Diabetes is a chronic metabolic disease that is becoming more common in British Columbia, with predicted prevalence rates rising from 8.3% in 2013 to 10.3% in 2020.[1] The complications of diabetes contribute significantly to morbidity and mortality, and increase the cost burden to patients, our medical system, and society as a whole.[2,3] Primary care physicians manage the majority of people living with diabetes, and more than 20% of a typical physician’s caseload will likely involve caring for people with either diabetes or prediabetes.[4] Not only is the prevalence of diabetes increasing,[5] but the management of patients with diabetes is becoming more complicated as patients live longer and require additional care for frailty and comorbid conditions. There are now nine classes of antihyperglycemic agents, which often need to be used in combination owing to the progressive nature of diabetes,[6,7] a situation that increases the complexity of therapeutic decision making.

Diabetes requires a multifaceted approach to reduce both microvascular and macrovascular complications.[8] Glycemic control is an important risk factor for microvascular disease, including retinopathy, nephropathy, and peripheral neuropathy.[9-13] Early improved glucose control slows progression to these endpoints.[9,14-17] An association between macrovascular disease and aggressive glycemic control is less clear.[16,18,19] Cardiovascular (CV) benefit, most likely from better glucose control, has been seen in long-term (10- to 20-year) observational studies such as EDIC,[20] long-term follow-up of the UKPDS,[21] and a subset of VADT (although no overall survival benefit was seen in this group with established cardiovascular disease),[22] suggesting that good glycemic control achieved with less hypoglycemia, if initiated early in the course of the disease, reduces long-term CV risk.

Worldwide, clinical practice guidelines based on the best available evidence support the use of antihyperglycemic agents to reduce the risk of long-term complications of diabetes.[2,23-25] In large, randomized controlled CV safety studies, agents such as empagliflozin,[26] liraglutide,[27] semaglutide,[28] and canagliflozin[29] have demonstrated CV benefits. Conflicting information regarding appropriate use of these and other antihyperglycemic agents can confuse physicians and may result in widely variable quality of care as well as clinical inertia, which can mean physicians fail to implement or intensify a beneficial therapy.

Sources of recommendations

British Columbia physicians’ management of diabetes is guided by recommendations from three principle sources:

• Diabetes Canada (DC), formerly known as the Canadian Diabetes Association, which publishes clinical practice guidelines for the prevention and management of diabetes in Canada[2,3] and updates these as necessary.[23]
• The Guidelines and Protocols Advisory Committee (GPAC), which publishes clinical practice guidelines for use in BC on many topics, including diabetes care.[30]
• The Therapeutics Initiative (TI), which publishes recommendations regarding drug therapy for managing diabetes in their regular Therapeutics Letters.[31]

Table 1 [17] summarizes the composition and methodology of the bodies and shows how they vary in their guideline development and publishing processes. The recommendations produced by all three are widely disseminated.

Diabetes Canada

In 1998 the Canadian Diabetes Association published one of the first evidence-based guidelines for the management of diabetes in Canada.[32] In this and subsequent publications an independent expert committee developed and graded recommendations based on the quality of evidence from key studies. Updates were published in 2003, 2008, 2013, and 2018.[3] These guidelines are ranked among the best in the world with respect to quality, rigor, and process[33] as assessed using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation).[34] Each recommendation addresses a clinically important question related to the management of diabetes and its sequelae. Health benefits of interventions as well as risks and side effects are considered in formulating the recommendations. Patient preferences and values are considered by consulting people with diabetes and reviewing the literature. Each recommendation is justified using the strongest clinically relevant, empirical evidence that can be identified. Sources of evidence are cited and the strength of this evidence is indicated based on criteria from the epidemiological literature and other guidelines processes. Recommendations based on biological or mechanistic reasoning, expert opinion, or consensus are explicitly identified and graded as such. Finally, harmonization is sought with guidelines issued by other bodies, including the Canadian Cardiovascular Society, the Canadian Hypertension Education Program, the Canadian Cardiovascular Harmonization of National Guidelines Endeavour, and the Society of Obstetricians and Gynecologists of Canada.

Guidelines and Protocols Advisory Committee

The Guidelines and Protocols Advisory Committee consists of representatives from the BC Ministry of Health and Doctors of BC. The committee advises the Medical Services Commission regarding both the effective utilization of medical services and high-quality, appropriate patient care,[35,36] and oversees a number of working groups responsible for developing guidelines and protocols on almost 100 topics (see www.bcguidelines.ca [18]). The diabetes care guideline does not include an independent literature review but instead relies heavily on existing documents, including the Diabetes Canada clinical practice guidelines. The diabetes care guideline also addresses circumstances in BC and includes BC-specific information such as Medical Service Plan billing rules and incentive fees, lab test availability, Pharmacare coverage, referral pathways, and local resources. A handbook outlining the process for guideline development indicates that “For guidelines published after 2014, lists of contributors may be published on the website.”[36]

