#96: Diabetes: A1C targets & ACP guidelines controversy

May 21, 2018 | By Matthew Watto, MD

Get schooled on hemoglobin a1c targets in type 2 diabetes by American College of Physicians guidelines coauthor, Devan Kansagara MD MCR, Associate Professor of Medicine, Oregon Health Sciences University. We summarize outcomes from the landmark diabetes trials (ACCORD, ADVANCE, VADT, UKPDS 33 & 34), how a1c targets effect microvascular and macrovascular events, estimating life expectancy, and how to personalize diabetes control for your patients. We’re proud to announce our new partnership with the ACP to provide free CME credit and MOC points on select episodes of The Curbsiders. ACP members can visit acponline.org to redeem free CME/MOC credit.

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Credits:
Written, produced, and edited by: Matthew Watto MD.
Hosts: Stuart Brigham MD, Paul Williams MD, Matthew Watto MD.
Guest: Devan Kansagara MD, MCR

Clinical Pearls

1. Microvascular complications such as albuminuria (ADVANCE), need for retinal photocoagulation (UKPDS 33) can be prevented with long term control of DM2, though the clinical significance of these outcomes is controversial (Circ Cardiovasc Qual Outcomes 2016)
2. Early initiation of metformin after diagnosis of DM2 reduces MI, and all cause mortality at median 10.7 years (UKPDS 34) and persists at 20 years when compared to diet alone.
3. Intensive therapy (for up to 11 years) with insulin, sulfonylureas and other early generation hypoglycemic agents does not prevent macrovascular complications of death, CV death, nonfatal stroke (VADT, ACCORD, ADVANCE, UKPDS 33), but seems to confer a small 15% relative risk reduction for nonfatal MI (Circ Cardiovasc Qual Outcomes 2016). The ACCORD trial found an increase in all cause mortality.
4. Ten year follow up to VADT and UKPDS showed an emerging risk reduction in cardiovascular events despite similar glucose levels in the treatment and control groups suggesting “metabolic memory” or a “legacy effect” of early intensive therapy.
5. Bottom line: Intensive glucose control with early generation hypoglycemic agents (excludes metformin and newer agents e.g. GLP-1, DPP4i, SGLT2i) carries risk of weight gain, hypoglycemia and possibly increased mortality (ACCORD trial) without prevention of clinically important macrovascular and microvascular endpoints like death, CV death, nonfatal stroke, renal failure, blindness, and neuropathy (VADT, ACCORD, ADVANCE, UKPDS 33).
6. Clinical inertia: It goes both ways. Clinicians should consider both intensifying and deintensifying therapy as part of personalized diabetes care plans. –Dr Williams and Dr Kansagara’s opinions.
7. EMPA-REG Trial (empagliflozin), CANVAS Trial (canagliflozin), and Leader Trial (liraglutide): Each of these randomized placebo controlled trials in patients with DM2 at “high risk for CV events” showed lower incidence of primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke with empagliflozin, canagliflozin, and liraglutide.

ACP Guidance Statements: HbA1C Targets for Glycemic Control w/Pharmacologic Therapy for Nonpregnant Adults with Type 2 Diabetes Mellitus (DM2):

Guidance Statement 1: Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients’ preferences, patients’ general health and life expectancy, treatment burden, and costs of care.

Guidance Statement 2: Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes.

Guidance Statement 3: Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%.

Guidance Statement 4: Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.

In-depth Show Notes

Summary and links to five landmark trials of intensive control vs standard therapy in DM2

1. VA Diabetes trial VADT NEJM 2009: Mostly men, mean 60 yo w/mean A1C 9.4%. Goal absolute A1C reduction by 1.5% in intensive arm w/maximal doses of metformin + rosiglitazone or glimepiride. Insulin added if A1C remained above 6%. Standard group started the same drugs at half maximal dose. Insulin added if A1C remained above 9%. At median 5.6 years follow up no difference in primary outcome of major adverse cardiac events (MACE). No difference was seen in microvascular outcomes. Ten year follow up VADT showed 8.6 fewer MACE per 1000 person years, but no increased survival and no significant difference for individual cardiac events (see supplementary appendix).
2. ACCORD NEJM 2008: Multicenter, double-blinded, RCT w/N=10,251 targeting A1C <6% in intensive vs 7-7.9% in standard group. Stopped 17 months early after mean 3.5 years follow-up due to increased mortality w/intensive therapy. Also found increased hypoglycemia, and weight gain >10 kg. Used metformin, sulfonylureas, glinides, TZDs, alpha glucosidase inhibitors, insulin, and even incretins.
3. ADVANCE NEJM 2008: Multinational trial N= 11,140 w/mean baseline A1C 7.5%. Found a reduction in “nephropathy”, but not retinopathy, MACE, or mortality from any cause. In median 5 years follow up, achieved mean A1C <6.5% in intensive vs 7.3% in standard group using  sulfonylureas as base therapy, plus a combination of metformin, insulin, TZDs, acarbose and glinides.
4. UKPDS 33 The Lancet 1998: RCT with 10 year follow up of 3,867 patients newly diagnosed with DM2 given intensive therapy (sulfonylurea or insulin) to achieve a goal fasting plasma glucose (FPG) under 108 mg/dL, vs standard therapy with diet alone. Intensive group achieved A1C 7% vs 7.9 % in standard group. An absolute reduction of 5.1 events per 1000 patient years for the primary composite outcome of “any diabetes related endpoint” (death, MACE, or microvascular complications) was driven by decreased need for retinal photocoagulation. No reduction in macrovascular complications or mortality. Adverse effects of hypoglycemia and weight gain were seen in intensive arm (insulin > sulfonylurea). Note: Used older insulin agents and sulfonylureas not commonly used today.
5. UKPDS 34 The Lancet 1998: Multiple trials wrapped in one, but main RCT included 753 overweight patients with newly diagnosed DM2 given metformin vs standard therapy w/diet alone achieved median A1C 7.4% vs 8% respectively over a median follow-up of 10.7 years. They observed an absolute reduction of 13.5 events per 1000 patient years (29.8 vs 43.3) for the primary composite outcome of “any diabetes related endpoint”. A significant absolute reduction “all-cause mortality” of 7.1 per 1000 patient years (13.5 vs 20.6) and myocardial infarction of 7 per 1000 patient years (11 vs 18) was also observed. Metformin was also superior to intensive therapy with early generation insulin and sulfonylurea. These outcomes persisted after an additional 10 years of follow up (Holman RR, et al. NEJM 2008). Note: Less than 2% were on ASA and statin at baseline.

