Antidiabetic therapies (a sneak peek at my next book)

Here is a chapter of my next book, Perspectives on Type 2 diabetes, that will contain a lot of reader-friendly science and some stories. Enjoy!

What does the perennial herb, Galega officinalis, have in common with a venomous lizard, the Gila monster, and pancreatic extracts from collies? The answer is simple i.e., original sources for important antidiabetic therapies. A seminal paper, The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes, by Banting et al.1 that described results of experiments conducted on dogs laid the groundwork for the discovery of insulin, thereby forever changing treatment of the disease. A biguanidine derivative from the poisonous G. officinalis plant, metformin, is recommended by the American College of Physicians as monotherapy for the initial pharmacologic therapy of most Type 2 diabetics (except for pre-specified contraindications such as renal impairment; a complete list of contraindications is available).2 Saliva from the desert-dwelling Gila monster served as a source of incretin therapies—glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors. These compounds, hailed as breakthrough discoveries for the management of diabetes and possibly obesity, operate through switching on insulin and suppressing glucagon to control blood glucose. Based on evaluations performed in 2013, both the US Food and Drug Administration (FDA) agreed with the European Medicines Agency (EMA) concluded that available data did not corroborate published concerns regarding an increased risk for pancreatic side effects with GLP-1-based antidiabetic therapies.3

 

A multifactorial approach incorporating lifestyle changes and any one of several mainstay therapies is likely to form the basis of individualized algorithms designed by clinical teams for the treatment of each diabetic. It bears repeating that diabetics are more likely to be hospitalized with cardiovascular (CV) disease, have end-stage renal disease, go blind, and suffer non-traumatic lower limb amputations compared with non-diabetics.4 Intensifying case-finding in the general population to delay or prevent Type 2 diabetes therefore continues to be a national priority. Clinical symptoms (increased urination, increased thirst, unexplained weight loss, fatigue, blurred vision, increased hunger, and sores that do not heal) combined with any one of established blood tests (glycohemoglobin test [HbA1c], a fasting plasma glucose [FPG] test, an oral glucose tolerance test [OGTT], random plasma glucose [RPG] test) serve as diagnostic benchmarks.5 Following screening and diagnosis, patient-centered care and management usually includes individualizing an A1c target, establishing the frequency and pattern of self-monitoring blood glucose levels, reducing vascular risk, and tailoring pharmacotherapies taking comorbidities or downstream complications from diabetes into consideration. According to the 2013 clinical practice guidelines from the Canadian Diabetes Association, the desirable goal of vascular protection for all diabetics is potentially within reach by incorporating pharmacotherapies into an ABCDES-management algorithm. Simply put, A refers to A1c (optimal glycemic control, usually ≤7%), B = optimal blood pressure control (<130/80 mmHg), C = (LDL-C ≤2.0 mmol/L if decision made to treat), D refers to drugs to protect the heart, E refers to exercise and other behavioral changes (regular physical activity, healthy diet, achievement and maintenance of healthy body weight), and S = smoking cessation.4 In addition, a 2015 management algorithm from the American Association of Clinical Endocrinologists and American College of Endocrinology underscores the importance of tailoring treatments for obese or overweight diabetics in a milieu of clinical complications and attendant management risks. Moreover, pre-diabetes, glycemic-control, insulin addition or escalation-, and CV-risk-factor-modification algorithms have been summarized for the benefit of healthcare professionals.6,7

 

In the real world, a patient’s age, disease stage, body weight, comorbidities, work situation, income, level of health literacy, adherence, and personal priorities8 may all have to be taken into consideration in designing an appropriate management algorithm. Although the different algorithms may have to integrate clinical and socioeconomic factors, the long-term goals of each treatment plan remains the same: the prevention of micro-angiopathic complications—retinopathy, nephropathy, neuropathy; the prevention of macro-angiopathic complications—myocardial infarction, stroke, limb loss; restoration of quality of life; improvement in comorbidities; patient satisfaction and accompanying treatment adherence; the avoidance of hypoglycemia and weight gain. Anti-hyperglycemic pharmacotherapies to achieve individualized glycemic control include metformin, sulfonylureas, glinides, DPP-4 inhibitors, GLP-1 agonists, acarbose, pioglitazone, and insulin. Each medication may have independent associated risks such as hypoglycemia or weight fluctuations as well as other side effects. In addition, doses may need to be adjusted depending on a patient’s kidney function.8

 

