Which medicines work most effectively for diabetic neuropathy?

What treatments can improve pain and quality of life?

This comprehensive report was first published in April 2017 by Diabetes in Control and discusses what old and new medicines work for diabetic neuropathy and importantly which ones don’t.

Pharmaceutical Products and Drugs
Diabetic neuropathy is a nerve disorder that the National Institute of Diabetes and Digestive and Kidney disease estimates affects about 60 to 70% of diabetic patients in some form, with the highest rates of neuropathy occurring in patients who have had diabetes for over 25 years.

Although diabetic neuropathy can affect almost any organ in the body, the most common type of diabetic neuropathy is peripheral neuropathy. Peripheral neuropathy, which is often worse at night, results in tingling, numbness, and pain occurring in the hands, arms, fingers, legs, feet, and toes.

The best way to prevent diabetic neuropathy is keeping glucose under control and maintaining a healthy weight, but for those who experience this painful condition, finding the best relief can often be difficult and confusing.
Building upon a previously published study from 2014, a new systemic review was conducted to “systemically assess the effect of pharmacological treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life” plus a search of PubMed and Cochrane Database of systemic reviews (reviews from 2011 – March 2016).
A total of 106 randomized controlled trials were used in the final systemic review, including trials analyzed by the previously published study. Only two medications, duloxetine and venlafaxine, had a moderate strength of evidence (SOE) compared to the low strength of evidence found with the remaining 12 study medications. As a class, serotonin-norepinephrine reuptake inhibitors (SNRIs) was found to be an effective treatment for diabetic neuropathy with the most commonly reported adverse effects of dizziness, nausea, and somnolence. Venlafaxine and tricyclic antidepressants were also determine to be effective at relieving pain compared to placebo using the previous analysis’ data.

Pregabalin was determined to be effective at reducing pain compared to placebo but found to have a low SOE due to the inclusion of four unpublished studies causing potential bias. Pregabalin, as well as the other anticonvulsants included, had adverse effects of dizziness, nausea, and somnolence.

Oxcarbazepine was also found to be an effective neuropathy pain reliever compared to placebo.
Atypical opioids have a dual mechanism of action, norepinephrine reuptake inhibition and mu antagonism, which aids in a class wide effective pain relief compared to placebo, and more specifically tramadol and tapentadol were found to be effective vs placebo. The most common adverse effects reported for opioids were constipation, somnolence, and nausea.

The last medication that was determined to be an effective pain reliever of diabetic neuropathy compared to placebo was botulinum toxin

Gabapentin, using five randomized controlled trials, was determined at two different doses to be ineffective at treating pain when compared to placebo. Other agents that were determined to be ineffective treatments for diabetic neuropathy were typical opioids (oxycodone), topical capsaicin 0.075%, dextromethorphan, and mexiletine.

Practice Pearls:
Pregabalin, oxcarbazepine, and tapentadol have shown to be effective vs placebo at relieving pain due to diabetic neuropathy and are also FDA approved for this indication.
Serotonin-norepinephrine reuptake inhibitors may be a good choice for relief of diabetic neuropathy pain and have the additional benefit of relieving depression that is commonly associated with diabetic neuropathy
Additional studies are needed to assess long-term pain relief effectiveness.

References:
“Nerve Damage (Diabetic Neuropathies) | NIDDK.” National Institutes of Health. U.S. Department of Health and Human Services. Web 05 April 2017
Julie M. Waldfogel, Suzanne Amato Nesbit, Sydney M. Dy, Ritu Sharma, Allen Zhang, Lisa M. Wilson, Wendy L. Bennett, Hsin-Chieh Yeh, Yohalakshmi Chelladurai, Dorianne Feldman, Karen A. Robinson. “Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life”. Neurology, 2017; 10.1212/WNL.0000000000003882 DOI: 10.1212/WNL.0000000000003882
 
Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD

 

 

 

BMJ: Continuity and individualised care matter more to patients than guidelines

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By Martin Rowland and Charlotte Paddison
Adapted from article in BMJ 18 May 2013
As the population rises more people are living with multiple medical conditions. These can be diabetes, rheumatoid arthritis, macular degeneration, depression, cancer, coronary heart disease and dementia among others.