Estimating life expectancy: Consider the ‘surprise question’, “Would you be surprised if this patient died within one year or less?”, which has a negative predictive value of 94% for death within 12 months (White et al BMC Med 2017). Life expectancy is likely <10 years if advanced age (80 years or older), residence in a nursing home, or chronic conditions such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure (ACP HbA1C Statement 2018)

Patient-centered outcomes: The 2018 winner of NephMadness was “Patient-reported outcome measures” with the argument that patients don’t care about proteinuria. They care about symptoms, quality of life, and hard clinical endpoints like blindness, need for dialysis, painful neuropathy, MI, stroke, and death. Clinically relevant endpoints should supplant surrogate markers of end-organ damage in future diabetes trials.  -Dr Watto’s opinion

About the newer Agents for diabetes:

EMPA-REG Trial (empagliflozin), CANVAS Trial (canagliflozin), and Leader Trial (liraglutide): Each of these randomized placebo controlled trials in patients with DM2 at “high risk for CV events” showed lower incidence of primary composite outcome of death from CV causes, nonfatal MI, or nonfatal stroke with empagliflozin, canagliflozin, and liraglutide. Of note, possible increased risk lower extremity amputations in canagliflozin group. “High risk for CV events” was based on objective CAD, PAD, prior CV events (MI, stroke, revascularization) or age and other risk factors (Supplementary appendix to EMPA-REG, CANVAS, Leader). It’s interesting that these patients (in general) had baseline A1C >8%, established CVD, longstanding (>5 years) diabetes, were already taking statins, and/or metformin at trial entry, but still had a mortality benefit in median 3-4 years follow-up. Differences in A1C between treatment and placebo groups were small implying mortality benefit was not conferred purely by glucose lowering. -Dr Watto’s opinion.

Goal: Listeners will determine the risks and benefits of intensive glucose control and whether Hemoglobin A1C (HbA1C) is an appropriate target for treatment.

Learning objectives:
After listening to this episode listeners will…

1. Develop personalized goals for their patients with type 2 diabetes
2. Counsel patients on duration of therapy needed to prevent microvascular complications
3. Recall that intensive glucose control does not reliably prevent macrovascular complications.
4. Explain the potential harms and patient burden of more intense glucose control
5. Decide which patients might benefit from an A1C outside the range of 7-8%
6. Estimate life expectancy and identify groups who do not warrant strict HbA1C targets

Disclosures: Dr Kansagara and The Curbsiders report no relevant financial disclosures.

Time Stamps
00:00 Announcement
00:48 Disclaimer and intro
03:11 Getting to know our guest: one liner, book recommendation, mentorship
06:50 How and why did ACP write their guidance statement on diabetes, A1C targets
09:18 Landmark trials in type 2 diabetes
11:36 Does tight control prevent micro or macrovascular complications
13:20 Trials of newer agents like SGLT2i, GLP-1 and DPP4i
14:33 How do ACP’s guidelines differ from other published guidelines
17:20 Quick recap of landmark trial findings
22:24 Personalizing glycemic control
24:30 Controversy over an A1C goal of 7-8%
28:05 Clinical inertia
30:26 Legacy effect and metabolic memory
34:00 Deintensifying therapy
38:29 Life expectancy and comorbid conditions
43:15 Performance measures in diabetes
44:42 Take-home points
46:30 The Curbsiders recap and give some closing remarks
49:13 Outro

Links from the show:

1. Lincoln in the Bardo: A Novel by George Saunders
2. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA, et al. Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians. Ann Intern Med. 2018;168:569–576. doi: 10.7326/M17-0939
3. ADA is “Deeply Concerned” by the ACP’s guideline statement
4. Major Medical Associations Feud over guidelines NPR story
5. Five landmark diabetes trial summaries from Wiki Journal Club: UKPDS 33; UKPDS 34; ACCORD; VADT; ADVANCE (these pages link out to PubMed & full text PDFs).
6. Zheng SL, Roddick AJ, Aghar-Jaffar R, et al. Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes A Systematic Review and Meta-analysis. JAMA. 2018;319(15):1580–1591. doi:10.1001/jama.2018.3024
7. Cates’ Plot for visualizing data http://www.nntonline.net/visualrx/cates_plot/
8. VA/DoD guidelines pocketcard. See Figure 3 for Cates’ plot on preventing microvascular complications
9. Glycemic control and vascular complications in type 2 diabetes by McCulloch DK et al. UpToDate.com accessed May 8, 2018.
10. Ten year follow up VADT by Hayward et al NEJM 2015.
11. Study finding 26% of older patients had tight control with high risk agents. Use of Intensive Glycemic Management in Older Adults with Diabetes Mellitus by Arnold SV et al J Am Geriatr Soc 2018
12. (EMPA-REG) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes NEJM 2015
13. (CANVAS) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes NEJM 2017
14. Marso, SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. NEJM 2016; 375:311-322 DOI: 10.1056/NEJMoa1603827