[100] Questioning the basis of approval for non-insulin glucose lowering drugs

16 Sep 2016 [100] Questioning the basis of approval for non-insulin glucose lowering drugs

Download
Share
Posted at 10:12h in Therapeutics Letter by

100

Glucose lowering drugs are commonly prescribed in British Columbia, and 44% of adults with type 2 diabetes are receiving more than one drug (see Table). Annual spending on non-insulin glucose lowering drugs in Canada was $748 million in 2013.1 When these drugs are taken, the underlying unproven assumption is that by lowering glucose they will prevent the complications of diabetes: premature death, myocardial infarction, stroke, amputation, neuropathy, renal failure and blindness. This Letter documents that approval of new drugs is not based on these clinically important outcomes.

100table

How does Health Canada assess non-insulin glucose lowering drugs?

In 2007, Health Canada issued the following guidance for clinical trials in type 2 diabetes: “Clinical practice guidelines ensure the best standard of care based on current science and consensus in the medical and scientific communities. From the regulatory perspective, they are one of the measures against which the safety of the subjects is assessed during the review of clinical trial applications.”2 Health Canada claims that adherence to Canadian Diabetes Association (CDA) guidelines “will contribute to the safety of subjects” and emphasizes a recommendation for “more aggressive management of type 2 diabetes … tailored to aim for glycemic targets as close to normal as possible, and as early as possible, with the target HbA1c attained within 6 to 12 months”.2

On this basis, non-insulin glucose lowering drugs approved since 2007 include (by date of approval): sitagliptin (Januvia), saxagliptin (Onglyza), liraglutide (Victoza), exenatide (Byetta), linagliptin (Trajenta), alogliptin (Nesina), canagliflozin (Invokana), dapagliflozin (Forxiga), albiglutide (Eperzan), empagliflozin (Jardiance), dulaglutide (Trulicity) and exenatide extended-release (Bydureon).3

Health Canada’s Summary Basis of Decision website presents its interpretation of the benefits and harms of drug therapies which “reflects the information available to Health Canada regulators at the time a decision has been rendered”.3,4 As an example, Health Canada states that two 26-week studies supported a judgment on the clinical efficacy of liraglutide (Victoza), based on the surrogate outcome, change in HbA1c from baseline.4 Health Canada’s safety review identified the following signals: thyroid C-cell hyperplasia, thyroid C-cell tumors (animal studies), heart rate increase, PR interval prolongation, pancreatitis, hypoglycemia, gastrointestinal adverse events, immunogenicity, and injection site reactions.4

Health Canada approved liraglutide in 2010 noting that “Given the uncertainty regarding human risk for MTC [medullary thyroid cancer], the rejection of this product was considered; however, the clinical benefit of Victoza® as first-in-class in Canada for the treatment of Type 2 diabetes should also be considered and deemed worthwhile to balance the unknown human risk. Although there are several classes of products currently marketed in Canada for the treatment of Type 2 diabetes, there are still many patients with Type 2 diabetes (45% in the United States) who do not achieve the HbA1c target (< 7%) indicating that there is still an unmet need for new medications.”4

What are the potential benefits and harms of “more aggressive management of type 2 diabetes”?

