Vitamin D Supplementation In Prediabetes Does Not Prevent Progression To Type 2 Diabetes

/ News /

Patients at high risk for developing type 2 diabetes who received high-dose vitamin D supplementation showed no reduction in the risk of developing diabetes in a recent trial.

Anastassios G. Pittas, MD, with the Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, Boston, and colleagues reported their findings in the August 8, 2019 issue of The New England Journal of Medicine.

The Center for Disease Control and Prevention (CDC) reports that approximately 84 million adults in the United States have prediabetes. The first step in preventing progression to diabetes is lifestyle adjustment, mainly diet and exercise, to achieve weight loss and serum glucose level reduction. Given the difficulty many patients have adhering to lifestyle changes, researchers are studying several supplements and pharmaceutical agents to assist patients while lifestyle adjustments are ongoing. For example, metformin, a biguanide antihyperglyemic agent has been shown to independently reduce the risk of Type 2 diabetes in prediabetic patients. Other agents such as thiazolidinediones and alpha-glucosidase inhibitors are similarly being studied.

Vitamin D has also been linked to diabetes. Vitamin D levels are associated with several aspects of cellular function and health outcomes. Observational studies have shown a correlation between low vitamin D levels and decreased pancreatic beta-cell function and insulin resistance. Other short-term studies have shown an improvement in beta-cell function after vitamin D supplementation. It is unclear, however, if adding vitamin D prevents progression to diabetes.

This study was a randomized, double-blind, placebo-controlled trial, called the Vitamin D and Type 2 Diabetes trial (D2d). The trial enrolled participants 30 years of age or older who had a body-mass index (BMI) of 24 to 42, and had at least two of three criteria for prediabetes: increased fasting plasma glucose level (100-125 mg per deciliter), increased glucose level two hours after a 75-g oral glucose dose (140-199 mg per deciliter), and increased glycated hemoglobin level (5.7 to 6.4%). Patients were not selected for vitamin D deficiency and could be taking up to 1000 IU of vitamin D daily at the time of entry into the trial.

A total of 7133 persons were screened and 2423 were included in the intention-to-treat population. 1211 participants were randomly assigned to receive 4000 IU of vitamin D₃ daily, and 1212 participants to receive placebo. The development of new-onset diabetes was assessed and compared between groups.

After a mean follow-up period of 2.5 years, new-onset diabetes developed in 293 participants in the vitamin D group and 323 participants in the placebo group (9.4 events and 10.7 events per 100 person-years, respectively. The hazard ratio in the vitamin D group was .88; (95% confidence interval [CI], 0.75 to 1.04; P=0.12). The mean baseline serum 25-hydroxyvitamin D level was 28.0 ng per milliliter, with no significant between-group difference. Measured at months 12 and 24, the mean 25-hydroxyvitamin D levels in the vitamin D group were 52.3 and 54.3 ng per milliliter, respectively, and in the placebo group, the levels were 28.1 and 28.8 ng per milliliter, respectively. 

There was no significant difference in the rate of adverse events reported between the groups. This included specific vitamin D-related concerns for the development of hypercalcemia, nephrolithiasis, and decreased glomerular filtration rate (GFR). 47 participants (3.9%) in the vitamin D group stopped the study drug because of an adverse event, as compared with 37 (3.1%) in the placebo group (between-group difference, 0.8%; 95% CI, -0.7 to 2.3).

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others. A full list of disclosures is provided in the journal article.

Pittas, AG, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019; 381:520-30.  

Comments

  • in an editorial accompanying this study, Deborah J. Wexler, MD notes that the hazard ratio of 0.88 for development of new-onset diabetes does not rule out a modest benefit of vitamin D; a larger or longer trial would be needed to show this benefit
  • post hoc analysis done from 103 participants who had vitamin D deficiency (<12 ng per milliliter) showed a hazard ratio for the risk of developing diabetes with vitamin D supplementation of 0.38 (95% CI, 0.18 to 0.80)
  • further studies of those with vitamin D deficiency may help determine whether vitamin D supplementation prevents prediabetes from progressing to diabetes in that subgroup

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Pyrexia In Pasadena

/ Cases /

A 33-year-old woman presents with complaints of fever, headache, and rash for the past several days. She lives in Los Angeles and works as a physician’s assistant (PA) in an Internal Medicine office. She often volunteers with a city outreach clinic, providing basic on-site medical care for homeless people. She has no significant past medical history, no recent travel outside Los Angeles, takes no medications, does not smoke or drink alcohol, and has been in a monogamous relationship for the past several years. She recalls no recent insect or tick bites, and aside from occasionally seeing rats at various outreach sites, she has had no contact with animals.

