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.
- Nackerdien Z. The Story of Insulin. 2012; http://patch.com/connecticut/norwalk/bp–the-story-of-insulin-3febf556. Accessed April, 2015.
- 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.
- Brooks M. Medscape Medical News. FDA Sides With EMA on Incretin Diabetes Drugs. 2013.
- 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.
- 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.
- AACE/ACE comprehensive diabetes management algorithm 2015; https://www.aace.com/files/aace_algorithm.pdf. Accessed April, 2015.
- 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.
- Pfeiffer AF, Klein HH. The treatment of type 2 diabetes. Dtsch Arztebl Int. 2014;111(5):69-81; quiz 82.
- 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.
- Devaraj S, Maitra A. Pancreatic safety of newer incretin-based therapies: are the “-tides” finally turning? Diabetes. 2014;63(7):2219-2221.
- 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.