A 2013 Cochrane systematic review identified 28 randomized controlled trials (RCTs) in which 18,717 participants were randomized to intensive glycemic control vs. 16,195 participants randomized to conventional glycemic control.5 This review included studies commonly interpreted by contemporary guidelines as evidentiary support for glycemic targets.6-8 Two RCTs contributing most of the data aimed for HbA1c targets < 7% with intensive glycemic control: ADVANCE7 (follow-up 5 years), and ACCORD8 (follow-up 3.5 years). The Cochrane review found that key clinical outcomes such as all-cause mortality [RR 1.00, 95%CI 0.92 to 1.08], cardiovascular mortality [RR 1.06, 95%CI 0.94 to 1.21], non-fatal stroke [RR 1.0, 95%CI 0.84 to 1.19], and end-stage renal disease [RR 0.87, 95%CI 0.71 to 1.06] were not improved by intensive glucose lowering.5 It found marginal reductions in the risk of amputation of a lower extremity [RR 0.65, 95%CI 0.45 to 0.94; ARR 0.4%] and non-fatal myocardial infarction [RR 0.87, 95%CI 0.77 to 0.98; ARR 0.7%].5 The Cochrane reviewers rated this evidence as inconclusive, given the risks of bias of the RCTs and the limited amount of data for most outcomes. At the same time, intensive glycemic control significantly increased serious adverse events [RR 1.06, 95%CI 1.02 to 1.10; ARI 1.4%] and severe hypoglycaemia (requiring assistance from another person) [RR 2.18, 95%CI 1.53 to 3.11; ARI 3.5%].5

Is the current regulatory focus on cardiovascular safety rational?

In 2008, the U.S. Food and Drug Administration (FDA) convened advisors to consider the cardiovascular safety of glucose lowering drugs in people with type 2 diabetes.9 Prior to drug approval, evidence must now be provided to regulators that excludes an 80% or higher relative increase in cardiovascular risk from a new drug (defined as cardiovascular mortality, myocardial infarction, stroke, ± hospitalization for unstable angina).10 After licensing, a single phase 4 postmarketing trial is required to exclude a 30% or higher relative increase in risk.10 Evidence of cardiovascular benefit is not required for initial approval or for a drug to remain on the market.

Phase 4 trials have been published for saxagliptin, alogliptin, sitagliptin, empagliflozin, and liraglutide.11-15 These trials generally meet the regulatory requirement of excluding a 30% relative increase in cardiovascular risk.11-15 Each study compares the new drug added to usual care with placebo plus usual care and allows for modification of background glucose lowering drugs over the course of the trial according to unblinded HbA1c values.11-15 This design, the FDA notes, “limits the ability to tease apart the beneficial and detrimental effects of the investigational agent from among those of the other needed antidiabetic agents”.16 These trials must be interpreted cautiously considering the current uncertainty regarding the effects of standard of care on cardiovascular outcomes.17

Furthermore, the focus on cardiovascular safety could mean that other relevant drug effects are left unstudied. To illustrate, the CDA reports that “Diabetes is the leading cause of blindness, end stage renal disease (ESRD) and non-traumatic amputation in Canadian adults”.18 In 2014, after failing its first review cycle, Health Canada approved canagliflozin (Invokana) on the basis that it lowered HbA1c despite having identified that the drug increased non-traumatic amputation: “an apparent observed risk attributable to Invokana treatment of approximately one case per 480 patients treated for one year.”19

Conclusions

  • Widely prescribed glucose lowering drugs for people with type 2 diabetes have been approved in Canada without evidence that they reduce mortality or major morbidity.
  • The best available evidence does not support Health Canada’s assertion that intensive glucose lowering in persons with type 2 diabetes “will contribute to the safety of subjects”.
  • The current regulatory framework for glucose lowering drugs that bases benefit on lowering HbA1c and bases harms on not increasing specific cardiovascular outcomes requires rethinking.
RR = risk ratio; 95% CI = 95% confidence interval; ARR = absolute risk reduction; ARI = absolute risk increase.
The draft of this Therapeutics Letter was submitted for review to 65 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health through a grant to the University of BC. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies .
ISSN 2369-8691 (Online) // ISSN 2369-8683 (Print)

