Written by Maria Ali in collaboration with Suzanna Phelps-Fredette
Medical history began with a holistic approach
Medical philosophy and practice dates back to the Indian Ayurvedic system of medicine and ancient Greek, Roman and Islamic physicians. Both took a holistic approach that considered the physical, mental and emotional health of a person as well as their disposition. The oldest known medical book in the world was written by a great Ayurvedic master in around 8000 BCE. Ayurveda (knowledge/science of life), still in practice today, is based on the idea that disease stems from an imbalance in the total person.
The theory of the four humors (blood, phlegm, yellow bile and black bile) appears in a 5th century BCE Hippocratic treatise, The Nature of Man, and relates disease to the four seasons that correspond to the properties of the four humors. Both systems diagnosed every individual as a unique case whose entire “being” had to be considered.
In the mid 1800s, specialties were becoming popular, and the first journals devoted to medical specialization appeared in Paris in 1839. By 1841 a German physician, Carl August Wunderlich, published a study comparing the practice of medicine in Paris and Vienna. Concerning the Parisian tendency toward specialization he is much quoted to say, “Now a specialty is a necessary condition for everybody who wants to become rich and famous rapidly. Each organ has its priest, and for some, special clinics exist.” 
By 1850 there were 39 specialties listed in a Parisian medical curriculum, mostly for obstetrics but also covering the eyes, venereal diseases, urology, dermatology, mental diseases and diseases of the chest. This rise in specialization was triggered, in part, by the new practice of medical research and the desire for empirical evidence in the practice of medicine.
Specialization quickly spread to both Germany and the U.S. and later to London. By the mid 1880s specialist practitioners were becoming more common, and in the 20th century, the proper training and clear demarcation between specialties came into practice.
Today the Association of American Medical Colleges lists more than 135 specialties and subspecialties in the U.S. with fewer than 40 for Canada. 
More than 2/3 of U.S physicians are now specialists as opposed to 1/2 or less in other developed countries. In 1940, 3/4 of American physicians were GPs, but by 1960 generalists were outnumbered. Unfortunately, specialization sometimes leads to a myopic therapeutic targeting of specific symptoms of a disease rather than consideration of the disease mechanisms and a patient’s individual environment and lifestyle that are causing the symptoms.
New era in drug development targeting causes rather than symptoms
In the new era of clinical research, biomarkers and genomics are driving the development of drugs that target the mechanisms of disease progression rather than symptoms. Endpoints in clinical trials are crossing disease states to test the safety and efficacy of drugs across multiple organs. Advances are being made that bring treatments into clinical practice that can improve outcomes for patients, slow the progression of disease and prevent hospitalization and death from causes other than a single diagnosed disease.
Clinical research has demonstrated the effectiveness of drugs originally approved as antihyperglycemic agents for their cardiovascular benefits. One of these, SGLT2 inhibitors, have proven to reduce adverse cardiovascular events and progression to end stage kidney disease (ESKD) for patients with chronic kidney disease (CKD) with type 2 diabetes (T2D.) These drugs have also shown benefits for HFrEF patients independent of diabetes status. For a person living with T2D, SGLT2 inhibitors can help prevent heart failure and have favorable effects on the preservation of kidney function.
The complex relationships of cardio-renal-metabolic disease
As early as 1836, Sir Richard Bright identified the interdependent relationship between heart and kidneys when finding cardiac structural abnormalities in patients with advanced CKD. (It is interesting to note that prior to 2004, there was no commonly accepted definition of CKD, when global use of the Kidney Disease Outcomes Quality Initiative KDOQI 2002 classification system was endorsed.) The heart/kidney relationship is further complicated by their relationship with T2D.
In a study of 530,747 adults with T2D in a USA-based outpatient registry of 271 primary care, cardiology and endocrinology offices, patients were found to have multiple conditions in the cardio-renal-metabolic (CaReMe) spectrum. Fewer than 10% of patients had only T2D.
T2D + 1 CaReMe condition 19.9%
T2D + 2 CaReMe conditions 33.7%
T2D + 3 CaReMe conditions 19.9%
T2D + 4 CaReMe conditions 9.3%
The epidemic proportion of diabetes is evident. In 2019, approximately 463 million adults worldwide (20-79 years) were living with diabetes and by 2045 this is expected to rise to 700 million. 
The list of all the inter-related conditions in the CaReMe spectrum could fill volumes and demonstrates the difficulty for healthcare providers in managing/treating these patients. Diabetes is connected to both kidney and cardiovascular disease. More than 40% of people with diabetes are likely to develop CKD. Patients with CKD have an elevated risk of coronary artery disease (CAD), heart failure (HF), arrhythmias and sudden cardiac death. Cardiovascular, rather than ESKD, is the leading cause of death in this high-risk population. Patients with HF have diabetes; diabetes patients have heart failure; many patients hospitalized for acute heart failure will develop acute kidney injury or cardiorenal syndrome. Most patients with heart failure have some renal dysfunction. Both kidney failure and heart failure are associated with a high incidence of failure of other organs.The situation is further complicated by the fact that within this set of physiological conditions, treatment for one may exacerbate another.