These cause complex health, emotional and social problems which make their management difficult, especially in socioeconomically deprived areas. A new model of care is needed to manage patients optimally in these circumstances.
Although this seems obvious, care seems to be moving in the wrong direction for these patients.
Evidence based guidelines are really geared to patients with single conditions. They don’t cater to someone who has multiple conditions. Over treatment, and overly complex surveillance and assessment routines result. Older, less well educated and less affluent patients cope particularly poorly with these regimes. Guidelines also fail to recognise that patients get more frail as they age. The burdens of illness and treatment are different for a 100 year old compared to a 50 year old.
An individualised regime for each patient needs to be developed to focus on what matters most to each one.
Unfortunately doctors often feel that they can’t deviate from a guideline for fear of criticism and litigation. Perhaps guidelines should only be applied when they are clearly being used in the patient’s best interests, instead of the doctor’s? Exception reporting is a mechanism that allows doctors to deviate from guidelines and maybe should be used more.
Medical training does not as yet focus on this sort of individualised care. Medicine of old age comes the closest.
Listening to patients is the key thing that can help a doctor understand what their needs and goals are. The most appropriate care can then be built around that. The biggest barrier to this seems to be the over emphasis on single conditions.  This prevents rather than enhances goal oriented care.
Longer consultations are needed to help guide patients talk about their needs and think through complex decisions.
Satisfaction and outcomes are improved if this can be achieved. Despite this patients still often complain that they never see the same doctor twice both in hospital and primary care. It is also particularly difficult to provide a good quality of care when a doctor does not  know the patient and does not see the patient for follow up.
Young adults say they want to see the same doctor 52% of the time, but this increases to over 80% in those aged over 75.  More than a quarter of patients however say they struggle to see the doctor of their choice. This seems to be getting worse over time rather than better. Perhaps this is due to nurses taking over a lot of the care regarding chronic illness. Doctors are also increasingly working part time and may be involved in other tasks other than direct patient care. Shift systems in hospitals limit continuity a great deal.
In primary care, advanced access schemes give faster access but at the expense of continuity of care.
Older patients are particularly keen on waiting a few days longer to see the GP of their choice. Booking systems need to allow for both access and continuity.
This can be improved by receptionists attempting to book patients with their “own” doctor rather than simply the first available. Two or three doctors can share lists and try to see each other’s patients if one is not available.  E-mail booking of doctors directly can help. E-mail consultations can help.  Time for these must be built into the working day. The number of doctors who deal with  particularly complex needs may need to be restricted. Monitoring continuity of care can help. What gets monitored tends to get done more often after all.
As guidelines need to become less important for patients with multi-morbidity, a doctor’s clinical judgement becomes more critical.  There can be squads of other health care professionals involved in a patient’s care and deciding what ones are necessary and what ones are not is a useful task.  As the need for the traditional UK General Practitioner is increasing, sadly, their availability and time commitments to patient care seem to be decreasing.

The link between hypoglycaemia, cardiac arrythmia, and dead in bed syndrome

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Arrhythmia incidents differ in nocturnal and diurnal hypoglycemic patients.

In young adults with type 1 diabetes (T1D), severe hypoglycemia may increase the risk of all-cause mortality and cardiovascular diseases.

According to Peter Novodvorsky, from the University of Sheffield in the United Kingdom, and his colleagues, there are differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia. Hypoglycemia may exert proarrhythmogenic effects on the heart by sympathoadrenal stimulation and hypokalemia. The dysrhythmias induced by hypoglycemia have been associated with the “dead-in-bed syndrome,” a devastating condition that is rarely heard of. In this study, the effects of nocturnal and daytime clinical hypoglycemia are examined through electrocardiogram (ECG) in young people with T1D.