The numerous approved pharmacotherapies for lowering blood glucose concentration have contributed to declining death rates due to diabetes in richer countries. However, the tripling of the number of diagnosed American diabetics since 1980, and similar trends worldwide have added to the impetus to develop more effective treatments with reduced side-effect risks. Currently, 100 of 180 antidiabetic therapies are undergoing clinical investigation for the management of Type 2 diabetes.9 One of the medications in the current pipeline improves glucose-dependent insulin secretion. Other medications with potentially longer therapeutic lives are also undergoing evaluation. Any therapeutic innovations in incretin-based therapies would be especially interesting because of additional beneficial effects on blood pressure, dyslipidemia, reduction in body weight, and potential cardioprotective, and neuroprotective effects. Although the jury is still out regarding the purported pancreatic risks associated with these agents, the multi-organ benefits of the drugs have given healthcare professionals cautious optimism for further use until large, randomized clinical trials can educate the community about the actual risks of pancreatitis and pancreatic cancer.10 Optimized trial paradigms geared towards improving the CV safety profiles of antidiabetics such as enrichment of higher CV-risk enrollees to ensure that an adequate number of endpoints is obtained to allow a meaningful estimate of risk, using both glycemic efficacy and cardiac safety as primary measures in a single trial, conducting meta-analyses based on appropriate statistical considerations of accrued, adjudicated CV events recorded during phase 2 and 3 trials, and monitoring defined groups or populations for interim analysis or non-inferiority or superiority comparisons are also currently under consideration.11

 

Given that more than $1 in $10 is spent directly on diabetes and associated complications in the USA, and $1 in $5 is spent on caring for people with diabetes, a continued commitment to therapeutic innovations with acceptable benefit/risk profiles bodes well for the delivery of affordable, optimal care.

 

References

 

  1. Nackerdien Z. The Story of Insulin. 2012; http://patch.com/connecticut/norwalk/bp–the-story-of-insulin-3febf556. Accessed April, 2015.
  2. Qaseem A, Humphrey LL, Sweet DE, Starkey M, Shekelle P. Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2012;156(3):218-231.
  3. Brooks M. Medscape Medical News. FDA Sides With EMA on Incretin Diabetes Drugs. 2013.
  4. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.
  5. U.S. Department of Health and Human Services. National Diabetes Information Clearinghouse (NDIC). http://diabetes.niddk.nih.gov/dm/pubs/diagnosis/#3. Accessed April, 2015.
  6. AACE/ACE comprehensive diabetes management algorithm 2015; https://www.aace.com/files/aace_algorithm.pdf. Accessed April, 2015.
  7. American Association of Clinical Endocrinologists and American College of Endocrinology – Clinical Practice Guidelines for developing a diabetes mellitus comprehensive care plan 2015. Accessed April, 2015.
  8. Pfeiffer AF, Klein HH. The treatment of type 2 diabetes. Dtsch Arztebl Int. 2014;111(5):69-81; quiz 82.
  9. Pharmaceutical Research and Manufacturing Association. Medicines in Development. Biopharmaceutical Research Companies Are Developing 180 Medicines to Treat Diabetes and Related Conditions 2014; http://www.phrma.org/sites/default/files/pdf/diabetes2014.pdf. Accessed April, 2015.
  10. Devaraj S, Maitra A. Pancreatic safety of newer incretin-based therapies: are the “-tides” finally turning? Diabetes. 2014;63(7):2219-2221.
  11. Geiger MJ, Mehta C, Turner JR, et al. Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cardiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes. Therapeutic Innovation & Regulatory Science. 2015;49(1):50-64.

The Story of Insulin

This story that I published in 2012 for the Norwalk Patch is worth revisiting:

“Pharmaceutical company” and “doing the right thing” are words that do not belong in the same sentence, if critics are to be believed. Inflammatory rhetoric amplifies known examples justifying negative publicity. Therefore, one could have been forgiven for having viewed a past exhibit at the New-York Historical Society with a measure of skepticism. The title of the exhibit was: “Breakthrough–The Dramatic Story of the Discovery of Insulin and the Era of Hope,” co-sponsored by the pharmaceutical company, Eli Lilly. For a brief moment one was transported to an almost-forgotten success story, in which academia and industry collaborated positively towards conquering a hitherto incurable disease.

