 75.2 (2007): 303-314.

Burnett, Arthur L. “Phosphodiesterase 5 mechanisms and therapeutic applications.” The American journal of cardiology 96.12 (2005): 29-31.

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.

Phosphodiesterase Inhibitors and Diabetes

Santi, Daniele, et al. “Therapy of endocrine disease: effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis.” European journal of endocrinology 172.3 (2015): R103-R114.

Cardiac risk factors and prevention

Anderson, Simon G., et al. “Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality.” Heart 102.21 (2016): 1750-1756.

Objective Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study.

Research design and methods Between January 2007 and May 2015, 5956 men aged 40–89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality.

Anderson, Simon G., et al. “Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality.” Heart 102.21 (2016): 1750-1756.

Of the total cohort, we identified men who had received a pre-
scription of a PDE5i (sildenafil, vardenafil or tadalafil) prior to
1 January 2007 and at least once, up to 30 June 2015.

A total of 5956 men with known type 2 diabetes aged 40–
89 years were identified at cohort entry date of 1 January 2007.
Of the total, 1359 (22.8%) received a PDE5i, prescribed a

All-cause mortality
Participants were followed up for a mean of 7.5 years (range
0.4–8.5 years). From the same background population, a
random (reference) sample of 32 330 men without diabetes or
PDE5i use, followed up for a mean 8.3 years, had mortality
rates of 4.8 (4.5 to 5.0) per 100 person-years. Fewer deaths (age
adjusted) occurred among PDE5i users with type 2 diabetes:
248 (19.1%) versus non-users (1170, (23.8%); 2=12.47,
p=0.0004).

Men on treatment with a PDE5i had a 31% lower risk of all-
cause mortality compared with non-users

Among those with a prior history of MI (n=1031), there were
fewer deaths in those previously treated with a PDE5i compared
with those who were never treated (25.7% (49/191) vs 40.1%
(337/840)).

Results Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup. Conclusion In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! BEST !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Hackett, Geoffrey, et al. “Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes.” World journal of diabetes 8.3 (2017): 104. We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men. METHODS We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual.

Four PDE5i are currently FDA approved for the treatment of ED:
sildenafil (Viagra®),
tadalafil (Cialis®),
vardenafil (Levitra®, Staxyn®), and
avanafil (Stendra®).

Drug Time to Onset Duration of
Avanafil 15 minutes 6 hours
Vardenafil 20-30 minutes 8-12 hours
Sildenafil 30-60 minutes 2-4 hours
Tadalafil 60-120 minutes 36 hours
Activity Onset Delayed by High Fat Meal
Yes
Yes
Yes
No

Only tadalafil is indicated for daily dosing, all others are dosed as needed prior to sexual activity. Pharmacodynamically, these medications differ in their time to onset and duration of activity5,6,7,8

PDE5 inhibitors for Diabetics with Peripheral Neuropathy

Hackett G. PDE5 inhibitors in diabetic peripheral neuropathy. Int J Clin Pract. 2006 Sep;60(9):1123-6. d

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.

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.

daily tadalafil 5 mg, and L-arginine 2500.

Gallo, Luigi, Stefano Pecoraro, and Pasquale Sarnacchiaro. “Adjuvant daily therapy with L-arginine 2,500 mg and tadalafil 5 mg increases efficacy and duration of benefits of low-intensity extracorporeal shock wave therapy for erectile dysfunction: A prospective, randomized, single-blinded study with 1-year follow-up.” Investigative and Clinical Urology 63.1 (2022): 83.

Purpose: To investigate a therapeutic protocol for erectile dysfunction (ED) based on the combination of low-intensity extracorporeal shock wave therapy (Li-ESWT), tadalafil, and L-arginine.