In an observational study, 37 participants were recruited from Sheffield Teaching Hospitals outpatient clinics with a median age of 34 years with T1D for at least four years. The purpose of this study was to examine the effect of clinical hypoglycemia in T1D patients age 50 or less and compare it with matched euglycemia on the frequency of cardiac arrhythmias, HRV, and cardiac repolarization.

Participants were told to avoid vigorous exercise, caffeine, and smoking 12 h prior to monitoring. Hypoglycemia awareness was assessed using a visual analog scale of 1 to 7. All subjects underwent 96 h of simultaneous  ECG and blinded continuous interstitial glucose monitoring (CGM) while continuing daily activities and symptomatic hypoglycemia were recorded.

The researchers obtained 2,395 hours of simultaneous ECG and CGM recordings with 159 and 1,355 hours designated hypoglycemia and euglycemia respectively. The median duration of hypoglycemia was longer during the night (60 min) than daytime (44 min) [P =0.020]. Overall, there were 24.1% of nocturnal and 51% of daytime symptomatic episodes respectively.

Bradycardia (low heart rate ) was more frequent during nocturnal hypoglycemia in comparison to matched euglycemia with an incidence rate ratio [IRR] 6.44 [95% CI, 6.26-6.66; P <0.001].

During daytime hypoglycemia, bradycardia was less frequent with an IRR 0.023 [95% CI, 0.002-0.26; P =0.002], while atrial ectopic was more frequent (IRR: 2.29; 95% CI, 1.19-4.39; P =.013). Moreover, during nocturnal and daytime hypoglycemia there was decreased T-wave symmetry, but prolonged QTc and T-peak to T-end interval duration.

The study confirmed that asymptomatic hypoglycemia commonly occurs in T1D. This causes abnormal heart rhythms and these are more abnormal at night, more frequent  and last longer.

 

Practice Pearls:

  • Hypoglycemia is pro-arrhythmogenic.
  • The study confirmed that there is high frequency of hypoglycemia, particularly of nocturnal asymptomatic episodes among young people with type 1 diabetes.
  • Hypoglycemia-induced mechanism is independent of the type of diabetes, age, or cardiovascular risk profile.

References:

  1. American Diabetes Association. 5. Glycemic targets. Diabetes Care. 2016;39 (Suppl. 1):S39–S46
  2. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia. 2010;53:1552–1561
  3. Novodvorsky P, bernjak A, Chow E, Iqbal A, Sellors L, Williams S, et al. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Diabetes Care. 2017, Feb 17.

From Diabetes in Control  18th March 2017

 

Lost to follow up diabetic patients do badly

 

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People with diabetes who had annual diabetes checks in the previous seven years had half the mortality rate of those who did not attend. 

This study  in England and Wales for the National Diabetes Audit 2015-16 also revealed that type ones have a mortality rate 127.8% more than the general population and those with type two diabetes are 28.45 more likely to succumb earlier than they otherwise would.

My comment: These seem very disturbing figures especially for type ones. Of course type ones are still not being guided about having normal blood sugars. There could be a reverse causality here going on as well, with the least fit people, perhaps housebound or with amputations or with visual problems less able to attend clinics. In my area there is a good deal of effort put into tracking down children who don’t attend clinics, but once they move to the adolescent and adult clincs there does not seem to be the provision of liaison nurses to do outreach work. 

 

Adapted from news article BMJ 22 July 17

 

Retinopathy Update

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American Diabetes Association Updates on Diabetic Retinopathy

 

Improvements in assessment and treatment of diabetic retinopathy position statement

Diabetic retinopathy (DR) is a complication of diabetes that affects vision.

High blood sugar levels can damage the blood vessels starving the retina of vital nutrients and oxygen resulting in blurry vision. Without appropriate treatment this condition may lead to complete vision loss.

The four stages of retinopathy range from mild non-proliferative diabetic retinopathy (NPDR) to moderate NPDR, to severe NPDR, to the most advanced stage – proliferative diabetic retinopathy (PDR).