References

  1. Morgan S, Smolina K, Mooney D, et al. The Canadian Rx atlas. 3rd Edition. Vancouver (BC): UBC Centre for Health Services and Policy Research; Dec 2013. [Internet]. Accessed February 26, 2016. Available from: http://chspr.ubc.ca/
  2. Health Canada. Drugs and Healt h Prod ucts. Guidance for Industry: Standards for Clinical Trials in Type 2 Diabetes in Canada. September 24, 2007. [Internet]. Accessed February 8, 2016. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/type2_diab-eng.php
  3. Health Canada. Drugs and Health Products. Summary Basis of Decision (SBD) Documents: Drugs. [Internet]. Accessed February 8, 2016. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/index-eng.php
  4. Health Canada. Drugs and Health Products; Summary Basis of Decision (SBD) for Victoza. October 26, 2010. [Internet]. Accessed February 8, 2016. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbdsmd/drug-med/sbd_smd_2010_victoza_119928-eng.php
  5. Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; Issue 11. Art. No.:CD008143. [Internet]. Accessed February 8, 2016. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008143.pub3/full
  6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837-53. [Erratum appears in Lancet 1999 Aug 14;354(9178):602]
  7. ADVANCE Collaborative Group. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358(24):2560-2572
  8. Action to Control Cardiovascu lar Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358(24):2545-2559
  9. U.S. Food and Drug Administration. 2008 Meeting Documents. Endocrinologic and Metabolic Drugs Advisory Committee. July 1 and 2, 2008. [Internet]. Accessed February 8, 2016. Available from: http://www.fda.gov/ohrms/dockets/ac/cder08.html#EndocrinologicMetabolic
  10. U.S. Food and Drug Administration. Guidance for Industry. Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. [Internet]. December 2008. Accessed February 8, 2016. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf
  11. Scirica DM, Bhatt DL, Braunwald E, et al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369(14):1317-26
  12. White WB, Cannon CP, Heller SR, et al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369(14):1327-35
  13. Green JB, Bethel MA, Armstrong PW, et al. TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373(3):232-42
  14. Zinman B, Warner C, Lachin JM, et al. EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 Diabetes. N Engl J Med 2015;373(22):2117-28
  15. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016 Jul 28;375(4):311-22
  16. U.S Food and Drug Administration. CDER 2008 Meeting Documents. Endocrinologic and Metabolic Drugs Advisory Committee. July 1 and 2, 2008. FDA Briefing Material. [Internet]. Accessed February 8, 2016. Available from: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4368b1-00-FDA-index.htm
  17. Bolen S, Tseng E, Hutfless S, et al. Diabetes Medications for Adults With Type 2 Diabetes: An Update. Comparative Effectiveness Review No. 173. AHRQ Publication No.16-EHC013-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2016. [Internet]. Accessed August 30, 2016. Available from: https://effectivehealthcare.ahrq.gov/ehc/products/607/2215/diabetes-update-2016-report.pdf
  18. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 clinical practice guidelines. Can J Diabetes 2013:37:S1-S212.
  19. Health Canada. Drugs and Health Products; Summary Basis of Decision (SBD) for Invokana. August 26, 2014. [Internet]. Accessed February 8, 2016. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2014_invokana-157505-eng.php#sbd
Tags:
10 Comments
  • jauca
    Posted at 11:10h, 16 September Reply

    See also CBC News report by Kelly Crowe: New study questions Type 2 diabetes treatment http://www.cbc.ca/news/health/study-type-2-diabetes-questions-medical-dogma-no-evidence-1.3762658

  • Ray Shroves
    Posted at 12:18h, 20 September Reply

    Is it not possible that the looked for effects will not manifest themselves significantly in three to five years but, rather, will do so much further out (ten years? 15? 20?) as persons living with Type 2 Diabetes age and, indeed, enter old age? I worry that just because no significant benefits were found in three to five years, longer term benefits — including life-saving ones — may be missed.

