15 Mar 2017 [103] Is the current ‘glucocentric’ approach to management of type 2 diabetes misguided?
A recent Alberta modeling study suggests that lifetime risk of diabetes is now 50% for non-indigenous Canadians and 80% for First Nations Canadians.1 If true, type 2 diabetes (DM2) will become the most common primary care diagnosis. Costs including medical visits, capillary blood glucose (CBG) testing, laboratory tests, and drug therapies will threaten other social priorities. In 2013, British Columbia spent over $52 million for CBG tests alone.2 It is critical that the benefits of future therapy for this condition substantially outweigh the harms. However, there is a growing international recognition that the current ‘glucocentric’ approach (i.e. controlling blood glucose with multiple medications in patients without symptoms of hyperglycemia) may be misguided.
Therapeutics Initiative Letters
7 Therapeutics Letters (TL) relate to the management of DM2.
1998: TL 233 documented the drugs that were available in 1998 and noted “there is no conclusive evidence that improved glucose control with oral agents leads to a decrease in the complications of type 2 diabetes.”
1998: TL 274 summarized the results of the United Kingdom Prospective Diabetes Studies (UKPDS). In one arm sulfonylurea or insulin was compared with diet and the only potential benefit of the drugs was a 2.4% reduction in retinopathy requiring photocoagulation. In contrast drug therapy increased major hypoglycemic episodes: diet 1%; chlorpropamide 4%; glyburide 6%; and insulin 23%. In a second arm of UKPDS, 1704 obese diabetic patients were randomised to metformin, diet or treatment with sulfonylurea or insulin. Metformin reduced mortality as compared to diet or drug therapy. We were aware of and commented on a third arm that showed that metformin added to maximal sulfonylurea therapy was harmful. However, like most of the rest of world we focused on the positive arm and concluded “For first-line type 2 diabetes therapy the benefit/risk ratio for metformin is many fold greater than that for sulfonylureas or insulin.”
2000: TL 365 reviewed rosiglitazone, a new drug for DM2, and concluded “rosiglitazone improves some surrogate markers and worsens others.”
2008: TL 686 reviewed the trials testing lower glycemic targets in DM2 and concluded, “The optimal glycemic target in patients with type 2 diabetes is unknown.”
2011: TL 817 reviewed self-monitoring of blood glucose (SMBG) in DM2 and concluded, “Most non-insulin treated patients with DM2 do not require routine SMBG.”
2014: TL 928 documented the limitations and potential hazards of using surrogates, including glycosylated hemoglobin (A1C), an estimate of glucose blood levels in the last 3 months.
2016: TL 1009 questioned the use of A1C as the basis of approval for non-insulin glucose lowering drugs.
Our research has led us to conclude that the ‘glucocentric’ approach to the management of DM2 is probably not in the best interests of patients.
Other analyses of the current evidence
2009: Endocrinologists from the Mayo Clinic concluded: “Our review and critique of recent large randomized trials in patients with type 2 diabetes suggest that tight glycemic control burdens patients with complex treatment programs, hypoglycemia, weight gain, and costs and offers uncertain benefits in return.”10
2011: A systematic review showed that when intensive glucose lowering was compared with standard care the magnitude of the harms outweighed the benefits.11
2011: Leading diabetes experts argued in the British Medical Journal that our obsession with A1C as a surrogate is damaging patient care.12
2016: Researchers conducted a systematic review of metformin documenting that the cardiovascular and mortality benefit of metformin seen in one arm of UKPDS was contradicted in another arm of the same trial, not seen in any other RCTs and has never been replicated.13
2016: Researchers reviewed practice guidelines from 2006 to 2015 and compared them with meta-analyses and individual RCTs comparing glycemic targets.14 The authors examined outcomes that “patients experience and consider important”. Microvascular outcomes were: end-stage renal disease or dialysis, renal death, blindness and clinical neuropathy. Macrovascular outcomes were: all-cause mortality, cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), fatal and nonfatal stroke, and peripheral vascular events or amputations. The authors concluded that “evidence accrued in the past 2 decades consistently demonstrates no significant benefit of tight glycemic control on patient-important micro- and macrovascular outcomes”. Furthermore they note that “most published statements and all guidelines unequivocally endorse tight glycemic control to prevent microvascular complications”. They emphasize the discordance between research evidence and guidelines for DM2 and conclude that it is time for us to rethink our approach.
