1. Flawed transmission of the "Best Evidence": What should we know about the treatment of type 2 diabetes? David Slawson, MD University of Virginia Department of Family Medicine Allen F. Shaughnessy, PharmD Tufts University School of Medicine

2. Typical Flow of Information in Medicine Medical Research Published Results Summarized by Experts Review ArticlesContinuing Medical Education Clinicians Patient Care

3. Flow of Information from the UKPDS Results Selectively Presented by Experts Results of UKPDS Published Flawed Review Articles? Continuing Medical Education Clinicians Patient Care Based on Wrong/Incomplete Information

4. Brief Review of the United Kingdom Prospective Diabetes Study (UKPDS) 10.7-year study of 4,000 pts newly- diagnosed with type 2 diabetes Goal 1: Evaluate value of tight (<110 mg/dL) vs. loose (<270 mg/dL) control of blood glucose Goal 2: Evaluate value of tight (<150/85) vs. loose (<180/105) blood pressure control in diabetics

5. Uniqueness of the UKPDS Most significant study of the treatment of type 2 diabetes published in 25 years Only two other outcomes trials evaluating “real- world” patients University Group Diabetes Project (1975) Increased CV mortality in patients treated with tolbutamide “Black Box Warning” (widely ignored) Multifactorial intervention trial of 160 patients (Steno-2) Glucose, BP, lipid control, + ASA, ACE I, metformin (All of these were in favor of the intervention group) Decreased composite of CV death, MI, stroke, PVD Gaede P, et al. Effect of a multifactorial intervention on mortality in type 2 DM. NEJM 2008;358:580-91.

6. Findings of the UKPDS Tight glucose control Decreased diabetes-related outcomes (NNT = 196) Almost all of this benefit was on the decreased need for photocoagulation No effect on any single outcome, including visual loss Had no effect on mortality A1c changes did not correlate to outcomes (Stratton) In overweight patients, metformin Decreased mortality (NNT = 141) Decreased diabetes-related outcomes (NNT = 74) Independent of A1c

7. Findings of the UKPDS Tight blood pressure Decreased diabetes-related mortality (NNT = 152) Decreased diabetes-related outcomes (NNT = 61) No difference between b-blocker and ACE I In overweight patients, sulfonylurea drugs and insulin Had no effect on diabetes-related outcomes Had no effect on mortality

8. Results from the UKPDS (#33, comparing insulin for intensive vs conventional control)

9. 0.940.80 1.1 Benefit could be this high (20% decrease) Risk could be this high (10% increase) 95% C.I. Since the 95% CI crosses 1.0, the difference is not significant 1.0

11. Our study Identified 40 review articles written >1.5 years after publication of UKPDS results Journals Electronic Sources “Throwaways” Books Each article reviewed independently by 2 researchers masked to journal, author Each paper read to determine presence of 16 patient-oriented results from the UKPDS Agreed with each other 85.4% (phi = 0.622)

12. Study Results UKPDS Finding Reported in Review N (%) Tight glucose control did not prevent premature mortality 6 (15) In overweight patients, treatment with metformin decreased diabetes-related or all-cause mortality 7 (18) In overweight patients, metformin decreased diabetes-related outcomes 14 (35)

13. Study Results UKPDS finding Reported in Review N (%) Tight blood pressure control decreased diabetes-related mortality 10 (25) Tight blood pressure control decreased complications 17 (43) Control of blood pressure had a greater effect on complications than blood glucose control 5 (13) In overweight pts, insulin or sul- fonylureas: no effect on outcomes 0

14. Recommendations Not Based on the UKPDS Findings Recommendation Reported in Review N (%) Blood glucose monitoring necessary 30 (75) Drugs without outcomes data recommended as first line 15 (38) Meds with an equiv. effect on A1c have an equivalent effect on complications/ outcomes 7 (18)

15. Health Information Websites Google and Altavista search engines Random sample of 66 sites 56%- tight blood pressure control important 18%- important benefit of metformin 2%- no benefit of tight control or insulin/sulfonylureas More POEMs- non commercial sites Gimenez-Perez G, et al. Diabetic Med 2005;22:688-92

16. Why the Discrepancy? The UKPDS is dense and difficult to read Over 50 papers written Major results published in 4 papers = 20 pages How many reviewers read the original studies? Paul Simon: “Still a man sees what he wants to see and disregards the rest” “People would rather be deceived than have the truth create anxiety” ADA statement published 2 months after the major papers Ignored, misrepresented many of the results Much written before the results were available Template for many reviewers?

17. Who Should Write Reviews? Study of 36 review articles using 10 criteria for determining rigor Overall rating of rigor: Experts correlation = 0.23 Non-experts correlation = 0.78  expertise of writer = stronger prior opinion  less time spent on review  lower quality Study of quality of 40 review articles on type 2 DM Ave. score 1/15; best score 5/15; UpToDate = 2/15 Experts – should do research Non-experts – should write reviews due to less bias Oxman AD, Guyatt GH. The science or reviewing research. Ann N Y Acad Sci 1993;703:125-33. Shaughnessy AF, Slawson DC. What happened to the valid POEMs? A survey of review articles on the treatment of type 2 diabetes. British Medical Journal 2003;327:266-9.