    • Anonymous
      Posted at 13:45h, 14 October Reply

      Written by authors of Therapeutics Letter #100:
      Thank you for adding your comment and for contributing to this important conversation. The two RCTs contributing most of the data to the Cochrane systematic review were ADVANCE (follow up 5 years) and ACCORD (follow up 3 years). The ACCORD trial was stopped early because of an increased risk of mortality with the intensive glucose lowering strategy. In the Cochrane systematic review, the trial contributing almost as much data as the ACCORD trial to the mortality analysis was much longer in duration: UKPDS (follow up 10 years). It failed to show a survival benefit in 3867 people with a new diagnosis of type 2 diabetes.
      Many of the intensive glucose lowering trials have published “extension trials” whereby some of the original participants are followed for longer periods of time, beyond that of the original trial’s pre-specified follow up. Unfortunately these observational studies suffer from a lack of randomisation, substantial losses of original participants, selective outcome reporting, and unblinding.
      The Cochrane authors conclude that “Our review therefore underscores the need to collect more information from randomised clinical trials before evidence-based general recommendations can be made regarding the choice between conventional glycaemic control and intensive glycaemic control in these patients”.
      Several questions remain, including:
      1. Which diabetes-related complications do we expect to be affected by intensive glucose lowering interventions?
      2. What are the baseline risks of diabetes-related complications with conventional or only symptomatic treatment (lowering blood glucose below the point of osmotic diuresis, etc.)?
      3. How long and how large should an intensive glucose lowering trial be in order to determine the net balance of benefits and harms of intensive glucose lowering?

  • JP
    Posted at 11:57h, 07 November Reply

    Citations please?

  • jauca
    Posted at 14:48h, 09 November Reply

    Reply from the authors of Therapeutics Letter #100:
    Thanks kindly for your comment. According to rankings on the New England Journal of Medicine these 3 trials in particular are indeed receiving significant social media attention, the so-called “negative trials” much less so. We do give consideration to the methodology of the cardiovascular safety trials on page two; please see the paragraph that begins “Phase 4 trials have been published …” The SUSTAIN-6 trial for semaglutide is not referenced because it was not designed to exclude a 30% relative increase in cardiovascular risk; it was designed to exclude a 80% relative increase in cardiovascular risk (a pre-approval requirement). EMPA REG OUTCOME (empagliflozin) was reviewed by the U.S. FDA and an advisory committee in June, which is as close as we might get in the nearest future to a more independent review of the trial than that provided by the drug sponsor. The 23-member advisory committee (comprised of methodologists, cardiologists, endocrinologists, public health experts, patient & consumer representatives) were divided on whether a claim for a reduction in cardiovascular mortality could be attributed to empagliflozin on the basis of the EMPA REG OUTCOME trial. Several important methodological issues were identified during their review which are not apparent in the journal publication of EMPA-REG OUTCOME. In addition to concerns raised regarding the quality of the evidence, considerable attention was given by the advisory committee to the U.S. FDA’s standard of effectiveness which generally requires two studies. This information is publicly accessible: http://www.fda.gov/AdvisoryCommittees/.

  • Maureen
    Posted at 08:33h, 16 November Reply

    Why was the Cochrane review withdrawn ( ref. 5) ?

    Cochrane Database Syst Rev. 2013 Nov 11;(11):CD008143. doi: 10.1002/14651858.CD008143.pub3.
    Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus.
    Hemmingsen B1, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterslev J.
    Author information
    Update in
    WITHDRAWN: Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. [Cochrane Database Syst Rev. 2015]