2017: An evidence based analysis of DM2 RCTs questions the likelihood that an individual patient will benefit from treatment of DM2 over an expected life span and suggests we balance this against the inevitable burdens and harms of treatment. The authors conclude: “Current evidence strongly supports that there is a potential epidemic of overtreatment with antihyperglycemic therapies in diabetes.”15
2017: The perspective in TL 1009 is shared by cardiology and endocrinology experts at Yale: “Trials that use outcomes based solely on glycemic parameters are no longer acceptable for clinical decision making. Clinicians and patients need evidence about outcomes associated with different drug classes and likely with different agents within a class. Investments in pragmatic studies of existing agents are needed to understand the impact on outcomes of all treatment options.”16
What is needed now?
The only way to improve the management of DM2 is to conduct trials that will answer the questions important to patients. Patients expect treatment that is proven to maintain healthy function, prevent premature death, hospitalization, stroke, ischemic heart disease, kidney disease, neuropathy, amputation and blindness. At the present time we do not have that proof for the ‘glucocentric’ approach or for any drug for DM2.
Boussageon et al13 are correct to push for large long-term independent trials, which test different approaches and drugs, and most critically, measure outcomes that are important to patients. While we await the trial evidence, it is rational to emphasize lifestyle measures in these patients: weight loss, low carbohydrate diets and exercise.
Conclusions
- The increasing prevalence of type 2 diabetes presents a serious challenge to society.
- There is growing evidence that the ‘glucocentric’ drug management approach is misguided.
- Large long-term randomized controlled trials measuring outcomes important to patients are needed urgently to test different approaches and drugs for the management of type 2 diabetes.
- While waiting for the evidence, it makes sense to focus efforts and resources on lifestyle measures.
References
- Turin TC, Saad N, Jun M, et al. Lifetime risk of diabetes among First Nations and non-First Nations people. CMAJ. 2016; 188(16):1147-53. DOI:10.1503/cmaj.15078
- BC PharmaCare. New PharmaCare quantity limits for blood glucose test strips. BC PharmaCare Newsletter. 2014; 14(9): 3-6. http://www2.gov.bc.ca/assets/gov/health/health-drug-coverage/pharmacare/newsletters/news14-009.pdf
- Therapeutics Initiative. Management of type 2 diabetes. Therapeutics Letter. 1998; 23(Jan-Mar):1-4. http://ti.ubc.ca/letter23
- Therapeutics Initiative. Review & Update 1998. Therapeutics Letter. 1998; 27(Nov-Dec):1-2. http://ti.ubc.ca/letter27
- Therapeutics Initiative. New Drugs VI. Therapeutics Letter. 2000; 36(Jul-Aug):1-2. http://ti.ubc.ca/letter36
- Therapeutics Initiative. Glycemic targets in type 2 diabetes. Therapeutics Letter. 2008; 68(Jan-Feb):1-2. http://ti.ubc.ca/letter68
- Therapeutics Initiative. Self-monitoring of blood glucose in type 2 diabetes. Therapeutics Letter. 2011; 81(Apr-Jun):1-2. http://ti.ubc.ca/letter81
- Therapeutics Initiative. The limitations and potential hazards of using surrogate markers. Therapeutics Letter. 2014; 92(Oct-Dec):1-2. http://ti.ubc.ca/letter92
- Therapeutics Initiative. Questioning the basis of approval for non-insulin glucose lowering drugs. Therapeutics Letter. 2016; 100(May-Jun):1-2. http://ti.ubc.ca/letter100
- Montori VM, Fernandez-Balsells M. Glycemic control in type 2 diabetes: Time for an evidence-based about-face? Ann Intern Med. 2009; 150(11):803-8. DOI: 10.7326/0003-4819-150-11-200906020-00008
- Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ. 2011; 343:d4169. DOI: 10.1136/bmj.d4169
- Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ. 2011; 343:d7995. DOI: 10.1136/bmj.d7995
- Boussageon R, Gueyffier F, Cornu C. Metformin as first-line treatment for type 2 diabetes: are we sure? BMJ. 2016;352:h6748. DOI: 10.1136/bmj.h6748
- Rodriguez-Gutierrez R, Montori VM. Glycemic control for patients with type 2 diabetes mellitus: Our evolving faith in the face of evidence. Circ Cardiovasc Qual Outcomes. 2016. 9(5):504-12. DOI: 10.1161/CIRCOUTCOMES.116.002901
- Makam AN, Nguyen OK. An evidence-based medicine approach to antihyperglycemic therapy in diabetes mellitus to overcome overtreatment. Circulation. 2017; 135(2):180-95. DOI: 10.1161/CIRCULATIONAHA.116.022622
- Lipska KJ, Krumholz H. Viewpoint: Is hemoglobin A1C the right outcome for studies of diabetes? JAMA. 2017; Published Online: January 26, 2017.
DOI: 10.1001/jama.2017.0029
Peter Teitelbaum
Posted at 09:33h, 15 MarchConflict of Interest Disclosure: Dr. Peter Teitelbaum has no conflicts of interest to disclose.
I’ve long considered that oral agents for type 2 diabetes were likely of little or no benefit to my patients. The remarkable lack of evidence of clinical benefit in the literature supports that. I am happy to see your latest report stating this possibility/likelihood clearly.
Amrish
Posted at 08:39h, 17 MarchConflict of Interest Disclosure: Dr. Amrish Joshi is an MD with a family practice background working in British Columbia and has no conflicts of interest to disclose.
It would be interesting to see how many of the ‘glucocentric’ studies are sponsored by drug companies. Call me sceptical, but I have always felt a drug company push to prescribe in the setting of type II Diabetes.
Thomas L. Perry MD, FRCPC (Chair, Education Working Group, UBC TI)
Posted at 21:01h, 21 MarchConflict of Interest Disclosure: Dr. Perry is a member of the Therapeutics Initiative and his completed Conflict of Interest Disclosure form is posted on the TI web site. Dr. Perry has served as a consultant for the plaintiff litigation team in several class action litigations in the United States and Canada. Dr. Perry has not received any benefit from a pharmaceutical company since 1997 (travel to a meeting to consider recruiting patients for a large RCT) and has never received any other financial support from any pharmaceutical company.
Most studies have been sponsored by one drug manufacturer. Exceptions include UKPDS, ACCORD, and VADT. Recent trials (e.g. empagliflozin, liraglutide) compare the sponsor’s drug against placebo; however in both groups a relatively low A1C target is sought. This requires that in the control (“placebo”) group more patients receive insulins, sulfonylureas, and other glucose-lowering drugs. It raises the possibility that the apparent benefit on mortality or cardiovascular outcomes seen in some recent large RCT could reflect any of:
a) benefit exclusively due to the new drug;
b) harm exclusively due to insulins and other older glucose-lowering drugs (e.g. sulfonylureas);
c) a combination of a and b;
d) other factors unknown which may become apparent over time, or if an attempt to replicate the trials is made
So long as the glucocentric paradigm dominates clinical trial design as well as clinical practice, RCT will not compare new drugs with “no drug treatment” or with “conservative drug treatment”, or with “aggressive exercise and diet treatment”, etc.
This is a personal comment. As a group, TI has not felt that we have sufficient understanding of recent trials to be confident what they really mean.
