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

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

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

Mode of action of gliatzones rosiglitazone, pioglitazone PPARg

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

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

Sir Karl Popper

"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 ..."

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?

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

Metformin: mode of action

Metformin: The REACH Registry Arch Intern Med 170: 1892

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

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

GLP-1 as an "incretin" Endocrine Rev 33: 187f J Clin Invest. 46:1954-1962.

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)

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

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

Nature Rev Endo 8: 728

Nature Rev Endo 8: 728

HbA1c -1% DPP4i, -1.5% GLP-anlg Lancet 375: 1447f HbA1c -1% DPP4i, -1.5% GLP-anlg HbA1c -0.8 kg DPP4i, -3 kg GLP-analogue

Lancet 373: 438f

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

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

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 90-100% NEJM 358: 580f

NEJM 358: 580f death cv-events

Safety?

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

Lancet 380: 475f

GLP-1-based Rx & pancreatitis use of GLP-1-based Rx w/i last 30d OR 2.2 (1.4-3.7) 20d – 2y OR 2.0 (1.4-3.2) JAMA Intern Med 173: 534f

JAMA Intern Med 173: 539f

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)

Novel antidiabetic drugs

Sodium-GLucose coTransporter 2

SGLT-2 – Efficacy & Adverse effects HbA1c lowering by 0.5 - 0.8% dehydration increased creatinin & potassium uro-genital infections placebo dapagliflozin UTI 8% 8-13% Genital infection 5% 12-15% BMC Medicine 11: 43f

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

Comparative U.S. prices (per month) for add-on therapies to metformin Steno-2 Glimepiride US$ 4 Glinides US$ 105-280 Gliptins US$ 240 Liraglutide US$ 300 Canagliflozin US$ 263 no outcome data 60x more expensive! The Medical Letter 55: 37 (May 13th, 2013)

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

Current ADA/EASD guidelines for the Rx of T2DM

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

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

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) - 2.6 mmmol/L

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