The narratives, photos, and videos focusing on the researchers involved in the prelude to, and actual discovery of, insulin drew immediate attention. Diabetes mellitus, the latter word derived from the Latin for “honey,” had affected sufferers for centuries, as evidenced by historical quotes (Aretaeus, the famed second century physician from Cappadocia, who practiced in Greece and Rome, referred to diabetes in terms of “the melting down effect on flesh and limbs”) and diagnoses, e.g. descriptions on an Egyptian papyrus of sweet-smelling urine characteristic of the disease. The anatomy and physiology homage to the boomerang-shaped pancreas and histological stains highlighting the islets of Langerhans provided insights into some of the methods used to study the disease.

Many people were also fascinated by the stories of the scientific pioneers. Dr. Elliott P. Joslin was acknowledged for making patient involvement and empowerment the key features of diabetes management. Dr. Frederick Allen, an alumnus of The Rockefeller University in New York City, showed that diets below 1000 calories could lower blood sugar levels. The shoulders of these and other research giants formed the platforms for the men who would eventually share the Nobel Prize in Physiology and Medicine in 1923 for the discovery of insulin, Drs. Frederick Banting and John Macleod. The two discoverers shared their cash awards with Best and Collip, two contributors to the work.

Their studies are further elaborated upon in a book, Breakthrough: Elizabeth Hughes, the Discovery of Insulin, and the Making of a Medical Miracle (St. Martin’s Press, New York, 2010 , written by Thea Cooper and Arthur Ainsberg. The image of Banting that coalesced from the book was one of a loner, with no sense of purpose when he first enrolled in freshman classes at the University of Toronto. Contrast Banting’s persona with that of Professor John Macleod, a Scottish recruit to the University of Toronto and an authority on carbohydrates and metabolism, and one begins to grasp why there was discord between the two men. At the start of his research, Dr. Banting was already aware of the elusive secretions from the pancreas that could normalize blood sugar levels. However, because of degradation caused by digestive enzymes, no one in the English-speaking world had been able to isolate this secretion. In 1916, the Romanian scientist, Nicolas Paulesco, was successful in normalizing the blood sugar levels of dogs by injecting them with an extract called “pancrein,” but this success was not yet widely known. So much of Dr. Banting’s early work was conducted in a vacuum, with only his assistant, Charles Best, serving as an immediate sounding board for his ideas. Endless months of labor by both of them finally paid off when dog 408, a collie, finally responded positively to injections of the pancreatic extract. Buoyed by ensuing successes, Dr. Banting drafted a seminal paper titled “The Beneficial Influences of Certain Pancreatic Extracts on Pancreatic Diabetes,” that would eclipse all prior discoveries in the field and change the field.

Enter Big Pharma in the form of Alec Clowes, the man charged with identifying medical projects with commercial potential for Eli Lilly. According to the book, Eli Lilly, the grandson of the company’s founder, was a man who thought that the future of the company hinged on patenting fundamentally new ideas, not improvements of old ideas. Basing his thoughts on the successful collaboration between inventors, George Westinghouse and Thomas Edison, he proposed that basic biological research could provide the source of information enabling pharmaceutical companies to develop and patent entirely new proprietary drugs. Risk was not new to the Lilly family. Colonel Lilly built the first plant in 1895 to manufacture gelatin capsules, in essence a more palatable delivery mechanism for unpalatable medications.

The transfer of production rights from Toronto to the Lilly plant in Indianapolis was by no means a straightforward exercise. It seemed as if every short-term victory was followed by failure, with batches of variable quality insulin being produced, and insulin shortages becoming a huge issue. Diabetes specialists were also faced with the ethical dilemma of whom to treat and whom to turn away. Through a large monetary investment by Lilly and further interactions between the Canadian group and Mr. Clowes, large-scale production of insulin was finally undertaken at the Indianapolis plant.

Celebrities often bring more attention to a cause, and this was the case with Elizabeth Hughes (daughter of the Supreme Court Justice Evans Charles Hughes), who went on to live a full and productive life after receiving insulin.

Fast forward to the present day, and the rising numbers of diabetes sufferers seem to overshadow the successes from this positive academic-industry collaboration. In 2006, the United Nations passed a resolution declaring diabetes as serious a health threat as infectious diseases such as HIV/AIDS. As if to reinforce that theme, the exhibit concluded with flickering images of children in the developing world walking long distances to a clinic to receive life-saving medications. The International Diabetes Federation’s Life for a Child Program supports the care of children in 26 countries worldwide; benefits from the sale of the book on the discovery of insulin will also go towards its activities.

