1. Novel Antidiabetics: Should they be used at all - and in whom?
Prof. Christoph A. Meier Dept. of Medicine & Specialities

2. Challenges in the management of T2DM
many patients
many complications
many (new!) drugs
many dollars (particularly for new drugs)
intenisve marketing

3. Pathogenesis & treatment of T2DM
euglycemic hyperinsulinemia
insulin- resistance
obesity
glitazones
genes, environement
relative  cell failure
Fasting hyperglycemia, glucotoxicity
T2DM

4. Mode of action of gliatzones rosiglitazone, pioglitazone
PPARg

5. Risks & adverse effects of pioglitazone
Efficacy of pioglitazone
lowers HbA1c by about 1%
Risks & adverse effects of pioglitazone
heart failure (HR 1.4; JAMA 298: 1180)
osteoporosis (RR 1.7; Diab Care 31: 845)
bladder cancer (+5 / 100'000 p-y; Ferwana, Diab Med 2013 in press)
others: weight gain, fluid retention

6. Risks & adverse effects of rosiglitazone
Efficacy of rosiglitazone
lowers HbA1c by about 1%
Risks & adverse effects of rosiglitazone
Myocardial infarction (OR 1.16 vs. pio)
heart failure (OR 1.22 vs. pio)
osteoporosis (RR 1.7; Diab Care 31: 845)
overall mortality (RR 1.14 vs. pio)
BMJ 342: d1309

8. Sir Karl Popper

9. "The difference between the amoeba and Einstein is that
"The difference between the amoeba and Einstein is that ... he consciously searches for his errors in the hope of learning ..."

10. Do you treat blood sugars ... or patients?
Seduced by surrogates
- surrogate end-points (e.g. blood sugar!)
- nice mechanisms
- just because it's new
.... amplified by marketing
Do you treat blood sugars ... or patients?

11. Pathogenesis & treatment of T2DM
euglycemic hyperinsulinemia
insulin- resistance
obesity
metformin
genes, environement
relative  cell failure
Fasting hyperglycemia, glucotoxicity
T2DM

12. Metformin: mode of action

13. Metformin: The REACH Registry
Arch Intern Med 170: 1892

14. Pathogenesis & treatment of T2DM
euglycemic hyperinsulinemia
insulin- resistance
obesity
genes, environement
relative  cell failure
Fasting hyperglycemia, glucotoxicity
T2DM

15. Drugs targeting the b-cell
sulfonylureas
glinides
GLP-1 (incretins)

16. GLP-1 as an "incretin" Endocrine Rev 33: 187f
J Clin Invest. 46:

17. DPP-4 inhibitors (gliptins)
endogenous GLP-1 is very rapidly inactivated by the DiPeptidylPeptidase 4
inhbitors of DDP-4 prolong the half-life of GLP-1 (alo-, lina-, saxa-, sita-, vildagliptin)
Lancet 368:1696f (2006)

18. D HbA1C 1% for linagliptin & sulfonylurea
Lancet 380: 475f
D HbA1C 1% for linagliptin & sulfonylurea
Reduction of hypoglycemia
7% for linagliptine vs 34% for sulfonylureas
Weight loss
-1.4 kg for linagliptine
+1.3 for sulfonylureas

19. DPP inhibitors GLP-1 other GI-hormones Cytokines Chemokines
DPP-8 DPP-9
GLP-1 other GI-hormones
Cytokines
Chemokines
degradation

20. Nature Rev Endo 8: 728

21. Nature Rev Endo 8: 728

22. HbA1c -1% DPP4i, -1.5% GLP-anlg
Lancet 375: 1447f
HbA1c -1% DPP4i, % GLP-anlg
HbA1c kg DPP4i, kg GLP-analogue

23. Lancet 373: 438f

24. Nausea during Rx with DPP-4i or GLP-1 analogs
Lancet 375: 1447f

25. No outcome date for GLP-1 analogs or DPP-4 inhibitors!

26. No fancy new diabetes drugs (0% glitazone use)
STENO-2
Glucose (HbA1c <6.5%) & lipids (TC <4.5 mmol/L) & blood pressure (<130/80) treated according to standards of care using metformin, sulfonylureas & insulin.
No fancy new diabetes drugs (0% glitazone use)
ASS, statins & ACE-I used in %
NEJM 358: 580f

27. NEJM 358: 580f
death
cv-events

28. Safety?

29. GLP-1 receptors are abundant
Nature Rev Endocrinology 8: 728

30. Lancet 380: 475f

31. GLP-1-based Rx & pancreatitis
use of GLP-1-based Rx w/i last 30d OR 2.2 ( )
20d – 2y OR 2.0 ( )
JAMA Intern Med 173: 534f

32. JAMA Intern Med 173: 539f

33. When to use DPP-4 inhibitors (in 2013 with no longterm data available
3rd oral agent after metformin and sulfonylureas, when the patient refuses insulin
patients with renal failure, who decline insulin
elderly patients to avoid insulin & hypoglycemia
patients with increased incidence of hypoglycaemia (see e.g. ACCORD trial)

34. Novel antidiabetic drugs

35. Sodium-GLucose coTransporter 2

36. SGLT-2 – Efficacy & Adverse effects
HbA1c lowering by %
dehydration
increased creatinin & potassium
uro-genital infections
placebo dapagliflozin
UTI 8% %
Genital infection 5% %
BMC Medicine 11: 43f

37. Be a (economically) responsible prescriber
Take Home Message I
Be a (economically) responsible prescriber

38. Comparative U.S. prices (per month) for add-on therapies to metformin
Steno-2
Glimepiride US$ 4
Glinides US$
Gliptins US$ 240
Liraglutide US$ 300
Canagliflozin US$ 263
no outcome data
60x more expensive!
The Medical Letter 55: 37 (May 13th, 2013)

39. Take Home Message II
Be a conservative prescriber (particularly in patients with chronic disorders)

40. Current ADA/EASD guidelines for the Rx of T2DM

41. Evidence-based Pharmacotherapy of T2DM in 2014
when diet fails, use a tablet
the tablet should probably be metformin
when this fails, use something else

42. Be a holistic prescriber
Take Home Message III
Be a holistic prescriber

43. Standards of Care (ADA)
Take Home Message IV
... diabetes is not only about sugar!
Standards of Care (ADA)
HbA1c <7.0 (- 8.0 in elderly)
BP < 140 / <80 mmg
LDL <(1.8) mmmol/L

44. Be a critical & intelligent prescriber
Take Home Message V
Be a critical & intelligent prescriber
Don't be an amoeba...
... learn from errors