History of Present Illness – about five days ago she recalls developing a fever, with mild chills, malaise, and a headache, which was more intense behind her eyes. Because of her many ill contacts related to her work, she thought she was developing a cold or flu, and aside from taking oral hydration and an occasional Tylenol dose, she ignored her symptoms. One to two days later, she developed worsening fevers, increased retro-orbital headache, and diffuse muscle aches. This was soon followed by a rash, first over her abdomen, then on her arms and legs.

Exam – ill-appearing; T – 38.8⁰C; P – mild tachycardia; BP, RR, and O2 sat – normal; skin – erythematous, maculopapular rash over the abdomen, and extremities; no other focal finding or abnormalities

Labs – normal CBC, basic chemistries and U/A; rapid flu test – negative

Discussion

Acute febrile illness has a broad differential diagnosis, which requires close attention to the patient’s underlying health status (e.g. immune status, prior illness history), work and travel history, exposures, and other epidemiologic factors. Given this patient’s presentation and the fact that she resides in a subtropical region, consideration should be given to arthropod-borne viruses (arboviruses). The list of possibilities is extensive and is made even longer given that she works with a transient population, many of which have unknown medical and travel histories. The Los Angeles County Department of Public Health’s statistics show West Nile virus has been the most common arbovirus infection in Los Angeles County for the past few years. Some other arboviruses present in southern California include St. Louis encephalitis, Zika virus, dengue fever, chikungunya, and western equine encephalitis.

This case is also consistent with many other infectious etiologies, including leptospirosis, coccidioidomycosis, measles, EBV infection – and despite her reported sexual history, consideration should also be given to acute HIV, disseminated gonococcal infection, and secondary syphilis. Given the lack of nuchal rigidity and normal neurologic exam, meningococcal meningitis is less likely. Non-infectious etiologies, such as autoimmune disease (e.g. lupus), and neoplastic conditions are also possibilities.

This clinical picture, in a patient working on city streets, in proximity to rats, places a specific rickettsial disease near or at the top of the differential diagnosis. While tick-borne rickettsia such as Rocky Mountain spotted fever should be ruled out in this case, rickettsia carried by rat fleas is more likely, especially as there have been reports of increasing numbers of such cases in Los Angeles over the past several years.

Murine Typhus

Murine typhus, also known as endemic typhus or flea-borne typhus, is caused by Rickettsia typhi, a gram-negative, obligate, intracellular bacillus. Fleas ingest R. typhi while biting an infected animal (host), typically a rat or opossum. The bacterium is spread when the flea bites another host. The flea defecates while feeding, and the host will unwittingly scratch the infected feces into a pruritic flea bite wound. Human infections are incidental, as the main vector cycles are either rat-flea-rat or opossum-cat flea-opossum.

flea – scanning EM

The incubation period for murine typhus is one to two weeks. The most common symptoms are fever, headaches, and malaise. The “classic triad” of fever, headache, and rash only occurs in about one-third of cases. Severe complications include meningitis, focal neurologic changes, respiratory failure, acute renal failure, and septic shock. The majority of cases, however, are relatively mild, and the case fatality rate, even without antibiotic therapy, is low. Increased mortality is associated with older age and immune compromise.

Given the clinical overlap observed among rickettsial diseases, PCR and/or indirect immunofluorescence assays (IFA) can be done to discriminate between them (and other etiologies). Prior to the return of specific diagnostic lab assays, empiric antibiotic therapy includes doxycycline due to its effectiveness against rickettsial infections.

References

CDC, Flea-borne (murine typhus), (2019), Retrieved from https://www.cdc.gov/typhus/murine/ (Accessed 07 August 2019).

Chu, J.T., Hossain, R., et al. Case 22-2017 – A 21-year-old Woman with Fever, Headache, and Myalgias. N Engl J Med 2017; 377:268-78. doi: 10.1056/NEJMcpc1616399

Flea-Borne (Endemic) Typhus, (2019), Retrieved from www.publichealth.lacounty.gov/acd/VectorTyphus.htm (Accessed 07 August 2019).

Stern, R.M., Luskin, M.R., et al. A Headache of a Diagnosis. N Engl J Med 2018; 379:475-79. doi: 10.1056/NEJMcps1803584

West Nile Virus and Other Arbovirus Diseases: 2017 Los Angeles County Epidemiology Final Report May 1st, 2018, (2018), Retrieved from publichealth.lacounty.gov/acd/docs/Arbo2017.pdf (Accessed 07 August 2019).