DR is  a neurovascular complication of both type 1 and type 2 diabetes and its rate of occurrence depends on the level of glycemic control and the duration of diabetes.

Other risk factors associated with DR include hyperglycemia, nephropathy, hypertension, and dyslipidemia. Studies have proven that reduction in blood pressure (BP) decreases the progression of retinopathy in people with type 2 diabetes, but strict BP targets (systolic blood pressure of 120 mmHg vs. 140 mmHg) do not provide additional benefits. In another study, retinopathy progression was slowed in patients with dyslipidemia by adding fenofibrate, mainly in NPDR at baseline. In addition, several studies propose that pregnant patients with type 1 diabetes may exacerbate retinopathy with poor glycemic control during conception and may threaten their vision.

Optimization of blood glucose, blood pressure, and serum lipid levels in conjunction with appropriately scheduled dilated eye examinations can decrease the risk of vision loss from DR complications, but a substantial amount of those affected with diabetes develop diabetic macular edema (DME) or proliferative changes that require intervention. Large prospective randomized studies have shown that the use of intensive therapy could possibly prevent or delay DR with the goal of attaining near-normoglycemia. Although, intravitreal injection of anti–vascular endothelial growth factor agents may treat DME and PDR, it may threaten reading vision.

A meta-analysis study, conducted worldwide from 1980–2008 and consisting of 35 studies, predicted the global prevalence of DR to be 35.4% and PDR to be 7.5%. In developed countries, DR is mostly the cause of new cases of blindness among those 20 to 74 year old and eye disorders, such as glaucoma and cataracts, are frequently seen in diabetes patients. However, recent advancements in systemic therapy of diabetes have helped patients to improve their metabolic control. The statement incorporates these medical developments for the use of physicians and patients to aid in diagnosis and treatment of DR. It also provides an opportunity to improve glucose management and avoid or delay potential progression of the retinopathy.

The statement includes that screening recommendations for patients with diabetes depend on the rates of appearance and progression of DR and the associated risk factors. Ophthalmologist or optometrist examinations in patients with type 1 and 2 diabetes should be within 5 years after onset of diabetes and at the time of diabetes diagnosis, respectively. Women planning for pregnancy or who are pregnant with pre-existing diabetes should be examined before pregnancy or in the first trimester. In diabetes patients where no evidence of retinopathy is found, follow-up eye exams can be scheduled every two years. If any retinopathy is identified, then subsequent dilated-pupil retina exams are advised at least yearly, but more frequently if progressive retinopathy is diagnosed.

Fortunately, the cost-effectiveness of screening and traditional laser treatment for DR has been established with no more disputes. It is focused on telemedicine’s impact on the detection and eventual management of DR that appears to be most effective with lower ratio of providers to patients, with prohibitive distance to reach a provider, or when the alternative is no patient screening. The latest advancement in retinopathy treatment, anti-VEGF therapy has been taken into consideration, as they are more cost-effective than laser monotherapy for DME. Also, having retinopathy is not contraindicated with aspirin therapy for cardioprotection because studies suggest that aspirin does not increase the risk for retinal hemorrhage. Nonetheless, future studies are needed to determine the cost-effectiveness of anti-VEGF as a first-line treatment option for PDR.

Practice Pearls:

  • Optimize glycemic control, blood pressure, and serum lipids to reduce the risk or slow the progression of diabetic retinopathy.
  • Follow the screening recommendations for patients with diabetes for eye examination by ophthalmologist or optometrist.
  • The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection because aspirin does not increase the risk of retinal hemorrhage.

Reference:

Javitt JC, Canner JK, Sommer A. Cost effectiveness of current approaches to the control of retinopathy in type I diabetics. Ophthalmology 1989;96:255–264 42

Pasquel FJ, Hendrick AM, Ryan M, Cason E, Ali MK, Narayan KMV. Cost-effectiveness of different diabetic retinopathy screening modalities. J Diabetes Sci Technol 2015;10:301–307

Solomon SD, Chew E, Duh EJ, Sobrin L, Sun JK, VanderBeek BL, Wykoff CC, and Gardner TW. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. Mar 2017; 40(3): 412-418.https://doi.org/10.2337/dc16-2641

 

What should happen to you if you are admitted to hospital with an acute illness?

hospital

Adapted from BMJ 24 June 17 Managing adults with diabetes in hospital during an acute illness by Tahseen Chowdhury, Hannah Cheston and Anne Claydon.