Materials and Methods: Recruited patients completed the International Index of Erectile Function erectile function domain (IIEFEF)
and the Erection Hardness Score (EHS) questionnaires at baseline and were randomly assigned in two groups: A (treatment
group) and B (control group). Men in both groups received six weekly applications of Li-ESWT. Group A was prescribed adjuvant
oral therapy with tadalafil 5 mg and L-arginine 2,500 mg. Follow-up visits were scheduled 1, 6, and 12 months after the last Li-ESWT
application. At each follow-up visit, the IIEF-EF and EHS questionnaires were administered again. The main outcome measures were the changes from baseline to every follow-up visit in IIEF-EF and EHS scores.
Results: The mean IIEF-EF score in group A was 16.0±4.0, 24.8±3.4, 23.3±4.6, and 21.6±5.5 at baseline, 1, 6, and 12 months of follow-up, respectively, whereas in group B the mean IIEF-EF score was 16.5±4.1, 22.7±4.2, 21.5±4.5, and 19.5±4.9, respectively.  We reported an increase in the mean EHS score in group A from 2.07±0.72 at baseline to 3.39±0.59, 3.17±0.67, and 2.98±0.72 at 1,6, and 12 months, respectively, and in group B from 2.12±0.80 at baseline to 3.07±0.78 and 2.95±0.76 at 1 and 6 months, respectively.
Conclusions: Adjuvant daily therapy with L-arginine 2,500 mg and tadalafil 5 mg was safe and effective in increasing the efficacy and the duration of benefits of Li-ESWT.

El‐Wakeel, L. M., et al. “Efficacy and tolerability of sildenafil/l‐arginine combination relative to sildenafil alone in patients with organic erectile dysfunction.” Andrology 8.1 (2020): 143-147.

Randomized controlled study with two parallel groups of erectile dysfunction patients; One group received sildenafil 50 mg every other day, while the other group received a combination of sildenafil (every other day)/l-arginine on a daily base. Efficacy was assessed using International Index of Erectile Function-5 score at the baseline and after 8 weeks. Side effects were evaluated across the two groups.
Results

The mean age was 56.3 ± 5 and 56.2 ± 4.4 years in sildenafil and combination groups, respectively. International Index of Erectile Function-5 score was comparable between the two groups at the baseline (p value 0.44). International Index of Erectile Function-5 score was improved from 15.3 ± 2.5 at baseline to 19.2 ± 2.3 after treatment, and this was statistically significant with p value <0.0001. The score was slightly better in combination group in which the average International Index of Erectile Function-5 score was (19.8 ± 2.2) vs. (18.5 ± 2.3) in sildenafil group with p value 0.05. Side effects were more or less the same between the two groups except for gastritis which was more common on combination group.
Conclusion

Adding l-arginine to sildenafil demonstrated more efficacy than sildenafil alone for treatment of erectile dysfunction patients.

Mirone, Vincenzo, et al. “A new original nutraceutical formulation ameliorates the effect of Tadalafil on clinical score and cGMP accumulation.” Archivio Italiano di Urologia e Andrologia 93.2 (2021): 221-226.

Risk of Ocular Adverse Events Associated With Use of Phosphodiesterase 5 Inhibitors in Men in the US
Mahyar Etminan, PharmD, MSc1,2,5; Mohit Sodhi, MSc1,3; Frederick S. Mikelberg, MD1; et al

Chronic Pelvic Pain Syndrome

https://tau.amegroups.com/article/view/38522/30198
Pineault, Kevin, et al. “Phosphodiesterase type 5 inhibitor therapy provides sustained relief of symptoms among patients with chronic pelvic pain syndrome.” Translational Andrology and Urology 9.2 (2020): 391.

Contributions: (I) Conception and design: K Pineault, AS Herati; (II) Administrative support: AS Herati; (III) Provision of study materials or patients: K Pineault, AS Herati; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: K Pineault, S Ray; (VI) Manuscript writing: all authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Amin S. Herati, MD. Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Park Building 217, 600 North Wolfe St., Baltimore, MD 21287, USA. Email: aherati1@jhmi.edu.

A total of 25 patients (mean age 44.4±12.9 years) met study criteria. The mean duration of PDE5i therapy was 1.3±1.6 years. Continued use of daily PDE5is was associated with significant decreases in total CPSI, pain, urinary symptom and quality of life scores [total CPSI: −12.8, standard deviation (SD) 9.5; pain: −6.1, SD 4.1; urinary symptoms: −2.4, SD 2.1; quality of life: −4.5, SD 3.9; P<0.001].

Conclusions: This prospective data suggests that PDE5i therapy is associated with durable decreases in CP/CPPS symptoms past 3 months.

Chronic Prostatitis Pelvic Pain

Benelli, Andrea, et al. “Once-daily 5 mg tadalafil oral treatment for patients with chronic prostatitis/chronic pelvic pain syndrome.” Therapeutic Advances in Urology 10.12 (2018): 377-381.