West Nile Virus Testing, (2019), Retrieved from www.publichealth.lacounty.gov/lab/wnv.htm (Accessed 07 August 2019).

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Rimegepant Shows Effectiveness In Migraine Therapy

/ News /

A new phase 3 study shows the efficacy of rimegepant when compared with placebo in acute migraine treatment.

Richard B. Lipton, MD, with the Department of Neurology and Epidemiology and Population Health, Albert Einstein College of Medicine, and Montefiore Medical Center, New York, and colleagues reported their findings in the July 11, 2019 issue of The New England Journal of Medicine.

Migraine is a very common chronic headache disorder – it is estimated that up to one billion people worldwide suffer migraines. Since their introduction in the early 1990s, triptans have been the most commonly used prescription medication class for migraine therapy. They work by acting as serotonin (5-hydroxytryptamine [5-HT]) agonists with a strong affinity for the 5-HT1B and 5-HT1D receptors, which are associated with vasoconstriction and at least partial inhibition of the release of vasoactive peptides from trigeminal neurons. Many previous published studies have shown that triptans are highly effective, with 70-80% of patients reporting significant pain reduction within ninety minutes of one dose.

Although proven effective, triptans use has been limited by a large adverse side effect profile and many contraindications. They cannot be used in cardiac, cerebral, or peripheral vascular disease, severe hypertension, and Raynaud’s syndrome, due to their vasoconstrictive properties. Many patients report being unable to tolerate triptans because of side effects such as nausea, flushing, dizziness, malaise, chest tightness, tingling, taste disturbance, and headache recurrence.

A new class of migraine drugs, currently in development, are the small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (gepants). CGRP levels correlate with the presence of migraine, and the gepants have been shown to be effective in migraine pain relief. Rimegepant, one such gepant, has been shown in a previous dose-ranging phase 2b study to be effective in treating migraine at the 75-mg dose. The gepants do not cause vasoconstriction, thus are free from the cardiovascular effects of the triptans.

This phase 3 trial was a multicenter, randomized, double-blind study, which enrolled 1186 adult migraine patients from 49 centers in the United States. 1072 of them were included in the modified intention-to-treat population. 537 patients were randomly assigned to receive rimegepant 75 mg, and 535 patients to receive placebo, for a single migraine attack of moderate or severe intensity. Pain intensity and the presence of associated symptoms were assessed and compared between groups.

Evaluated at two hours after the dose, 19.6% of the patients in the rimegepant group and 12.0% in the placebo group reported complete pain relief (between-group difference 7.6%; 95% confidence interval [CI] 3.3 to 11.9; P<0.001). Also, patient-reported relief from photophobia at two hours post-dose was 37.4% in the rimegepant group and 22.3% in the placebo group (P<0.001), relief from phonophobia was reported at 36.7% in the rimegepant group and 26.8% in the placebo group (P=0.004), and relief from the most bothersome symptom was 37.6% and 25.2%, respectively (P<0.001).

The most common adverse events were nausea (reported by 1.8% of the patients in the rimegepant group and 1.1% of the patients in the placebo group) and urinary tract infection (1.5% and 1.1%, respectively).

Although this study showed the efficacy of a single dose of rimegepant in acute migraine, Dr. Lipton and colleagues concluded that “larger and longer trials are needed to determine the consistency of response and the safety and effectiveness of the drug as compared with other migraine treatments.”

The study was funded by Biohaven Pharmaceuticals.

Lipton, RB, et al. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. N Engl J Med. 2019; 381:142-49.

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C-Reactive Protein Test Safely Reduces Antibiotic Use In COPD Exacerbation

/ News /

Chronic obstructive pulmonary disease (COPD) is a complex amalgam of lung diseases, associated with alveolar destruction, inflammation, mucus production, and airway obstruction. The Center for Disease Control and Prevention (CDC) estimates that approximately 16 million people suffer from COPD in the United States. Several studies have shown that each year one-half of COPD sufferers will experience at least one COPD exacerbation. This typically involves increased debility, sometimes involving hospitalization, steroid therapy, and a course of antibiotics.

Although pulmonary infection is the leading cause of COPD exacerbation, it is not present in every case, and in cases that are due to infection, many are viral in origin. Thus, antibiotic stewardship has been an ongoing challenge in the treatment of COPD exacerbation. Point-of-care tests, such as CRP, are being sought to help safely decrease antibiotic use where they not only provide no benefits, but contribute to increased costs, adverse drug effects, and antimicrobial resistance.