Around one in five inpatient beds are occupied by someone who has diabetes. As patients, one in ten will have a severe hypo in hospital and in any one week, one in four will have an error made regarding their medication.

Poorly managed hyperglycaemia in patients with an acute illness do worse, stay in hospital longer and can even cause death. Blood sugars can be harder to manage because of the ongoing illness, erratic eating habits, changes to liver and kidney function, and changing medication, particularly starting and stopping steroids and metformin.   But here is no evidence that tight glycaemic control for hospital patients improves outcomes other than during cardiac surgery and liver transplantation.

The consensus is that blood glucose values between 6-10 mmol/L is probably optimal, given the need to prevent hypos, and that a range of 4-12 is acceptable.

The sorts of things that can cause high blood sugars in hospital are: sepsis, steroids, omission of insulin or oral hypoglycaemic medication, an overtreated hypo, stress and anxiety, surgery, a relative lack of insulin and long term poor glucose control.

In type one patients and type twos on insulin they should not stop their insulin even when fasted or when oral intake is poor.  At the very least basal insulin needs to be continued. The DAFNE plan is that blood sugars over 11 should be corrected by 2-6 units of rapid acting insulin and levels checked every 2 hours. Correction doses are advised not to be given at intervals more than every 4 hours to reduce insulin stacking.  Staff are advised to ASK THE PATIENT what they would normally do outside hospital.  

Treatment for diabetic ketoacidosis should be initiated if the blood ketone level is 3mmol/L or above.  In mild or moderate cases subcutaneous insulin may be used, but if severe, intravenous insulin will be needed.

When dealing with type two patients, where there is less risk of ketoacidosis, higher blood sugar levels may be acceptable over the short term. It is important to ask the patient if they are actually getting their correct medication. It is helpful to figure out exactly WHY the patient’s blood glucose is elevated, as this can be the clue to effective treatment, eg an ongoing urine infection.

Most hospitals have a diabetes liaison team and they can be particularly helpful in for instance surgical wards where staff may have less expertise in treating diabetic patients.

Insulin is sometimes required if a type two patient needs blood sugars stabilised promptly.  Doses will need frequent review as the patient becomes more active and eats more as they improve and as their condition returns to their normal state.

BMJ 2017;357:j2551

Sheri Colberg: Joint health is critical to staying active

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Joint Health Is Critical to Staying Active

Diabetes in Control

Without properly functioning joints, our bodies would be unable to bend, flex, or even move. A joint is wherever two bones come together, held in place by tendons that cross the joint and attach muscles to a bone on the other side and ligaments that attach to bones on both sides of the joint to stabilize it. The ends of the bones are covered with cartilage, a white substance formed by specialized cells called chondrocytes. These cells produce large amounts of an extracellular matrix composed of collagen fibers, proteoglycan, elastin fibers, and water. Tendons and ligaments are also made up primarily of collagen.

Joints can be damaged, however, making movement more difficult or painful. Joint cartilage can be damaged by acute injuries (i.e., ankle sprain, tendon or ligament tears) or overuse (related to repetition of joint movements and wear-and-tear over time). Damage to the thin cartilage layer covering the ends of the bones is not repaired by the body easily or well, mainly because cartilage lacks its own blood supply.

