novel antidiabetics: should they be used at all - and in whom? prof. christoph a. meier dept. of...
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Novel Antidiabetics:Should they be used at all -
and in whom?Prof. Christoph A. Meier
Dept. of Medicine & Specialities
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Challenges in themanagement of T2DM
• many patients
• many complications
• many (new!) drugs
• many dollars (particularly for new drugs)
• intenisve marketing
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obesity
genesinsulin-
resistanceeuglycemic
hyperinsulinemia
relative cellfailure
genes,environement
Fasting hyperglycemia,glucotoxicityT2DM
Pathogenesis & treatmentof T2DM
glitazones
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Mode of action of gliatzonesrosiglitazone, pioglitazone
PPAR
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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%
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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
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Sir Karl Popper
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"The difference between the amoeba and Einstein is that ...
he consciously searches for his errors in the hope of learning
..."
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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?
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obesity
genesinsulin-
resistanceeuglycemic
hyperinsulinemia
relative cellfailure
genes,environement
Fasting hyperglycemia,glucotoxicityT2DM
Pathogenesis & treatmentof T2DM
metformin
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Metformin: mode of action
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Metformin: The REACH Registry
Arch Intern Med 170: 1892
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obesity
genesinsulin-
resistanceeuglycemic
hyperinsulinemia
relative cellfailure
genes,environement
Fasting hyperglycemia,glucotoxicityT2DM
Pathogenesis & treatmentof T2DM
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Drugs targeting the -cell• sulfonylureas• glinides
• GLP-1(incretins)
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GLP-1 as an "incretin"
Endocrine Rev 33: 187f J Clin Invest. 46:1954-1962.
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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)
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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
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DPP inhibitors
GLP-1other GI-hormonesCytokinesChemokines
degradation
DPP-4 DPP-8DPP-9
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Nature Rev Endo 8: 728
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Nature Rev Endo 8: 728
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Lancet 375: 1447f
HbA1c -1% DPP4i, -1.5% GLP-anlg
HbA1c -0.8 kg DPP4i, -3 kg GLP-analogue
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Lancet 373: 438f
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Lancet 375: 1447f
Nausea during Rx with DPP-4i or GLP-1 analogs
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No outcome date for GLP-1 analogs or DPP-4 inhibitors!
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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
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NEJM 358: 580f
death
cv-events
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Safety?
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Nature Rev Endocrinology 8: 728
GLP-1 receptors are abundant
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Lancet 380: 475f
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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)
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JAMA Intern Med 173: 539f
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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)
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Novel antidiabetic drugs
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Sodium-GLucose coTransporter 2
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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
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Take Home Message I
Be a (economically) responsible prescriber
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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)
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Take Home Message II
Be a conservative prescriber(particularly in patients with
chronic disorders)
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Current ADA/EASD guidelines for the Rx of T2DM
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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
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Take Home Message III
Be a holistic prescriber
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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
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Don't be an amoeba...
... learn from errors
Be a critical & intelligent prescriber
Take Home Message V