Virendra
Posted at 11:48h, 20 MarchConflict of Interest Disclosure: Dr. Virendra Sharma has no conflicts of interest to disclose.
In the conclusion it is mentioned that “While we await the trial evidence, it is rational to emphasize lifestyle measures in these patients: weight loss, low carbohydrate diets and exercise”. When we say low carbohydrate diets, does that mean low simple carbohydrates diet or it includes both simple and complex carbohydrates? Thanks.
Thomas L. Perry MD, FRCPC (Chair, Education Working Group, UBC TI)
Posted at 21:05h, 21 MarchConflict of Interest Disclosure: Dr. Perry is a member of the Therapeutics Initiative and his completed Conflict of Interest Disclosure form is posted on the TI web site. Dr. Perry has served as a consultant for the plaintiff litigation team in several class action litigations in the United States and Canada. Dr. Perry has not received any benefit from a pharmaceutical company since 1997 (travel to a meeting to consider recruiting patients for a large RCT) and has never received any other financial support from any pharmaceutical company.
We are not experts on evidence about diet. UKPDS advised a “high carbohydrate diet” for mostly overweight or obese British people when commencing the trial in 1977. This now appears anachronistic. Other readers of Letter 103 may wish to post comments referring readers to scientific references bearing on whether there is a meaningful difference between consumption of simple vs. complex carbohydrates, or other dietary evidence. Any references bearing on clinically important outcomes (even weight) would be more compelling than references to studies showing small differences in surrogate measures such as fasting glucose of A1C.
If you wish to comment further, please remember to submit your conflict of interest disclosure on an ICMJE form PDF, easily available on the internet.
William Acosta
Posted at 11:55h, 20 MarchConflict of Interest Disclosure: Dr. William Daniel Acosta Naranjo reports personal fees from Merck Serono, AstraZeneca, NovoNordisk, Sanofi and Roche.
About 27 TL: The UKPDS trial was designed and showed benefit for glycaemic control with improvement in chronic complications. Sub analysis about medications must be interpreted with caution. The conclusion was: “The primary outcome, any of 21 diabetes related endpoints, was significantly reduced by intensive treatment, 35.3% v 38.5%, ARR = 3.2%, NNT = 31 for 10 yrs. This difference was predominantly due to reduction in the microvascular complication, retinopathy requiring photocoagulation. Cardiovascular events were not significantly reduced; there was a trend towards reduction in total MI, 14.2% v 16.3%, p=0.052.”
About 100 TL: The author´s conclusion was: “Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality. Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events.”
About 2009: Endocrinologists from the Mayo Clinic concluded: “Once clinicians and patients have set an HbA1c Target, which is often an iterative process, they need to decide how to achieve the target. Because we cannot confidently distinguish the relative effectiveness of different diabetes medications in reducing complications, we recommend basing their selection on such factors as burden of administration and side effects.”
About 2011: A systematic review by Boussageon, focused only on cardiovascular outcomes, not evaluating microvascular complications, showed: “the overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death.”
About 2011 BMJ comment: This affirmation is false. This conclusion doesn’t align with the conclusion in the summary. The true conclusion is: there is some evidence that glycaemic control reduces only microvascular complications of diabetes, and has no effect on mortality, and may even increase mortality. Current guidelines all over the world address individualized treatment which MUST be based on the balance of harms/benefits from therapy which MUST be based on lifestyle changes plus anti-diabetic drugs (when needed).
Finally, the term “hypoglycaemic drug” must not to be used, because most of the drugs do not cause hypoglycaemia but normoglycaemia.
Thomas L. Perry MD, FRCPC (Chair, Education Working Group, UBC TI)
Posted at 18:07h, 06 AprilConflict of Interest Disclosure: Dr. Tom Perry, Dr. Cait O’Sullivan and Dr. Aaron Tejani are members of the UBC Therapeutics Initiative. Their Conflict of Interest Disclosures are posted on the TI website. They have no conflicts of interest to report.