  • Nivitha Jeyakumar
    Posted at 17:42h, 09 January Reply

    Conflicts of Interest Declaration: Canadian Diabetes Association receives funds from general fundraising, donations, foundations, provincial governments, and private corporations including, but not exclusively, pharmaceutical companies. These pharmaceutical companies include: AMGEN, AstraZeneca, Bayer, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Stonebridge, Valiant.
    ===
    We are disappointed in the BC Therapeutics Initiative’s decision to write an opinion piece, Questioning the basis of approval for non-insulin glucose lower drugs, which, in the process of addressing the drugs approvals process at Health Canada, raises unwarranted questions regarding the benefit of treating blood glucose levels in type 2 diabetes. The benefit of glucose lowering drugs in managing both acute symptoms and the risk of long term complications of diabetes have been well documented in the evidence-driven Canadian Diabetes Association (CDA) Clinical Practice Guidelines (CPGs). We hope that, in the future, the members of the Therapeutics Initiative (TI) will instead choose to join in the process of building a consensus around the best way to treat diabetes. This is a good way to ensure that Canadians are getting consistent access to the most current evidence-based treatments wherever they live.
    The TI reviewed studies of the outcomes of intensive blood glucose control in type 2 diabetes and found only modest reductions in major complications of diabetes and some concurrent health risks. Given these narrow trade-offs the CDA CPGs emphasize individualizing therapy after a careful consideration of both the risks and benefits of treating to tight control. What the TI fails to note is that the comparison group in those studies was receiving usual care and achieving significant reductions in glucose levels (A1c of 7.3-7.6% in ADVANCE and ACCORD). Thus those studies do not answer the question of whether lowering blood glucose offers meaningful health benefit but rather, whether in people who are already treated there is additional benefit in further reducing A1c levels through what the TI calls “more aggressive management of type 2 diabetes”.
    By implication, the TI letter raises questions as to the net benefit of any treatment to control blood glucose levels. The UK Prospective Diabetes Study, as well as others have shown a clear reduction of microvascular complications and, in post study follow-up of microvascular complications with blood glucose reduction. While the benefit of aggressively lowering glucose to an A1c of less than 7 may not outweigh the benefit in all patients, the benefits of comprehensive care to achieve individually appropriate blood glucose levels are clear.
    Given that evidence, it is concerning that a recent Canadian survey found that fully one in three patients with diabetes had A1c levels above 7.6%. In another Alberta study, more than 40% of patients had A1c levels greater than 7% notwithstanding the fact that 60% of them were on two or more glucose lowering medications. These findings suggest that it is under-treatment rather than over-treatment of diabetes that may be the problem and they reinforce the need for multiple medications to achieve even moderate reductions in blood glucose. In addition to providing additional tools to help patients reach glucose targets, trials of some of the new agents provide additional improvements in cardiovascular outcomes, weight and hypoglycemia.
    In this context, the implication of the TI letter that blood glucose management in type 2 diabetes does not provide meaningful benefit and that additional medications are not needed sends a confusing signal to patients and to health care providers.
    The Therapeutics Initiative is funded by the BC Ministry of Health which, like its provincial counterparts around the country, is struggling with the rising cost of health care across the board. Diabetes medicines are a big ticket item because millions of Canadians are living with diabetes. The Canadian Diabetes Association is committed to working with the BC Ministry of Health and its partners in the private sector to improve care for Canadians in a way that contains cost. Confusing Canada’s hard-working health care professionals is not a good way to contain costs and is a disservice to Canadians living with diabetes.
    Jan Hux
    Chief Science Officer
    Canadian Diabetes Association

    • Cait O'Sullivan
      Posted at 17:59h, 09 January Reply

      Conflicts of Interest Declaration: Cait O’Sullivan does not have any conflicts of interest to declare.
      ===
      Does Therapeutics Letter 100 “Raise Unwarranted Questions”?
      We thank Dr. Jan Hux for the Canadian Diabetes Association response to Letter 100. The underlying evidence can seem complex and confusing, so we will try to address some of the issues you raised point by point, by referring directly to the CDA response:

      1. “… in the process of addressing the drugs approvals process at Health Canada, raises unwarranted questions regarding the benefit of treating blood glucose levels in type 2 diabetes.”
      Therapeutics Letter #100 reports on the results of a Cochrane systematic review “Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus”.[1] Health Canada’s position is that there is an “unmet need for new medications” for patients with HbA1c ≥ 7%.[2] It is not possible to discuss the approval process for glucose lowering drugs without examining the evidence that underlies Health Canada’s assertion. Neither Letter 100 nor any of our other Letters dealing with type 2 diabetes refer to the management of acute symptoms of hyperglycemia or diabetes.