Demirtaş, Abdullah, et al. “Is Tadalafil an Effective Treatment Option for Interstitial Cystitis/Painful Bladder Syndrome? A Report of a Challenging Case.” Cureus 13.7 (2021).

BPH

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054509/
Hatzimouratidis, Konstantinos. “A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction.” Therapeutic Advances in Urology 6.4 (2014): 135-147. Tadalafil 5 mg once daily has been approved for the treatment of men with LUTS with or without comorbid ED.

Singh, Sanket Narayan, et al. “Comparing the effect of Alpha blocker (Silodosin) and Phosphodiesterase type 5 inhibitor (Tadalafil) in benign prostate hyperplasia patients with lower urinary tract symptoms: a single centre study.” International Surgery Journal 5.5 (2018): 1866-1872.

Casabé, Adolfo, et al. “Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia.” The Journal of urology 191.3 (2014): 727-733.

Cai, Zhonglin, Jianzhong Zhang, and Hongjun Li. “Two birds with one stone: regular use of PDE5 inhibitors for treating male patients with erectile dysfunction and cardiovascular diseases.” Cardiovascular Drugs and Therapy 33.1 (2019): 119-128.

PDE5 for Neurologic and Cognitive Function

Peixoto, Christina Alves, Ana Karolina Santana Nunes, and Ana Garcia-Osta. “Phosphodiesterase-5 inhibitors: action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition.Mediators of Inflammation 2015 (2015).

Peixoto, Christina A., Ana KS Nunes, and Catarina Rapôso. “The role of NO/cGMP signaling on neuroinflammation: a new therapeutic opportunity.” Mechanisms of neuroinflammation (2017): 167-208.

Nabavi, Seyed Mohammad, et al. “Phosphodiesterase inhibitors say NO to Alzheimer’s disease.” Food and Chemical Toxicology 134 (2019): 110822.

Ben Aissa, Manel, et al. “Targeting NO/cGMP signaling in the CNS for neurodegeneration and Alzheimer’s disease.” Current medicinal chemistry 23.24 (2016): 2770-2788.

de Santana Nunes, Ana Karolina, et al. “Sildenafil (Viagra®) prevents and restores LPS-induced inflammation in astrocytes.” Neuroscience Letters 630 (2016): 59-65.

Memory

França, Maria Eduarda Rocha, et al. “Tadalafil restores long-term memory and synaptic plasticity in mice with hepatic encephalopathy.” Toxicology and Applied Pharmacology 379 (2019): 114673.

Peripheral Neuropathy

Wang, Lei, Michael Chopp, and Zheng Gang Zhang. “PDE5 inhibitors promote recovery of peripheral neuropathy in diabetic mice.” Neural regeneration research 12.2 (2017): 218.

da Rocha Araújo, Shyrlene Meiry, et al. “Effect of sildenafil on neuroinflammation and synaptic plasticity pathways in experimental autoimmune encephalomyelitis.” International Immunopharmacology 85 (2020): 106581.

Duarte-Silva, Eduardo, et al. “Phosphodiesterase-5 inhibitors: Shedding new light on the darkness of depression?.” Journal of Affective Disorders 264 (2020): 138-149.

El-Bakly, Wesam, et al. “The efficacy and underlying mechanism of phosphodiesterase-5 inhibitors in preventing cognitive impairment and Alzheimer pathology: A systematic review of animal studies.” Behavioural Brain Research 372 (2019): 112004.

Klutzny, Saskia, et al. “PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling.” Cell death & disease 9.2 (2018): 1-15.

PDE5 inhibitors include: Dipyridamole, caffeine, theophylline, Viagra, Cialis and Levitra.
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation in vitro and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.

Cruz-Burgos, Marian, et al. “New approaches in oncology for repositioning drugs: the case of PDE5 inhibitor sildenafil.” Frontiers in Oncology 11 (2021): 208.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494657/
Das, Anindita, et al. “PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer.” Pharmacology & therapeutics 147 (2015): 12-21.

Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308237/
Hackett, Geoffrey. “Should all men with type 2 diabetes be routinely prescribed a phosphodiesterase type 5 inhibitor?.” The world journal of men’s health 38.3 (2020): 271.