18. Conclusions Review articles/health care websites on diabetes can’t be trusted Many reviews do not focus on POEMs (Patient-Oriented Evidence that Matters) Instead, many reviews feature PROSE (Prescriptive Recommendations based On Substandard Evidence)

19. Gold Standard: Valid POEM or PROSE? “… All individuals with type 2 diabetes have insulin resistance. Insulin resistance is the problem. Metformin (and insulin and sulfonylureas) treats only the symptom of hyperglycemia. Therefore, the thiazolidinediones should be used as the very first-line agent...” J Fam Pract 2002;51:984 “… This apparent ability of TZDs to rejuvenate beta-cells is a compelling reason to use these agents as initial therapy for type 2 diabetes.” Am J Med. 2003 Dec 8;115 S8A:20S-23S. Where else do we use PROSE instead of valid POEMs to guide “best practice? Is our current system of information transfer flawed?

20. Clinical Question: Is there a relationship between cancer-related mortality and treatments for type 2 diabetes mellitus? Bottom Line: Death due to cancer seems to be more prevalent in patients with type 2 diabetes treated with either insulin or a sulfonylurea than in patients treated with metformin (Glucophage). It may be that hyperinsulinemia increases cancer risk, or that metformin is protective. Another explanation could be that, although cancer is related to certain medication use, it is not caused by their use. We need a controlled study to answer these questions. (LOE = 2b)(LOE = 2b) Reference: Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29:254-58. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29:254-58. Perhaps it is true that insulin/sulfonylureas reduce diabetes related deaths, but is over all death increased 2 nd to cancer?

21. Recent type 2 DM studies ACCORD. NEJM 2008;358:2545-59 Stopped early due to increased mortality in intensive control (HBA1C<6) group ADVANCE. NEJM 2008;358:2560-72 Reduced microvascular but not major macrovascular events Strong benefit to treating hypertension

22. Highly Controlled Research  Randomized Controlled Trials  Systematic Reviews Physiologic Research Preliminary Clinical Research  Case reports  Observational studies Uncontrolled Observations & Conjecture Effect on Patient-Oriented Outcomes  Symptoms (drivers license)  Functioning (visual loss)  Quality of Life (leg ulcer)  Lifespan Effect on Disease Markers  Diabetes (photocoagulation, GFR, NCV)  Arthritis (x-ray, sed rate)  Peptic Ulcer (endoscopic ulcers) Effect on Risk Factors for Disease  Improvement in markers (blood pressure, HbA1C, cholesterol) Valid Patient- Oriented Evidence Validity of Evidence Relevance of Outcome

23. Highly Controlled Research  Randomized Controlled Trials  Systematic Reviews Physiologic Research Preliminary Clinical Research  Case reports  Observational studies Uncontrolled Observations & Conjecture Effect on Patient-Oriented Outcomes  Symptoms (drivers license)  Functioning (visual loss)  Quality of Life (leg ulcers)  Lifespan Effect on Disease Markers  Diabetes (Photocoagulation, GFR, NCV)  Arthritis (x-ray, sed rate)  Peptic Ulcer (endoscopic ulcer) Effect on Risk Factors for Disease  Improvement in markers (blood pressure, HBA1C, cholesterol) SORT A Validity of Evidence Relevance of Outcome SORT B SORT C

24. Information Mastery Method Medical Research Published Results evaluated by Information Masters Cochrane Reviews Clinical Evidence Essential Evidence Valid POEMs Evidence-Based CME Clinicians Highest Quality Patient Care

25. Conclusions Imagine your hand: thumb = smoking; pointer = BP control; tall man = lipids (LDL<100 or lower), ring man = metformin and ? aspirin; pinky = blood sugar control Thumb>pointer>tall man>ring man>pinky; pinky = ? benefit at all. Most reverse order! Law of diminishing return, fallacy of division Don’t do the “Keflex-Reflex”! Wisdom is the individual application of knowledge

26. Smoking Blood pressure Cholesterol Metformin/?ASA Glucose control? Lending a Hand to Patients with Type 2 Diabetes Slawson DC, Shaughnessy AF. Lending a Hand to Patients with Diabetes. Data from: Vijan S. Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals, choice of agents, and setting priorities in diabetes care. Ann Intern Med 2003; 138:593-602.

27. “Mundus Vult Decipi” (The world wishes to be deceived) -We would rather be deceived than have the truth cause anxiety- -Caleb Carr, “Killing Time”

28. Insulin: When all else fails. Holman RR, et al. NEJM 2007;357:1716-30 708 adults with type 2 DM, HbA1C 7%-10%, on maximal metformin and sulfonylurea RCT: 1) 2x daily biphasic insulin (NovoMix 30); 2) 3 x daily preprandial insulin (NovoRapid); 3) 1x daily basal insulin (Levemir) at bedtime Follow-up 1 year

29. Insulin: When all else fails. At 1 year, basal insulin group least improvement in HbA1C (0.8% vs 1.3 % for biphasic and 1.4% for prandial). Basal also fewest patients with final HbA1C < 7.0% (increased mortality in ACCORD)

30. Insulin: When all else fails. However (DOE vs POEM)….. Basal group least amount of moderate to severe hypoglycemia (48% vs 77% (biphasic) vs 90% (prandial); NNTH=3;2) MOST IMPORTANT (UKPDS/ACCORD correlation with mortality):...

31. Insulin: When all else fails. Increased Weight (?mortality) Basal- 1.9 kg Biphasic- 4.7 kg Prandial- 5.7 kg Also waist circumference : 2 cm (basal) vs 4 cm (both)

32. Insulin: When all else fails. BOTTOM LINE: Once daily basal insulin at bedtime. Strongly consider stopping sulfonylurea but continuing metformin.