      2. “The TI reviewed studies of the outcomes of intensive blood glucose control in type 2 diabetes and found only modest reductions in major complications of diabetes and some concurrent health risks.”
      Therapeutics Letter #100 reports on the results of a Cochrane systematic review of 28 intensive glucose-lowering RCTs.[1] The authors of this systematic review, based in Copenhagen, include some former members of the STENO Diabetes Center and an employee of Boehringer-Ingelheim (Germany). The review includes an appropriate COI declaration. It does not identify firm evidence for reductions in the risk of major complications with intensive glucose control as compared with conventional glucose control. Risks of premature death, cardiovascular death, non-fatal stroke, and end-stage renal disease were not reduced. The review identified statistically significant but small absolute reductions in the risk of non-fatal myocardial infarction (0.7%; “moderate” GRADE evidence) and of lower extremity amputation (0.4%; “low” GRADE evidence). The Summary of Findings Table explains: “more data are needed”. The American Association of Clinical Endocrinologists and American College of Endocrinology 2015 Clinical Practice Guidelines states plainly: “it is unknown whether treating patients with DM—some with pre-existing diabetic complications—using complicated regimens to force glucose concentrations into the normal range actually prevents or delays those complications”.[3]

      3. “By implication, the TI letter raises questions as to the net benefit of any treatment to control blood glucose levels.”
      Therapeutics Letter #100 is explicit about the 2013 Cochrane review: “A Cochrane systematic review identified 28 randomized controlled trials (RCTs) where 18,717 participants were randomized to intensive glycemic control and 16,195 participants were randomized to conventional glycemic control.”

      4. “The UK Prospective Diabetes Study, as well as others have shown a clear reduction in microvascular complications and, in post study follow-up of macrovascular complications with blood glucose reduction.”
      This statement is unreferenced and the UKPDS dataset includes numerous publications. We assume this refers to UKPDS 33 “Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes”[5] which is included as just one of many RCTs in the Cochrane systematic review. UKPDS 33, an unblinded study which began enrolling patients in 1977, did not demonstrate a reduction in major morbidity or mortality with a strategy of what was then considered intensive glucose lowering (target FPG < 6 mmol/L) as compared with conventional glucose control (intervening only if FPG exceeded 15 mmol/L or for acute symptoms of hyperglycemia). Median HbA1C during the 10-year experiment was 7.0% vs. 7.9%, respectively, in patients instructed to aim for 50% of calories from carbohydrates. While often cited as providing evidence for a general “microvascular benefit”, the UKPDS authors concluded that “the intensive treatment group had a substantial, 25% reduction in the risk of microvascular endpoints, most of which was due to fewer patients requiring retinal photocoagulation”. This corresponds to an absolute difference of 2.8 microvascular events per 1000 patient years. We presume Dr. Hux’ reference to post-trial follow up is the “10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes”, a non-randomized extension of UKPDS 33.[6] This is an observational study at high risk of bias, including important losses of the patients originally randomized in UKPDS 33. The Canadian Diabetes Association’s guideline methods recommend differentiating a systematic review of high quality RCTs from non-randomized and observational studies.[6] 5. “While the benefit of aggressively lowering glucose to an A1c of less than 7% may not outweigh the benefit in all patients, the benefits of comprehensive care to achieve individually appropriate blood glucose levels are clear.”
      The intended wording appears to be “While the benefit of aggressively lowering glucose to an A1c of less than 7% may not outweigh the harm in all patients …”. The Cochrane systematic review did not find reductions in mortality or major morbidity from intensive glucose lowering, and considered the evidence for small reductions in non-fatal MI and a composite of microvascular outcomes to be potentially compromised by biases. Targeting intensive control did increase hypoglycaemia, severe hypoglycaemia, and total serious adverse events.
      Therefore an important clinical question remains: in which patients do the benefits of intensive glucose lowering outweigh the harms? Are there high quality RCTs that inform the benefits and harms of achieving “individually appropriate blood glucose levels”? The 2013 Canadian Diabetes Association Guideline reads “Glycemic targets should be individualized based on age, duration of diabetes, risk of severe hypoglycemia, presence or absence of cardiovascular disease, and life expectancy [Grade D, Consensus].”[7]

      6. “It is concerning that a recent Canadian survey found that fully one in three patients with diabetes had A1c levels above 7.6%.”
      Given:
      a) the absence of firm evidence that intensive glucose control reduces the risk of major morbidity and mortality; and
      b) the Canadian Diabetes Association’s recommendation to individualize glycemic targets;
      Why is it concerning if one in three Canadians with type 2 diabetes have A1c levels above 7.6%? How can one construe this as evidence for under-treatment of diabetes and/or the need for more medications?