THE CASE FOR DAILY TADALAFIL 5 mg FOR ENDOTHELIAL DYSFUNCTION IN MEN WITH TYPE 2 DIABETES

DAILY TADALAFIL EFFECTS ON TESTOSTERONE LEVELS

THE CASE FOR TADALAFIL 5 mg DAILY FOR ERECTILE DYSFUNCTION IN MEN WITH TYPE 2 DIABETES

THE CASE FOR TADALAFIL FOR SYMPTOMATIC LOWER URINARY TRACT SYMPTOMS/BENIGN PROSTATIC HYPERPLASIA IN MEN WITH TYPE 2 DIABETES

THE CASE FOR TADALAFIL FOR BENIGN PROSTATIC HYPERPLASIA PREVENTION IN TYPE 2 DIABETES

 

EVIDENCE THAT PHOSPHODIESTERASE TYPE 5 INHIBITORS MIGHT REDUCE DIABETES RELATED MORBIDITY AND MORTALITY

PREVENTION OF DIABETIC PERIPHERAL NEUROPATHY

DPN occurs in approximately 30% of men with T2DM and currently the mainstay of prevention is through tight glycaemic control. There are numerous case reports of improvement in neuropathic pain and paraesthesia with PDE5 inhibitors. NO is the major neurotransmitter of the vasa nervorum, suggesting an important preventive role in microvascular complications. Currently, drugs used to treat established DPN effectively block pain pathways and frequently aggravate ED. There is huge potential for savings by the prevention of complications of DPN [72,73].

 

CANCER PREVENTION

T2DM is associated with increased risk of many cancers, particularly colon. Review articles suggested a role for PDE5 inhibitors in cancer prevention [75]. In a Swedish national database study, Huang et al [76] studied a total of 4,823 patients who were prescribed PDE5 inhibitors during the study period; the incidence rate of colorectal cancer (CRC) was 2.64 per 1,000 person-years for men prescribed PDE5 inhibitors compared with 4.46 per 1,000 person-years for men without a prescription. They found a significant negative association between PDE5 inhibitor use and risk of CRC (adjusted hazard ratio, 0.65; 95% confidence intervalI, 0.49–0.85); the decreased risk of CRC was associated with an increased cumulative dose of PDE5 inhibitors (p=0.003).

 

COGNITIVE IMPROVEMENT

Choi et al [77] treated 30 men with ED and mild cognitive impairment with tadalafil 5 mg for 8 weeks. Mean baseline IIEF and Montreal Cognitive Assessment (MoCA) scores were 7.52±4.84 and 18.92±1.78. After the eight-week treatment, mean IIEF and MoCA scores were increased to 12.92±7.27 (p<0.05) and 21.8±1.71 (p<0.05), respectively. Patients showed increased relative regional cerebral blood flow in the postcentral gyrus, precuneus, and brainstem after tadalafil administration versus at baseline (p<0.001).

 

https://www.jacc.org/doi/full/10.1016/j.jacc.2021.02.021
Maas, Renke, and Roman N. Rodionov. “Phosphodiesterase-5 inhibitors and survival in men with coronary artery disease.” Journal of the American College of Cardiology 77.12 (2021): 1551-1553.

In conclusion, the observed association of PDE5i use and survival in men with coronary artery disease is intriguing but still insufficient to support any change in clinical practice. Issues of confounding and bias by indication can only be resolved by a randomized placebo-controlled trial. However, before initiating such a trial one question should be addressed first: Why has the pharmaceutical industry not already conducted any larger trials in this broad indication in the last 20 years? This is puzzling, considering the ample experimental data indicating beneficial effects in the cardiovascular system and that PDE5i were originally developed in the 1990s with the very large potential markets in coronary artery disease and hypertension in mind.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308237/
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.

Important health problems in men such as type 2 diabetes (T2DM), insulin resistance, erectile dysfunction, benign prostatic hyperplasia and depression have been shown to have to share common pathological processes, such as endothelial dysfunction and inflammation. This paper discusses the role of phosphodiesterase type 5 (PDE5) inhibitors, through beneficial effects on endothelial function and mediators of chronic inflammation and the possibility to treat or preventing these common conditions.

 

 

 

 

 

 

Yang, Han-Mo, et al. “Sildenafil reduces neointimal hyperplasia after angioplasty and inhibits platelet aggregation via activation of cGMP-dependent protein kinase.” Scientific reports 9.1 (2019): 1-12.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242821/

Sanders, Owen. “Sildenafil for the treatment of Alzheimer’s disease: a systematic review.” Journal of Alzheimer’s Disease Reports 4.1 (2020): 91-106.

