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
genes
obesity
insulinresistance
euglycemic
hyperinsulinemia
glitazones
genes,
environement
relative  cell
failure
T2DM
Fasting hyperglycemia,
glucotoxicity
Mode of action of gliatzones
rosiglitazone, pioglitazone
PPARg
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
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 ...
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?
Pathogenesis & treatment
of T2DM
genes
obesity
insulinresistance
euglycemic
hyperinsulinemia
metformin
genes,
environement
relative  cell
failure
T2DM
Fasting hyperglycemia,
glucotoxicity
Metformin: mode of action
Metformin: The REACH Registry
Arch Intern Med 170: 1892
Pathogenesis & treatment
of T2DM
genes
obesity
insulinresistance
euglycemic
hyperinsulinemia
genes,
environement
relative  cell
failure
T2DM
Fasting hyperglycemia,
glucotoxicity
Drugs targeting the -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
Lancet 368:1696f (2006)
• inhbitors of DDP-4 prolong the half-life of
GLP-1 (alo-, lina-, saxa-, sita-, vildagliptin)
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
DPP-4
GLP-1
other GI-hormones
Cytokines
Chemokines
DPP-8
DPP-9
degradation
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
Nausea during Rx with DPP-4i or GLP-1 analogs
Lancet 375: 1447f
No outcome date for GLP-1 analogs or DPP-4 inhibitors!
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
20d – 2y
OR 2.2 (1.4-3.7)
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
UTI
Genital infection
placebo
8%
5%
dapagliflozin
8-13%
12-15%
BMC Medicine 11: 43f
Take Home Message I
Be a (economically) responsible prescriber
• Glinides
US$ 105-280
• Gliptins
• Liraglutide
US$ 240
US$ 300
no outcome data
• Glimepiride US$ 4
Steno-2
Comparative U.S. prices (per month)
for add-on therapies to metformin
60x more
expensive!
• Canagliflozin US$ 263
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
Take Home Message V
Be a critical & intelligent prescriber
Don't be an amoeba...
... learn from errors