Editor’s note: Thank you for the comment. As it is detailed and complex, we have responded separately to each paragraph. – Cait O’Sullivan PharmD, Aaron Tejani PharmD, Tom Perry MD.
Dr. Acosta: About 27 TL: The UKPDS trial was designed and showed benefit for glycaemic control with improvement in chronic complications. Sub analysis about medications must be interpreted with caution. The conclusion was: “The primary outcome, any of 21 diabetes related endpoints, was significantly reduced by intensive treatment, 35.3% v 38.5%, ARR = 3.2%, NNT = 31 for 10 yrs. This difference was predominantly due to reduction in the microvascular complication, retinopathy requiring photocoagulation. Cardiovascular events were not significantly reduced; there was a trend towards reduction in total MI, 14.2% v 16.3%, p=0.052.”
TI Response: Yes, we agree that reporting subgroups warrants caution. As discussed in Therapeutics Letter 103, we (and most others) emphasized the reportedly beneficial subgroup (metformin) and disregarded the possibly harmful subgroup (addition of metformin to sulfonylurea).
Dr. Acosta: About 100 TL: The author´s conclusion was: “Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differences for all-cause mortality and cardiovascular mortality. Targeting intensive glycaemic control seemed to reduce the risk of microvascular complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events.”
TI Response: Yes, Therapeutics Letter 100 outlines these findings from the 2013 Cochrane systematic review. The review authors explain that the microvascular composite outcome includes both severe and less severe complications (eg, surrogate outcomes) making it difficult to decipher the clinical relevance of a 1% absolute risk reduction attributable to intensive glycaemic control. They write: “There is a need for more powerful RCTs with low risk of bias to guide the choice of targeting intensive versus conventional glycaemic control in patients with T2D.”
Reference: 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]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008143.pub3/full
Dr. Acosta: About 2009: Endocrinologists from the Mayo Clinic concluded: “Once clinicians and patients have set an HbA1c Target, which is often an iterative process, they need to decide how to achieve the target. Because we cannot confidently distinguish the relative effectiveness of different diabetes medications in reducing complications, we recommend basing their selection on such factors as burden of administration and side effects.”
TI Response: Yes, and given the absence of high quality evidence that tight glycaemic control in asymptomatic persons reduces the risk of major morbidity or mortality, they write: “Policymakers who want to use HbA1c as a performance measure should use an upper limit, such as an HbA1c level greater than 9%, to indicate possibly inadequate care, rather than one that would invite clinicians to ignore patient burden, context, and goals (for example, HbA1c level <7%).”
Reference: Montori VM, Fernandez-Balsells M. Glycaemic control in type 2 diabetes: Time for an evidence-based about-face? Ann Intern Med. 2009; 150(11):803-8.
Dr. Acosta: About 2011: A systematic review by Boussageon, focused only on cardiovascular outcomes, not evaluating microvascular complications, showed: “the overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death.”
TI Response: One of the Therapeutics Initiative researchers (Dr. J.M. Wright) was a co-author of this meta-analysis titled “Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes”. The primary endpoints included: all cause mortality and death from cardiovascular causes. Secondary endpoints included: myocardial infarction, stroke, congestive heart failure, photocoagulation, retinopathy, visual deterioration or blindness, neuropathy, renal failure, peripheral vascular events, amputation, and severe hypoglycaemia.
Reference: Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ. 2011; 343:d4169. DOI: 10.1136/bmj.d4169
Dr. Acosta: About 2011 BMJ comment: This affirmation is false. This conclusion doesn’t align with the conclusion in the summary. The true conclusion is: there is some evidence that glycaemic control reduces only microvascular complications of diabetes, and has no effect on mortality, and may even increase mortality. Current guidelines all over the world address individualized treatment which MUST be based on the balance of harms/benefits from therapy which MUST be based on lifestyle changes plus anti-diabetic drugs (when needed).
