Unmasking the evidence of efficacy and safety. Cheaper or Better DEBATE (pros) Panagiotis Halvatsiotis

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1 Unmasking the evidence of efficacy and safety. Cheaper or Better DEBATE (pros) Panagiotis Halvatsiotis 2 nd Department of Internal Medicine Research Unit & Diabetes Center of Athens University Medical School University General Hospital«Attikon»

2 Disclosures No Conflict of Interest

3 Diabetes Mellitus in USA

4 DM in USA Financial Burden Diabetes Care 2014; 37:

5 "Ambulatory Treatment of Type 2 Diabetes Mellitus " ambulatory diabetes visits increased from 23 million in 1997 to 35 million in However, fell slightly to 31 million in 2012 biguanide increased from 24 % in 1997 to 53 % of treatment visits in continuous decline in SU use from 61% in 1997 to 22 % in Diabetes Care, Nov 2013

6 "Ambulatory Treatment of Type 2 Diabetes Mellitus " glitazone medications increased from 6% of treatment visits in 1997 to 41% in 2005, but declined to 16% in The amount of money spent on medications increased 61% 2008 & 2012, which was driven mostly by the use of insulin glargine & DPP-4 inhibitors. Diabetes Care, Nov 2013

7 Projected prevalence of cancers, diabetes, coronary heart disease stroke, per of the population by 2030 by country. doi: /bmjopen BMJ Open : Laura Webber, Diana Divajeva, Tim Marsh, et al. interventions: a modelling study countries and the impact of effective diseases in the 53 WHO Europe

8 GENERICS EXIST FOR Sulfonylureas Metformin Glitazones α-glucosidase inhibitors Meglitinides Old fashioned insulins

9 NEW ORAL AGENTS in DM2 DPP-4 inhibitors SGLT-2 inhibitors

10 DPP-4 inhibitors DM2 Insulin Glucose Reduced incretin effect Reduced islet function hyperglycemia Glucagon DPP-4 inhibition Insulin Glucose Increased indogenous incretin effect Increased islet function Glucagon Improved glycemia DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus Adapted from Unger RH. Metabolism. 1974; 23: ; Ahrén B. Curr Enzyme Inhib. 2005; 1:

11 SGLT-2 inhibitors

12 Can you cure my diabetes doc! YES, we have now government approved guidelines (Roy Taylor, Newcastle UK)

13 Beyond Compliance Is Adherence Does the patient follows prescription? Source: National Association of Chain Drug Stores, Pharmacies: Improving Health, Reducing Costs, July Based on IMS Health data]

14 Beyond Compliance Is Adherence Reasons to deviate?

15 Non Adherence Consequencies in DM2 Gibson et al, Am J Manag Care 2010, 16(7):

16 Non Adherence Cost Less compliance fortifies financial burden for the health provider?

17 REASONS FOR NON ADHERENCE CONCERNS FOR IN DM2 1. Hypoglycemia 2. BW increase 3. Cardiovascular Risk Hauber et al, Diabet Med 26: , 2009

18 Emergeny hospitalisations for Adverse Drug Reactions Amongst population > 64 years Annual estimated ER visits Emergency hospitalization Budnitz et al. N Engl J Med 2011; 365:21.

19 Emergency Hospitalizations for Adverse Drug Effects in Older Americans

20 National Trends in US Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries, 1999 to Hospital admission rates for hypoglycemia now exceed those for hyperglycemia JAMA Intern Med May 17. doi: /jamainternmed

21 Hypoglycemia Admissions University General Hospital «Attikon» Diabetics>65 yo 158 (325) 49,1% Neurological Symptoms 23,6% Infection 3,6% Stroke 3,6% CVD 3,6% Kidney Failure 5,5% Neoplasms COPD- Liver Failure. 4 Deaths

22 Mortality at 1 st month (%) Glycemia & Mortality Intensive Cardiac Unit % *Thrombolysis P< % 4.3% 3.2% 2.5% < >199 n=62 n=123 n=280 n=186 n=200 n=196 Blood Sugar(mg/dL) 8.7% Pinto DS, et al. J Am Coll Cardiol. 2005;1:

23 Low Blood Sugar May Affect Heartbeat All volunteers monitored with a continuous glucose monitor for 5 days, as well as a 12-lead Holter monitor for heart activity. Overall, recorded 1,258 hours of time with normal blood sugar levels, 65 hours with high and 134 hours of low blood sugar The risk of a slow heart rate was 8 times higher when blood sugar was low at night compared to normal. Heller et al Diabetes Care 2014

24 GLUCOSE VARIABILITY PRE VILDAGLIPTIN POST PRE GLIMEPIRIDE POST

25 Heart Failure, Saxagliptin and Diabetes Mellitus: Observations from the SAVOR - TIMI 53 Randomized Trial saxagliptin treatment was associated with an increased risk for hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, prior heart failure, or chronic kidney disease Circulation Sep 4.

26 HYPOGLYCEMIA according to medication Dashed & dotted SU Solid: idpp4 Diabetes Ther DOI /s y

27 Hypoglycemia & Quality of Life Insomnia Circadian rhythm alterations Increased FBG for safety

28 The Gladiator Diet How to eat, exercise, and die a violent death "Gladiators needed subcutaneous fat, to be protected from cut wounds and shields nerves and blood vessels in a fight. Not only would a lean gladiator have been dead meat, he would have made for a bad show. Surface wounds look more spectacular Karl Grossschmidt The London Times 12/15/02

29 Financial Burden due to increased BW in DM2 Annual health burden due to the increased BW p<0.006 Increased BW Stable BW Total Health Cost Diabetes Cost Increased BW 1% Increased health cost 3,1% (213 USD) Yu et al, Current Med Res Opin 23(9): , 2007

30 Weight loss & BG Effect of BW loss on FBG in obesity with DM2 J Am Coll Nutrition. 2003;22(5):

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32 β cell & insulin resistance

33 islets-obesity-diabetes Butler et al, 2003 Diabetes 52: Post mortem autopsies

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35 «SMART» THERAPEUTIC MEANS EFFICATIOUS SPECIFIC TARGET ADVERSE EVENTS PLEIOTROPIC EFFECT WELLCOMED

36 FDA.Aprooved

37 GUIDELINES????

38 GUIDELINE LIMITATIONS What is best for patients overall, as recommended in guidelines, may be inappropriate for individuals Should be shared decision making, not ignoring patients preferences

39 GUIDELINE LIMITATIONS Perspective may be recommended: to help control costs serve societal needs protect special interests (those of doctors, or politicians)

40 PHARMACEUTICAL EXPENSE FOR DM2 Laiko, Nikea, Tzanio Liatis et al, Exp Clin Endo Diab 117:505-10, 2009

41 PHARMACEUTICAL EXPENSE Liatis et al, Exp Clin Endo Diab 117:505-10, 2009

42 CONCLUSION newer medication : less frequent dosing less invasive delivery systems fewer side effects

43 LOOKING FOR HOPE Drug evolution is not revolutionary but establishes in a very low pace Blind controversy due to financial issues delays research and cancels the investigation of new ideas

44 FUNDAMENTALS DIET & EXERCISE