Christopher C. Butler, F. Med. Sci., with the Nuffield Department of Primary Care Health Sciences, University of Oxford, United Kingdom, and colleagues reported their findings in the July 11, 2019 issue of The New England Journal of Medicine.

The trial is called the PACE study (Point of care testing to target antibiotics for chronic obstructive pulmonary disease exacerbations). It is a multicenter, open-label, randomized, controlled trial involving 86 general medical practices in the United Kingdom. They randomized 653 COPD patients presenting with a COPD exacerbation to either usual care, or care guided by point-of-care CRP testing. Guidance was given to the treating clinicians as follows: patients who had a CRP level below 20 mg per liter were unlikely to benefit from antibiotic therapy, those who had a CRP level above 40 mg per liter were likely to benefit from antibiotic therapy, and those with a CRP level between 20 and 40 mg per liter may benefit from antibiotic therapy, especially if those patients were reporting purulent sputum production. Patient-reported antibiotic use within four weeks after randomization was compared between groups.

Patient-reported antibiotic use was lower in the CRP-guided care group than in the usual-care group (57% and 77.4% respectively, a 20.4% between-group difference; adjusted odds ratio, 0.31; 95% confidence interval [CI], 0.20 to 0.47).

There was no significant difference in the rate of adverse events reported between the groups. In the four-week follow-up period two patients in the usual-care group died, one from pneumonia and one from respiratory failure, but the trial investigators deemed these events unrelated to the trial.

The study was funded by the National Institute for Health Research Health Technology Assessment Program.

Butler CC, Gillespie D, White, P, et al. C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations. N Engl J Med. 2019; 381:111-20.

Comments

The importance of this study, and others like it, cannot be overstated in that they address one of the most critical issues in medicine today: antibiotic stewardship. The pressure on clinicians to prescribe antibiotics for any of a wide range of symptoms is immense. It is well understood that antibiotics are critical and lifesaving when properly used – however, the CDC reports that 30-50% of antibiotics prescribed in both the outpatient and hospital settings are not necessary. The increasing number of multi-drug resistant bacteria and antibiotic-associated adverse events, such as Clostridium difficile colitis, greatly incentivize decreasing antimicrobial overuse. This study is good evidence that a point-of-care test can actually improve clinical decisions regarding the use of antibiotics.

NB: In spite of the much-needed attention being placed on these issues, and studies like this which are helping clinicians make good antibiotic prescription choices, it is important to realize that a significant amount of antibiotics are also used in animal agriculture and industrial farming. The exact amount or the percentage relative to what is used in humans is difficult to define (some reports state as much as 70-80% of ALL antibiotic use in the U.S. is in the farming industry). What is clear is that we continue to ignore the warning of Alexander Fleming at our peril – the discoverer of penicillin stated in a 1945 interview how the misuse of antibiotics would most certainly lead to the development of resistant bacteria.

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Fever in Florida

/ Cases /

A 42 year-old man presents with acute onset fever and chills, with headache, intermittent abdominal pain, and very severe pain in his wrists, ankles, and low back for the past two days. He has no significant past medical history; he lives in Florida and works as an electrician. He has had no recent travel, no recent sexual contacts, and takes no medications. Aside from an occasional mosquito bite, he recalls no significant insect or other animal exposure, recent ill contacts, and has had no known tick bites.

Exam – temperature: 39.0 C, mild tachycardia, ill-appearing, but otherwise without focal findings, including no rashes, joint effusions, and no neurologic findings

Labs – normal CBC and basic chemistry panel, except for mild lymphocytopenia

Discussion

Acute febrile illness challenges clinicians with a very broad differential diagnosis – infectious diseases, collagen vascular diseases, endocrine disorders, to name just a few categories. When fever is associated with hemodynamic stability and generally normal physical findings and initial labs, it is typically attributed to a “viral syndrome” and managed with supportive care and outpatient monitoring. This patient, however, resides in a subtropical region and is showing symptoms and findings which would place a specific emerging vector-borne threat at the top of the differential diagnosis.

Aedes mosquito

Chikungunya

Chikungunya virus is an arthropod-borne single-stranded RNA virus (arbovirus), spread via Aedes mosquitoes, mainly Aedes aegypti and Aedes albopictus.

Aedes distribution (blue)

Chikungunya attack rates are very high, with WHO reports as high as 45% in some areas. Endemic to Africa, it spread to the Americas, mainly to the Caribbean, during the 1980s. It is typically spread by travelers, with thousands of documented cases imported to the United States from the Caribbean in 2013 and 2014. There have now been several cases of locally-acquired chikungunya infections (autochthonous) reported in the past few years throughout Florida and most other southern states. Given that the distribution of Aedes mosquitoes includes all of the southern United States, this trend is likely to increase, reinforcing the need to institute excellent vector control programs.