Therapeutics Initiative

The Therapeutics Initiative was established in 1994 by the Department of Pharmacology and Therapeutics in cooperation with the Department of Family Practice at the University of British Columbia “to provide physicians, pharmacists, allied health professionals and the public with up-to-date, evidence-based, practical information on prescription drug therapy.”[31] Funding is provided by the BC Ministry of Health through a grant to UBC. Four TI working groups are engaged in the development of recommendations that are published bimonthly in Therapeutics Letters and distributed as unsolicited mail to physicians and pharmacists in BC. Each letter commonly focuses on adverse outcomes found in trials as opposed to the primary or secondary objectives of the trials reviewed. Authors of the letters are not named and there is no stated methodology for literature selection or review or grading of recommendations, nor a predefined schedule for discussion of specific therapeutic areas. Since 2010, 18 drugs or classes of drugs have been reviewed in detail in 27 Therapeutics Letters and only one drug has been given a full recommendation (intravenous iron in appropriately selected people with chronic severe iron deficiency).[37]

Recommendations compared

Both Diabetes Canada and the Guidelines and Protocols Advisory Committee identify a process, structure, and timeline for their work in advance. The recommendations produced by both are more comprehensive in scope than those of the Therapeutics Initiative, which focuses mainly on drug therapies and aims to “improve prescription habits.”

The composition of DC guidelines committees is broad-based and interprofessional, including people with diabetes as well as experts in various specialties from across Canada. The GPAC working groups responsible for developing guidelines are smaller than the DC committees, but also include medical experts and a Pharmacare pharmacist. The members of TI working groups include salaried employees and other health care professionals and academics who are identified on the organization’s website. While the authors of DC guidelines are named, authors of GPAC guidelines and Therapeutics Letters are not.

Recommendations issued by the TI are notable for not aligning with those of other bodies, while recommendations issued by DC and GPAC align closely with American and European guidelines for diabetes management[24,25] and those of the United Kingdom’s National Institute for Health and Care Excellence (NICE), which produces the only guidelines to receive a higher rating than the DC diabetes guidelines[33] and is cited in one Therapeutics Letter as a source of “independent information.”[38]

DC, GPAC, and these international bodies recommend monitoring patients with diabetes using a glycated hemoglobin (HbA1c) level, and that the target A1c should be individualized, with a reasonable level for most adults being less than 7.0% and a target for those who are younger being 6.5% so they may benefit from more years of excellent glycemic control to avoid microvascular complications. Algorithms in DC, GPAC, and other international guidelines provide diabetes care teams with direction for management. No such direction is provided by the TI other than a preference for lifestyle intervention: “While we await the trial evidence, it is rational to emphasize lifestyle measures in these patients: weight loss, low carbohydrate diets and exercise.”[39] This recommendation is made despite the statement in another Therapeutics Letter that “weight loss is difficult to maintain”[40] and a lack of any references to support emphasizing “low carbohydrate diets,” which a literature review by Diabetes Canada found no evidence to support.[3] In the comments section of the TI website, a request for clarification regarding exactly what kind of carbohydrates such a diet would include is answered as follows: “We [the TI] are not experts on evidence about diet” (reply to Dr Virendra Sharma by Thomas L. Perry, MD, FRCPC, Chair, TI Education Working Group, 21 March 2017, 9:05 p.m.).

BC Pharmacare coverage

The most recent Diabetes Canada clinical practice guidelines recommend that antihyperglycemic agents should be chosen based on both patient and agent characteristics.[2,3] While all agents named by DC have been evaluated and approved for use in Canada, in BC only a few (generally older and less-expensive agents such as glyburide, metformin, and human insulins) are fully covered under the provincial formulary.[41] This makes it much more difficult for physicians to use up-to-date evidence when managing their patients with diabetes.

Table 2 [19] and Table 3 [20] illustrate the extent to which BC restricts Pharmacare coverage compared with three other provinces: Alberta and Ontario (each historically considered a have province) and Nova Scotia (considered a have-not province). Although drug evaluation is now performed nationally by the Common Drug Review and the Canadian Agency for Drugs and Technologies in Health (CADTH), it appears that recommendations from the TI rather than those from the much more robust DC guidelines are determining BC Pharmacare policy. BC is the only province to require special authority for gliclazide (for use after hypoglycemia with glyburide),[41,42] and is the only province to not list empagliflozin. The rejection of empagliflozin appears to be influenced largely by cost and supported by the TI’s criticisms of the EMPA-REG OUTCOME trial.[43] These criticisms, however, do not accord with most interpretations of the trial and other recent CV safety trials[26-29] such as the LEADER trial of liraglutide,[27] which demonstrated benefit for people with type 2 diabetes and clinical cardiovascular disease.