Any one of these major chronic diseases can trigger a series of sequential physiological interactions in a feedback cycle that leads to, at the least, a lower quality of life and at the worst, increased disability and death. The following statistics are a sobering reminder of the fact that a more holistic approach is required to effectively manage and treat this myriad of inter-related conditions.
- More than 70% of patients with T2D die of cardiovascular causes.(NIH) 
- T2D patients have >2× the risk for developing HF. (AHA Circulation Research) 
- 37% of T2D patients have been diagnosed with CKD (stages 1 through 4); and fewer than 25% with moderate to severe CKD (stage 3 or 4) are aware of their condition. (CDC) 
- The prevalence of ESKD is up to 10 times higher in T2D patients. (IDF) 
- CKD often occurs in the context of multiple comorbidities and has been termed a “disease multiplier.” Almost 50% of individuals with CKD also have diabetes and self-reported cardiovascular disease (CVD). (NIDDK) 
- Atherosclerotic heart disease is the most frequent CVD linked to CKD; its prevalence is more than 40% among people ages 66 and older. (NIDDK)
Multidisciplinary approach needed
Patients with chronic diseases in the highly complex systems of CaReMe are often subjected to fragmented care where each specialist treats only one aspect of their condition. Consider that even though greater than 1/3 of patients seen in coronary care units have insulin resistance, metabolic syndrome or undiagnosed diabetes, cardiologists too often leave this to another specialist or general practitioner. At the same time, specialists treating a diabetes patient tend to only treat patients for glucose management. This approach can result in failure to diagnose, and consequently treat, disease progression in a timely manner.
This highlights the importance of a “whole-body” approach not only to drug development, but also to clinical practice. New, state-of-the-art interventions such as the SGLT2 inhibitors that overlap diseases and treat “cross-functionally” require careful monitoring for benefits vs. risks — best achieved when multiple physicians are aligned to reduce cascading risks for these vulnerable patients.
The prediction that by 2040, more than half a billion of the world’s people will be affected by obesity and diabetes is propelling the market for one-time therapies for metabolic disorders, along with the rising incidence of inherited metabolic diseases triggered by changing lifestyles. 
However, research is of little value if the treatments are not implemented for the millions of patients who could benefit. As impressive as these new interventional drugs may be in addressing multiple needs for patients with complex medical conditions, many clinicians are reluctant to prescribe them.
A recent study showed that among more than one million commercially insured and Medicare Advantage adult beneficiaries, only 7% of patients with T2D were being treated with an SGLT2 inhibitor. Providers stated that barriers included lack of full knowledge about the medications, and also an expressed reluctance to “cross traditional specialist boundaries.” 
Who should prescribe and monitor these drugs? It could be endocrinologists, nephrologists, cardiologists, or primary care providers. Ideally, CaReME care should include all of these specialists as well as nurses, surgeons, pharmacists, psychotherapists, social workers, nutritionists and other specialists working collaboratively, preferably in a single location.
This type of inter-disciplinary care would provide the opportunity to more closely monitor and adjust SGLT2 Inhibitor and other therapies in a prompt and meaningful manner to reduce risks and ensure their effectiveness to improve quality of life and slow the progression of disease.
” …there is a moral imperative for cardiovascular professionals to become more engaged in the management of diabetes because there are agents now that substantially reduce cardiovascular death and other cardiovascular complications.” — Mikhail Kosiborod, MD, FACC 
Coming full circle with science
While ancient medical practices were not sophisticated empirically-based systems, there was an underlying concept that has become obscured by our ever increasing knowledge and level of specialization — the concept that health and disease are both due to complex interactions — not only of physical, mental and emotional factors, but also of complex interactions between bodily systems. And each individual has a unique set of circumstances and physiological conditions that contribute to their overall health.
Modern clinical research and indeed specialization have given us vast and detailed empirical evidence on which to base treatment decisions. And the more we have learned, the more we have seen that the body must be looked at “in total” in order to make the wisest decisions for treatment, especially for the set of complex chronic diseases associated with the cardio-renal-metabolic system. The “silo” approach is not the most efficient nor most resource effective path to tackling this mounting global health problem.
It is time to overlay empirical knowledge over the wisdom of the past and return to viewing patients as, not only a complex organism of many organ systems that work together to perform, but as independent individuals with specific physical, mental, environmental and lifestyle circumstances that affect how the mechanisms of the human body function as one to either maintain or degrade a person’s overall health and well being.
 Carl Wunderlich, Wien und Paris: Ein Beitrag zur Geschichte und Burteiling den gegenwärtigen Heilkunde in Deutschland und Frankreich (Stuttgart, 1841; new ed., Bern: H. Huber, 1974), p. 35. The translation of this quote is taken from Ackerknecht, Medicine at the Paris Hospital (n. 13), p. 163
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 Bright R. Cases and observations illustrative of renal disease accompanied by the secretion of albuminous urine. Guys Hospital Reports. 1836:338–400.
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