Aging alone can lead to some loss of this articular cartilage layer in knee, hip, and other joints—leading to osteoarthritis and joint pain—but having diabetes also potentially speeds up damage to joint surfaces. Although everyone gets stiffer joints with aging, diabetes accelerates the usual loss of flexibility by changing the structure of collagen in the joints, tendons, and ligaments. In short, glucose “sticking” to joint surfaces and collagen makes people with diabetes more prone to overuse injuries like tendinitis and frozen shoulder (1; 2). It may also take longer for their joint injuries to heal properly, especially if blood glucose levels are not managed effectively. What’s more, having reduced motion around joints increases the likelihood of injuries, falls, and self-imposed physical inactivity due to fear of falling.

Reduced flexibility limits movement around joints, increases the likelihood of orthopedic injuries, and presents a greater risk of joint-related problems often associated with diabetes, such as diabetic frozen shoulder, tendinitis, trigger finger, and carpal tunnel syndrome. These joint issues can come on with no warning and for no apparent reason, even if an individual exercises regularly and moderately, and they may recur more easily as well (3). It is not always just due to diabetes, though, since older adults without diabetes experience inflamed joints more readily than when they were younger.

So what can you do to keep your joints mobile if you’re aging (as we all are) and have diabetes? Regular stretching to keep full motion around joints can help prevent some of these problems, and also include specific resistance exercises that strengthen the muscles surrounding affected joints. Vary activities to stress joints differently each day. Overuse injuries occur following excessive use the same joints and muscle in a similar way over an extended period of weeks or months, or they can result from doing too much too soon.

Doing moderate aerobic activity that is weight-bearing (like walking) will actually improve arthritis pain in hips and knees (4). People can also try non-weight-bearing activities, such as aquatic activities that allow joints to be moved more fluidly. Swimming and aquatic classes (like water aerobics) in either shallow or deep water are both appropriate and challenging activities to improve joint mobility, overall strength, and aerobic fitness. Walking in a pool (with or without a flotation belt around the waist), recumbent stationary cycling, upper-body exercises, seated aerobic workouts, and resistance activities will give you additional options to try.

Finally, managing blood glucose levels effectively is also important to limit changes to collagen structures related to hyperglycemia. Losing excess weight and keeping body weight lower will decrease the risk for excessive stress on joints that can lead to lower body joint osteoarthritis (5). Simply staying as active as possible is also critical to allowing your joints to age well, but remember to rest inflamed joints properly to give them a chance to heal properly. You may have to try some new activities as you age to work around your joint limitations, but a side benefit is that you may find some of them to be enjoyable!

References:

  1. Abate M, Schiavone C, Pelotti P, Salini V: Limited joint mobility in diabetes and ageing: Recent advances in pathogenesis and therapy. Int J Immunopathol Pharmacol 2011;23:997-1003
  2. Ranger TA, Wong AM, Cook JL, Gaida JE: Is there an association between tendinopathy and diabetes mellitus? A systematic review with meta-analysis. Br J Sports Med 2015;
  3. Rozental TD, Zurakowski D, Blazar PE: Trigger finger: Prognostic indicators of recurrence following corticosteroid injection. J Bone Joint Surg Am 2008;90:1665-1672
  4. Rogers LQ, Macera CA, Hootman JM, Ainsworth BE, Blairi SN: The association between joint stress from physical activity and self-reported osteoarthritis: An analysis of the Cooper Clinic data. Osteoarthritis Cartilage 2002;10:617-622
  5. Magrans-Courtney T, Wilborn C, Rasmussen C, Ferreira M, Greenwood L, Campbell B, Kerksick CM, Nassar E, Li R, Iosia M, Cooke M, Dugan K, Willoughby D, Soliah L, Kreider RB: Effects of diet type and supplementation of glucosamine, chondroitin, and msm on body composition, functional status, and markers of health in women with knee osteoarthritis initiating a resistance-based exercise and weight loss program. J Int Soc Sports Nutr 2011;8:8

 

In addition to my educational web site, Diabetes Motion (www.diabetesmotion.com), I also recently founded an academy for fitness and other professionals seeking continuing education enabling them to effectively work with people with diabetes and exercise: Diabetes Motion Academy, accessible at www.dmacademy.com. Please visit those sites and my personal one (www.shericolberg.com) for more useful information about being active with diabetes.