In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

 

 

 

PDE5 inhibitors

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537549/
Andersson, Daniel P., et al. “Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction.” Heart 103.16 (2017): 1264.

Forty-three thousand one hundred and forty-five men with mean age 64 (±10) years were included, of whom 7.1% had ED medication dispensed during a mean 3.3 years (141 739 person-years) of follow­-up. Men with, compared with those without treatment for ED, had a 33% lower mortality (adjusted HR 0.67 (95%CI 0.55 to ­0.81)), and 40% lower risk of hospitalisation for heart failure (HR 0.60 (95% CI 0.44 to 0.82)). There was no association between treatment with alprostadil and mortality. The adjusted risk of death in men with 1, 2–5 and >5 dispensed prescriptions of phosphodiesterase-5 inhibitors was reduced by 34% (HR 0.66 (95% CI 0.38 to 1.15), 53% (HR 0.47 (95% CI 0.26 to 0.87) and 81% (HR 0.19 (95% CI 0.08 to 0.45), respectively, when compared with alprostadil treatment.
Conclusions

Treatment for ED after a first MI was associated with a reduced mortality and heart failure hospitalisation. Only men treated with phosphodiesterase-5 inhibitors had a reduced risk, which appeared to be dose-dependent.

 

Peripheral neuropathy

https://pubmed.ncbi.nlm.nih.gov/16939556/

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.

Duchenne muscular dystrophy

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118495/
Nelson, Michael D., et al. “PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.” Neurology 82.23 (2014): 2085-2091.

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https://www.frontiersin.org/articles/10.3389/fonc.2021.627229/full
Cruz-Burgos, Marian, et al. “New approaches in oncology for repositioning drugs: the case of PDE5 inhibitor sildenafil.” Frontiers in Oncology 11 (2021): 208.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833477/
Klutzny, Saskia, et al. “PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling.” Cell death & disease 9.2 (2018): 1-15.

PDE5 inhibitors include: Dipyridamole, caffeine, theophylline, Viagra, Cialis and Levitra.
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation in vitro and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.

 

 

 

 

 

 

 

Click to access JOM_1998_13_2_02_High-dose_intravenous_Vitamin_C_in_the_Treatment_of_A-.pdf

Riordan, Hugh D., et al. “High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney.” Journal of orthomolecular medicine 13.2 (1998): 72-73.
The authors published a similar case study in 1990 concerning a patient with adenocarcinoma of the kidney and metastasis to the lung and liver who was treated with The Center’s intravenous vitamin C protocol.1 The patient recently died of congestive heart failure (cancer free) 12-years after his original diagnosis of kidney cancer. The Center has treated many patients since this first patient using the high-dose vitamin C protocol with good results. We present another patient in this case study

No Mortality Benefit with Statins for Diabetics
Robert J DuBroff, and Matthew Bouchonville have expressed this same opinion.
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.

Last updated on by Jeffrey Dach MD

2 thoughts on “Mortality Reduction in Diabetics with PDE5 Inhibitor Statin Testosterone Combo

  1. Comment received via email today from WD

    Dr. Dach,

    GREAT article. I’m not convinced about the benefits of statins for diabetics, however–but otherwise, you covered lots of good stuff. I’m especially interested in trying Cialis or Sildenafil for one of my patients with fluoroquinalone toxicity.

    I’m comfortable using PDEIs in women. Sildenafil, 20 mg BID was developed for those with pulmonary hypertension (men and women), and the August 12th, 2010 issue of the NEJM
    featured an article using Sildenafil for Pulmonary Fibrosis (“A Controlled Trial of Sildenafil in Advanced Idiopathic Pulmonary Fibrosis”) in both men and women.

    Your book, Cracking Cancer Toolkit is a goldmine–the best book I’ve seen on treating cancer. Thanks for putting that together. I just wish it had an Index.

    Respectfully,

    WD, MD

    • Hi WD,

      Regarding your comment questioning a mortality benefit for statins in Diabetics, you are not alone as a number of authors such as Robert J DuBroff, and Matthew Bouchonville have expressed this same opinion.

      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.

      Index

      The index for the book is the Kindle version. Use the Control F function to search for key words in the file once you have the e-book downloaded.

      Thanks for reading the book. If you have time, leave an Amazon review. That would be much appreciated.

      Regards
      Dr D

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