The incubation period for chikungunya infection is two to ten days (most commonly three days) and presents with sudden-onset severe fever, headache, and joint pains. A pruritic maculopapular rash has been observed with variable frequency in several different studies. Fever and other symptoms defervesce over seven to ten days, however, the arthralgias may persist for weeks to months, and in some cases, years.

If the patient presents early in the course of chikungunya infection, as in this case, diagnosis may require viral PCR testing as the IgM antibody response becomes detectable several days to one week after the onset of symptoms. If PCR is unavailable, the patient can be monitored closely to follow the antibody response, first with IgM, and then IgG antibodies.

Treatment of chikungunya is supportive, as there is no specific antiviral medication available. Given that chikungunya and dengue viruses both have the same vector and overlapping clinical features, dengue virus infection needs to be ruled out, especially since dengue fever has a significantly higher case-fatality rate. Until dengue is ruled out, aspirin and non-steroidal anti-inflammatory medications should be avoided, so as not to increase the risk of hemorrhage.

Vector control remains of paramount importance in the prevention not only of chikungunya virus, but of all other known viruses carried by Aedes mosquitoes, including dengue fever, yellow fever, zika, West Nile fever, eastern equine encephalitis, western equine encephalitis, Mayaro fever, Venezuelan equine encephalitis, Japanese encephalitis, and others!

References

CDC (2018), Chikungunya virus, Retrieved from https://www.cdc.gov/chikungunya (Accessed 02 August 2019).

Jameson, J.L., Fauci, A.S., et al, (Eds.)(2018). Harrison’s principles of internal medicine. 20th edition. New York: McGraw-Hill Education.

Thwaites, G.E., Day, N. Approach to fever in the returning traveler. N Engl J Med 2017; 376: 548-560. doi: 10.1056/NEJMra1508435

Weaver, S.C., Lecuit, M. Chikungunya virus and the global spread of a mosquito-borne disease. N Engl J Med 2015; 372:1231-1239. doi: 10.1056/NEJMra1406035

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Canagliflozin Decreases Risk Of Kidney Failure In Type 2 Diabetes

/ News /

Diabetes wreaks havoc on the kidneys – it is currently the leading cause of renal failure in the world. A relatively new class of diabetic drugs, called sodium-glucose cotransporter protein 2 (SGLT2) inhibitors has been shown to improve blood sugar control and improve cardiovascular outcomes. Unlike other diabetic drugs, the SGLT2 inhibitors work by blocking the reuptake of glucose in the kidneys, causing the glucose to be excreted directly into the urine. Previous trials done for cardiovascular outcomes showed trends toward improved renal outcomes, and these data led to the current trial, specifically evaluating kidney disease and the use of SGLT2 inhibitors.

Dr. Vlado Perkovic and colleagues reported their findings in the June 13, 2019 issue of The New England Journal of Medicine. The trial is called CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation). They enrolled 4401 patients with type 2 diabetes and preexisting chronic kidney disease. 2202 patients were randomly assigned to receive canagliflozin 100 mg orally once per day, and 2199 patients to receive a placebo. All patients were required to take either an angiotensin-converting-enzyme inhibitor or angiotensin II-receptor blocker for at least four weeks prior to randomization. End-stage renal disease outcomes (dialysis, transplantation, or sustained GFR below 15 ml/min) were compared between groups.

At a mean follow-up of approximately 2.6 years, the trial was ended (early) because of a significant reduction in renal outcomes in the canagliflozin group compared with the placebo group (43.2 and 61.2 per 1000 patient-years, respectively; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). Investigators also noted improved cardiovascular outcomes, which included a lower risk of cardiovascular death, myocardial infarction (MI), and stroke.

There was no significant difference in the rate of adverse events reported between the groups, including rates of amputation or fracture.

The study was funded by Janssen Research and Development.

Comments

  • approximately four hundred million people worldwide have diabetes, at least 40% will go on to develop renal injury
  • there has been no significant new renal treatment/prevention in the past two decades since the development of angiotensin-converting-enzyme inhibitors (ACE inhibitors) and angiotensin II-receptor blockers (ARBs)
  • although this trial enrolled only those with preexisting renal disease (caveat – those with severe renal disease were excluded), a risk reduction of 30% is very significant, especially with concomitant improvement in cardiovascular outcomes as noted
  • look for continuing updates to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) guidelines

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