      7. “Confusing Canada’s hard-working health care professionals is not a good way to contain costs and is a disservice to Canadians living with diabetes”.
      Our Letter #100 does not consider costs in its analysis. It concludes “Widely prescribed glucose lowering drugs for people with type 2 diabetes have been approved in Canada without evidence that they reduce mortality or major morbidity”. Why does the Canadian Diabetes Association (CDA) disagree with a requirement for evidence that a glucose lowering medication reduces the risk of diabetes related complications at the time of drug approval?

      Clinicians are not confused by evidence. But they are confused by the lack of meaningful evidence, or when evidence is ignored, cited inappropriately, or frankly distorted. [8], [9], [10], [11]

      The dilemma for evidence-based practice is highlighted in the 2017 Clinical Practice Guideline Update from the American College of Physicians, “Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus”.[12] The authors conclude that “Insufficient evidence exists for clinical outcomes, including mortality, cardiovascular morbidity, and micro- or macrovascular outcomes, for most drugs and drug comparisons.”

      We think the CDA could usefully join with others worldwide who advocate for non-commercially based scientific evaluation of the comparative benefits and harms of the numerous available glucose lowering medications. Such information, as yet unavailable, would provide an enormous service to Canadians and all others facing the epidemic of type 2 diabetes.

      We thank you again for the commentary and hope our responses help to explain our interpretation of the available evidence and thinking about how drug therapy for type 2 diabetes could be improved.

      Cait O’Sullivan
      Clinical Pharmacist, Continuing Medical Education
      UBC Therapeutics Initiative

      References:
      1. Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev 2013; Issue 11. Art. No.: CD008143. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008143.pub3/full
      2. Health Canada. Drugs and Health Products; Summary Basis of Decision (SBD) for Victoza. October 26, 2010. [Internet]. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2010_victoza_119928-eng.php
      3. Handelsman Y, Bloomgarden Z, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology – Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan—2015. Endocr Pract 2015;21(Suppl 1):1-87.
      4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
      5. Holman RR, Paul SK, Bethel MA, et al. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008;359:1577-89.
      6. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Methods. Can J Diabetes 2013;37:S4-S7.
      7. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Targets for Glycemic Control. Can J Diabetes 2013;37:S31-S34.
      8. Shaughnessy AF, Slawson DC. What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes. BMJ 2003; 327 doi: http://dx.doi.org/10.1136/bmj.327.7409.266 (Published 31 July 2003)
      9. Rodríguez-Gutiérrez R, Montori VM. Glycemic Control for Patients With Type 2 Diabetes Mellitus: Our Evolving Faith in the Face of Evidence. Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org DOI: 10.1161/CIRCOUTCOMES.116.002901
      10. Le Noury J, Nardo JM, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320. doi: 10.1136/bmj.h4320
      11. Zhang R, Persaud N (2017) 8-Way Randomized Controlled Trial of Doxylamine, Pyridoxine and Dicyclomine for Nausea and Vomiting during Pregnancy: Restoration of Unpublished Information. PLoS ONE 12(1): e0167609. doi:10.1371/journal.pone.0167609
      12. Qaseem A, Barry MJ, Humphrey LL, et al. Oral pharmacologic treatment of type 2 diabetes mellitus: A clinical practice guideline update from the American College of Physicians. Ann Intern Med 2017; http://annals.org/aim/article/2595888/oral-pharmacologic-treatment-type-2-diabetes-mellitus-clinical-practice-guideline

Post A Comment