TI Response: a) We cannot find the alternative conclusion you interpreted from the BMJ 2011 analysis “The idolatry of the surrogate”.
Reference: Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ. 2011; 343:d7995. DOI: 10.1136/bmj.d7995
TI Response: b) “Current guidelines all over the world address individualized treatment which MUST be based on the balance of harms/benefits from therapy which MUST be based on lifestyle changes plus anti-diabetic drugs (when needed).”
The effect of individualizing glucose targets and using glucose lowering medications to achieve these targets in persons without symptoms of hyperglycaemia is not known. From the 2013 Cochrane systematic review referenced in Therapeutics Letter 100: “Current evidence from randomised clinical trials is insufficient to conclude if individualisation of glycaemic targets is superior to either intensive glycaemic control or conventional glycaemic control in patients with T2D.” Given this, how would one engage patients in shared decision making if the harms and benefits of this approach remain impossible to estimate?
Reference: 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]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008143.pub3/full
Dr. Acosta: Finally, the term “hypoglycaemic drug” must not to be used, because most of the drugs do not cause hypoglycaemia but normoglycaemia.
TI Response: Therapeutics Letter 103 did not use the term “hypoglycaemic drug”. However, in the context of pursuing glycaemic targets in asymptomatic persons as recommended in clinical practice guidelines, it is not possible to estimate accurately the risk of severe hypoglycaemia (or lack of risk) attributable to each glucose lowering medication. This is especially true because patients are often prescribed 2 or more glucose lowering medications at a time. The 2013 Cochrane systematic review estimated the risk of severe hypoglycaemia attributable to tight glycaemic control at RR 2.18, 95%CI 1.53 to 3.11; ARI 3.5%. The backbone therapies used in these intensive glucose lowering trials were principally: metformin, sulfyonylureas, and insulin. This makes it difficult to interpret the applicability of any reported benefits (microvascular) or harms (severe hypoglycaemia, serious adverse events) with respect to newer glucose lowering medications. We do not feel confident of our ability to interpret the results of more recent large RCTs of these drugs given the imbalance between groups in the percentage of patients who received insulin and sulfonylureas (SU). The paradigm of seeking particular A1C targets leads to greater exposure to insulin and SU in the control (“placebo”) arms of recent trials with DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors.
Reference: 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]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008143.pub3/full
J. Lance De Foa, MD
Posted at 22:09h, 13 AprilI have a potential conflict, in that my RuralMed posting was quoted in the media release.
The “Glucocentric” approach is less what is misguided than the ” pharmacocentric” approach. A1c is a mediocre screening tool at best affected by red blood cell longevity, impaired fasting glucose and/or impaired glucose tolerance, and the “guidelines” suggest 75 g 2h OGTT is the appropriate response to an elevated result. I have collected OGTT & Fasting Insulin data on nearly 100 patients in the past 12 months. I have a few with multiple readings showing progressively reduced FBS, 2h, A1c, insulin, waist, weight and often BP. Some are on no meds due to intolerance. All are using low starch/sugar healthy fat diets with some element of intermittent fasting. What is needed is a paradigm and name change. All hormones have their deficiency and excess syndromes, like Cushing’s & Addison’s. Why should insulin be approached any differently. Just as Hypothyroidism (formerly ” Cretinism”) has Thyrotoxicosis, so we have AnInsulinHaemia [archaic spelling!] and Insulin-Toxicosis. (That beta cell failure is a very late phase was handily shown by Reaven in 1976. In that same paper he indicates the awareness that “Adult – onset DM” patients had ELEVATED insulin-like activity was first documented in about 1936, when a Mr. Hitler began distracting the world, and insulin was still freshly extending lives. So the focus needs to shift to reducing the toxic insulin levels, and away from A1c. Adding additional insulin is certainly misguided. My patients with elevated lead & mercury levels won’t get healthy by drinking contaminated water and eating contaminated fish or inhaling contaminated wood smoke. Q.E.D. as the “Queen’s Golden Words” used to say.