Novel Antidiabetics:Should they be used at all -

and in whom?Prof. Christoph A. Meier

Dept. of Medicine & Specialities

Challenges in themanagement of T2DM

• many patients

• many complications

• many (new!) drugs

• many dollars (particularly for new drugs)

• intenisve marketing

obesity

genesinsulin-

resistanceeuglycemic

hyperinsulinemia

relative cellfailure

genes,environement

Fasting hyperglycemia,glucotoxicityT2DM

Pathogenesis & treatmentof T2DM

glitazones

Mode of action of gliatzonesrosiglitazone, pioglitazone

PPAR

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

Efficacy of pioglitazone

• 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)

Efficacy of rosiglitazone

• lowers HbA1c by about 1%

BMJ 342: d1309

Sir Karl Popper

"The difference between the amoeba and Einstein is that ...

he consciously searches for his errors in the hope of learning

..."

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?

obesity

genesinsulin-

resistanceeuglycemic

hyperinsulinemia

relative cellfailure

genes,environement

Fasting hyperglycemia,glucotoxicityT2DM

Pathogenesis & treatmentof T2DM

metformin

Metformin: mode of action

Metformin: The REACH Registry

Arch Intern Med 170: 1892

obesity

genesinsulin-

resistanceeuglycemic

hyperinsulinemia

relative cellfailure

genes,environement

Fasting hyperglycemia,glucotoxicityT2DM

Pathogenesis & treatmentof T2DM

Drugs targeting the -cell• sulfonylureas• glinides

• GLP-1(incretins)

GLP-1 as an "incretin"

Endocrine Rev 33: 187f J Clin Invest. 46:1954-1962.

Lancet 368:1696f (2006)

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 380: 475f

Reduction of hypoglycemia7% for linagliptine vs 34% for sulfonylureas

Weight loss-1.4 kg for linagliptine+1.3 for sulfonylureas

HbA1C 1%for linagliptin & sulfonylurea

DPP inhibitors

GLP-1other GI-hormonesCytokinesChemokines

degradation

DPP-4 DPP-8DPP-9

Nature Rev Endo 8: 728

Nature Rev Endo 8: 728

Lancet 375: 1447f

HbA1c -1% DPP4i, -1.5% GLP-anlg

HbA1c -0.8 kg DPP4i, -3 kg GLP-analogue

Lancet 373: 438f

Lancet 375: 1447f

Nausea during Rx with DPP-4i or GLP-1 analogs

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

NEJM 358: 580f

Glucose (HbA1c <6.5%) & lipids (TC <4.5 mmol/L) & blood pressure (<130/80) treated according to standards of careusing metformin, sulfonylureas & insulin.

No fancy new diabetes drugs (0% glitazone use)

ASS, statins & ACE-I used in 90-100%

STENO-2

NEJM 358: 580f

death

cv-events

Safety?

Nature Rev Endocrinology 8: 728

GLP-1 receptors are abundant

Lancet 380: 475f

GLP-1-based Rx & pancreatitis

JAMA Intern Med 173: 534f

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: 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 dapagliflozinUTI 8% 8-13%Genital infection 5% 12-15%

BMC Medicine 11: 43f

Take Home Message I

Be a (economically) responsible prescriber

Comparative U.S. prices (per month) for add-on therapies to metformin• Glimepiride US$ 4

• Glinides US$ 105-280

• Gliptins US$ 240

• Liraglutide US$ 300

• Canagliflozin US$ 263

60x moreexpensive!

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

1. when diet fails, use a tablet

2. the tablet should probably be metformin

3. when this fails, use something else

Take Home Message III

Be a holistic prescriber

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

Don't be an amoeba...

... learn from errors

Be a critical & intelligent prescriber

Take Home Message V