As a result of TI conclusions, BC residents with diabetes are at a disadvantage when compared with Canadians in other jurisdictions. Essentially, BC has become a have-not province for people with diabetes, a problem likely to worsen as the rates of diabetes in BC continue to rise.[44]

Key recommendations considered

Clear, high-quality, evidence-based recommendations are the cornerstone of medical training and subsequent decision making for health care providers. Physicians and patients expect and deserve the best care possible based on transparent processes and unbiased sources.

In BC, comparing key recommendations on important clinical issues such as A1c targets and pharmacological therapy[45-55] reveals significant discord. The TI is at odds with DC and GPAC on a number of topics, as shown in Table 4 [21]. In an example regarding cardiovascular outcomes and the use of empagliflozin, the Therapeutics Letter of July/August 2017 disputes the conclusions of the EMPA-REG OUTCOME trial.[43] The TI authors question the design of the trial, which is one mandated by the FDA, and the “aggressive” use of insulin, sulfonylureas, and DPP4s in the control group, which are the very medications BC Pharmacare covers. The TI authors also focus on genital infections experienced by some study subjects, and emphasize these harms in a table. Despite these concerns, the Therapeutics Letter of September/October 2017 names canagliflozin and dapagliflozin as “drugs to avoid”[55] but does not name empagliflozin.

Contradictory recommendations serve to confuse medical care providers, and restrictive Pharmacare coverage only adds to this confusion and promotes clinical inertia. A recent evidence-based review of formulary coverage for diabetes and cardiovascular disease concluded that glucose-lowering agents that reduce mortality in patients at very high cardiovascular risk are now available, and that empagliflozin has been shown to be highly cost-effective. The authors urge all provincial formularies to “re-examine their access requirements for SGLT-2 inhibitors and to consider adding GLP-1 agonists to reflect current evidence and clinical guideline recommendations.”[56]

Patients in BC living with type 2 diabetes deserve care that meets nationally vetted standards and provincial support for the most up-to-date evidence-based approach to diabetes management.

Summary

Type 2 diabetes is a common disease and its management is becoming increasingly complex. Management recommendations used in BC come primarily from Diabetes Canada, the Guidelines and Protocols Advisory Committee, and the Therapeutics Initiative.

The use of antihyperglycemic therapy has been shown to reduce complications and save lives. Physicians in BC are receiving contradictory information and facing formulary restrictions not seen in other provinces. Better alignment of evidence-based recommendations and appropriate drug coverage is needed to improve clinical outcomes and the lives of people in BC living with diabetes, and to make the management of diabetes less challenging for physicians and patients alike.

Acknowledgments

The authors wish to acknowledge the editorial assistance of Cynthia N. Lank (Halifax, NS) and the logistical support of Aleta Allen (Division of Endocrinology, UBC) for their part in supporting the publication of this theme issue.

Competing interests

This and the other articles in the theme issue were developed under the auspices of the Division of Endocrinology at the University of British Columbia and supported by an educational grant from AstraZeneca Canada Inc., Merck & Co. Inc., Novo Nordisk Canada Inc., Boehringer Ingelheim Canada Ltd., and Janssen Inc., a Division of Johnson & Johnson. The authors were volunteers and received no remuneration for their time or efforts. With the exception of Dr Ur, all authors were unaware of the sponsors’ identities until after this article was submitted to the BCMJ. Funds were used exclusively for travel and logistical support. Sponsors were not involved in any aspect of the decision to develop this article, in the content of the article, in the selection of authors, or in any aspect of the editorial process. In the past, all authors of this article (except for Dr Mudaliar) have received fees and honoraria from pharmaceutical companies for a variety of activities, including speaking, attending meetings, and organizing education. Details are available upon request.

This article has been peer reviewed.

Dr Clement is a family physician in the Interior of British Columbia with a consulting practice in diabetes. She has been actively involved with Diabetes Canada and was a member of the expert committee, steering committee, and executive committee during development of the 2003, 2008, 2013, and 2018 Diabetes Canada clinical practice guidelines. Dr Paty is an endocrinologist and UBC clinical associate professor who specializes in diabetes and post-transplant endocrinology. Dr Mancini is professor of medicine in the UBC Division of Cardiology, director of the CardioRisk Clinic at Vancouver Hospital, staff physician in the Healthy Heart Program Prevention Clinic at St. Paul’s Hospital, and a member of the writing group for the 2018 Diabetes Canada clinical practice guidelines. Dr Miller is an endocrinologist in Victoria and a clinical associate professor, UBC and UVic. He was actively involved with the Diabetes Canada guidelines (2003–2018) and with the BC guidelines (2003–2018). Dr Mudaliar is a Vancouver family physician. Dr Shu is an endocrinologist at Royal Columbian Hospital, currently serving as the regional head of endocrinology for the Fraser Health Authority. Dr Thompson is medical director of the VGH Diabetes Centre and principal investigator for the cell implant trial. Dr White is an endocrinologist and UBC clinical assistant professor with a practice in Vancouver. Dr Ur is a professor in the Division of Endocrinology at UBC.