YouTube videos and images covering more aspects relating to the insulin story can still be found on the New York Historical Society web site.

Diabetes and pernicious anaemia (Appeared 2013 in The Norwalk Patch)

The Pernicious Anaemia Society members will already be familiar with Martyn Hooper’s book,”Pernicious Anaemia: the Forgotten Disease – the causes and consequences of vitamin B12 deficiency”(1). Briefly,  a complicated immune orchestra destroys cells in the stomach lining, increasing gastric pH, allowing bacteria (normally suppressed by low pH) to thrive, to possibly interfere with absorption of indispensable micronutrients, including vitamin B12 (2). The net result of progressive inflammation is the severe form of vitamin B12 deficiency, pernicious anemia (PA).

What happens when this misguided attack on the stomach lining is accompanied by a a second autoimmune/comorbid disease attacking a different organ in the body? This prospect is increasingly likely, given the rise in chronic diseases in aging populations. Stomach problems that may occur concurrently with the insidious progression from autoimmune gastritis to PA, can sometimes be a clinical signal of damage to another organ tucked behind the stomach, i.e. the pancreas. The pancreas secretes insulin, a critical hormone, that assists the body in absorbing glucose and other nutrients from food. Insulin and its precursors are also targets for autoimmune attack, leading to Type 1 or “juvenile” diabetes, a condition affecting 5-10% (3) of all diabetics. Adult-onset or type 2 diabetes (more information can be found in the Diabetes Portfolio [4]), which accounts for 90% (5) of all diabetic cases, occurs as a consequence of insufficient insulin production or resistance of the body’s tissues to normal or higher amounts of this hormone.

While PA is thought of as an under- or misdiagnosed disease (present in up to 2% of the general population) (6), for a variety of reasons,2 the number of known diabetics total more than 371 million across the globe (7). Autoimmune gastritis and PA are increased up to 5-fold in Type 1 diabetics (6). Moreover, metformin, a popular, oral antidiabetic medication, may contribute to vitamin B12 deficiency (8). These points underscore the need for a holistic approach in the management of PA and co-occurring illnesses.

References

1.   Hooper M. Pernicious Anaemia: the Forgotten Disease – the causes and consequences of vitamin B12 deficiency London: Hammersmith Health Books; 2012.

2.    Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic gastritis-pathogenesis, pathology and management. Nat Rev Gastroenterol Hepatol. 2013.

3.     Apple J, Aviad Mea. ASweetLife-Diabetes. 2013; http://asweetlife.org/diabetes/. Accessed July, 2013.

4.      Nackerdien Z. Diabetes Portfolio. 2013;http://znacke1.wix.com/diabetesportfolio. Accessed July, 2013.

5.       International Diabetes Federation. Types of Diabetes. 2013;http://www.idf.org/types-diabetes. Accessed July, 2013.

6.       De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune gastritis in type 1 diabetes: a clinically oriented review. J Clin Endocrinol Metab. 2008;93(2):363-371.

7.        International Diabetes Federation. IDF  Diabetes Atlas. 2012;http://www.idf.org/diabetesatlas/5e/Update2012. Accessed July, 2013.

8.        Warner J. Peripheral Neuropathy Patients Who Take Diabetes Drug May Have Vitamin B12 Deficiency. 2009; http://diabetes.webmd.com/news/20090608/metformin-linked-to-b12-deficiency. Accessed July, 2013.

Diabetes and Alzheimer’s disease

Information in this 2013 post (first published in The Norwalk Patch) continues to be relevant today.

Diabetes

Look around you and it seems as if the “healthy body, healthy mind” campaign is in full swing. Adherence to the latest health and fitness mantrasmay seem impossible to people coping with a sluggish economy, a confusing healthcare reform process and their own aches and pains. However, the latest epidemiology data from the International Diabetes Federation about this chronic disease [1] – which is linked to a host of other illnesses, including Alzheimer’s disease (AD) – may serve as an impetus to discard the fog of confusion in favor of pro-active health maintenance. An estimated total of 382 million people had diabetes in 2013 and this number is anticipated to rise to 592 million by 2035 [1]. Additionally, North America and the Caribbean lead other global regions in terms of money spent on the disease [1].

Having a healthy body and mind may empower diabetics awaiting solutions to the American healthcare paradox. The public-health specialists, Elizabeth Bradley and Lauren Taylor, have described the paradox as follows: “American per-capita spending on health far exceeds that of any other country on earth, the results achieved fall well short of other nations that spend much less. This includes such basic measures as life expectancy, maternal and infant mortality, and infant birth weight, for example.” For diabetics focused on also maintaining a healthy mind, these words may sound ominous as they grapple with a national fear of getting AD.

Alzheimer’s disease

A 4-minute captioned video depicting the brain changes characteristic of AD can be viewed at the National Institute on Aging’s  website. While the animation illustrates the advances that has been made in the understanding of AD progression, it does not address the complexities involved in accurately diagnosing the disease, especially within the context of comorbid illnesses such as diabetes. Scientific evidence is accumulating that suggests a link between Type 2 diabetes and AD, the most common form of dementia and the seventh leading cause of death in this country. The data pointing to an association between AD and low brain insulin levels has led some researchers to refer to this dementia sub-type as Type 3 diabetes.

A middle-aged or older diabetic  (≥40 years old) exhibiting one or more AD warning signs is likely to visit a primary care physician. In the absence of a lifelong relationship with a trusted clinician, any patient and family caregiver(s) will have to provide comprehensive medical histories to numerous doctors in order to facilitate optimal AD management in the context of diabetes. This task – usually assigned to caregivers – may be daunting, since recall bias or the presence of significant memory loss may hinder the collection of information. Nevertheless, ascertainment of complete medical histories will aid in the differential diagnosis of AD. Patients and members of their care team also need to remain vigilant about the potential for misdiagnosis and its accompanying excess costs [2].

References

1.       International Diabetes Federation. IDF Diabetes Atlas, 6th edition. Brussels, Belgium: International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

2.       Jeffrey, S. The High Cost of Alzheimer’s disease Misdiagnosis, 2013.  Medscape Medical News from the Alzheimer’s Association International Conference (AAIC),  2013

My journey (related to diabetes)

Hi everyone!

One of my brothers died two years ago due to complications from Type 2 diabetes. That tragic event caused me to channel my inner nerd and write a series of public-health-related articles about the disease that can be found here: http://znacke1.wix.com/diabetesportfolio. After much soul-searching I also started drafting my first book, “The Heroine Next Door.” It is very gratifying to receive positive feedback and I am happy to report to interested readers that a second manuscript is in the pipeline.

Enjoy your day.

ZEN Science Scan newsletter (Feb/March 2015)

Hi everyone,

My newsletter on SlideShare is a supplement (ZEN Science Scan Newsletter, Feb/Mar 2015) to highlight some of the exciting research and challenges in the fields of communicable and non-communicable diseases (with an emphasis on HIV/TB/diabetes as described in “The Heroine Next Door”).

The Heroine Next Door (and more about me)

Hi everyone!

I am so excited that my first book is finally in print.
My earliest memories of growing up involve sitting next to my father, as he drove a green truck filled with chattering children, to a Muslim primary school located in the whites-only neighborhood of Paarl. This prosperous South African tourist attraction and home of the Afrikaans Language monument can trace its roots of its name (Afrikaans for “pearl’) back to the description given by a Dutch colonist, Abraham Gabemma, when he saw a granite rock on one of its mountains gleaming after a rain storm. Three years later, in 1660, different Dutch settlers would give a street the same name after the oysters found in a New York river. Little did I know, as I watched my father teach overflowing classes of children the three R’s (reading, writing, and arithmetic) and I learned about nature from my mother (an avid gardener), that I would one day find myself in New York City.
Had I been the meticulous diarist of my later years, the stories of analyzing geraniums for signs of viral infections and probing the plump, yellow flesh of loquats in a tree (while hiding from my mother for some long-forgotten transgression), would be chronicled in glowing detail and cross-referenced with comments from my brothers. Instead, in my incarnation as a writer and given the vagaries of lost memories, I chose to write a work of fiction that is inspired by people and events that I have had the privilege to witness over the years. Because I am South African by birth, “The Heroine Next Door,” has a strong regional flavor, focusing on the pre-and post-apartheid era, before transitioning to the USA and Europe, and the impact of path-breaking infectious and non-communicable disease research on the lives of people in Africa. However, the core identity and relationship issues that the main character, Leila, struggles with are ones that resonate with me and hopefully with the readers. With that in mind, I plan on continuing to write about relationships, sometimes in the idiom of the religion in which I was raised, Islam, and to creatively meditate about my other great loves, including history, news (I am a news junkie), education for all, and science.