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Glycemie medicatie bij type 2 diabetes: anno 2015
Dr. Frank Nobels Endocrinologie-Diabetologie OLV Ziekenhuis, Aalst-Asse-Ninove
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glycemie verlagers •
metformine
•
sulfonylureum
•
glinide
•
acarbose
•
glitazone
•
DPP-4 inhibitor
•
SGLT2 inhibitor
•
GLP-1 analoog
•
insuline
… en combinaties
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ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140
patiëntgericht
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Metformine blijft 1ste keuze • goedkoop • geen hypoglycemie • geen gewichtstoename • reduceert microvasculaire complicaties (UKPDS) • reduceert macrovasculaire complicaties (UKPDS) • overbelast de b-cel niet • geen glycemie zelfcontrole nodig olv
• (cave nierfunctie)
Metformine: cave • gastro-intestinale neveneffecten (1 op 20) - op volle maag - langzaam opbouwen
• oppassen voor lactaatacidose (zeer zeldzaam) - dosis aanpassen bij nierinsufficiëntie - niet bij onstabiele hartdecompensatie, COPD, cirrhose - stop tijdelijk in alle acute situaties
(cave deshydratatie + slechte nierfunctie + ACE-i/ARB, NSAID)
- stop tijdelijk 24 u voor iv-contrast en voor heelkunde
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Nathan D et al. Diabetes Care 2009;32:193–203 Shaw J et al.Diabet Med 2007;24:1160–1163 Herrington W, Levy J. Int Urol Nephrol 2008;40:411–417
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DM2 op metformine • 48 j • obees, metabool syndroom • metformine 850 mg 1-1-1 • HbA1c (%) 7,2 ® 7,8 ® 8,6 • nierfunctie nl • dyslipidemie, hypertensie • taxichauffeur
DM2 op metformine • 71 j • licht obees • metformine 850 mg 1-1-1 • HbA1c (%) 7,2 ® 7,8 ® 8,6 • nierfunctie nl • dyslipidemie, hypertensie • alleenstaand, maar nog erg actief
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metformine + … •
sulfonylureum / glinide
•
glitazone
•
DPP-4 inhibitor
•
SGLT2 inhibitor
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Sulfonylurea • goedkoop • geen hypoglycemie • geen gewichtstoename • reduceert microvasculaire complicaties (UKPDS) • reduceert macrovasculaire complicaties (UKPDS) • overbelast de b-cel niet • geen glycemie zelfcontrole nodig • (cave nierfunctie) olv
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Mortaliteit: secretagogen « metformine
All Danish residents .20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years)
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Danish Registry. Schramm T et al. European Heart Journal 2011;32:1900–1908
Glitazones: neveneffecten • gewichtstoename • vochtretentie ® hartdecompensatie • meer coronaire events en mortaliteit met rosiglitazone? • atypische fracturen (distale BL en OL) • macula oedeem • (blaascarcinoom) olv
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DPP-4 inhibitoren (gliptines) + metformine - alogliptine:
Vipidia®
Vipdomet®
- linagliptine:
Trajenta®
Jentadueto®
- saxagliptine:
Onglyza®
Komboglyze®
- sitagliptine:
Januvia®
Janumet®
- vildagliptine:
Galvus®
Eucreas®
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www.bcfi.be
Incretine systeem • insulinesynthese • maaglediging ¯ • glucagonsecretie ¯ • glucose afhankelijke insulinesecretie -
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Metabolisme van GLP-1 Meal GLP-1 analoog
Intestinal GLP-1 release
Byetta, Lyxumia, Victoza, Bydurion (spuiten)
Active GLP-1
DPP-4 Januvia, Galvus, DPP-4 Onglyza, Trajenta, inhibitor Vipidia (tabletten)
GLP-1 inactive
Rothenberg P, et al. Diabetes 2000;49(suppl 1):A39 Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. olv
MF + sitagliptin « MF + glipizide
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Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9:194–205
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MF + sitagliptin « MF + glipizide hypoglycemia
50
Incidence (%)
Body weight (kg ± SE)
40
32% P<0.001
30
20
10
5% 0 Week 52 Glipizide + metformin Sitagliptin + metformin
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Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9:194–205
incretinetherapie en pancreatitis gelinkte medische en pharmaciedata van 786.656 pat, waarvan 38.615 DM (6545 op exenatide, 15.826 op sitagliptine)
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Garg R, et al. Diabetes Care 2010;33:2349
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incretinetherapie en pancreatitis gelinkte medische en pharmaciedata van 786.656 pat, waarvan 38.615 DM (6545 op exenatide, 15.826 op sitagliptine)
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Garg R, et al. Diabetes Care 2010;33:2349
DPP4i: cv events and heart failure • • •
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US commercial insurance claims data (2005–2012) propensity score-matched initiators of DPP4 versus non-DPP4i 79,538
Kim S, et al. Acta Diabetol 2014, online October 14
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SGLT2= Sodium-GLucose coTransporter-2
genetisch defect van SGLT2 ® benigne renale glucosurie
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SGLT2 inhibitie: verwachte (neven)effecten • goede nierfunctie nodig • glycemie ¯, HbA1c ¯ • weinig hypoglycemie • BD ¯ (natriurese, osmotische diurese) • gewicht ¯ (glucosurie, diurese) • urogenitale infecties (glucosurie) • veilig op lange termijn (‘benigne renale glucosurie’)
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Misra M. Journal of Pharmacy and Pharmacology 2013;65:317
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Sodium Glucose Co-Transporter (SGLT) Inhibitors Compound
Manufacturer
Development
Canagliflozin
Janssen
Approved in the EU & US Reimbursed in Belgium since 1 Dec 14
Dapagliflozin
Astra Zeneca
Approved in the EU & US
Empagliflozin
Boehringer Ingelheim, Lilly
Approved in the EU & US
Luseogliflozin
Taisho, Novartis
Approved in Japan
Tofogliflozin
Chugai, Kowa, Sanofi
Approved in Japan
*Other SGLT inhibitors are also in development.** Dual SGLT1/SGLT2 inhibitor
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Available at : www.clinicaltrials.gov.
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ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140
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The Renal Glucose Threshold (RTG) is increased in subjects with Type 2 Diabetes Below RTG minimal glucosuria occurs Urinary Glucose Excretion (g/day)
150
Above RTG glucosuria occurs
125 100 75
Healthy RTG
T2DM RTG
50
~180 mgl/dl
~240 mg/dl
25 0 60
100
140
180
220
260
300
Plasma Glucose (mg/dl) Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels RTG, renal threshold for glucose excretion. Polidori D et al. 2010. Abstract 2186-PO. American Diabetes Association. June 25-29, 2010; Orlando, Florida. Polidori D et al. 2010. Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden.
SGLT2 Inhibition Lowers RTG Urinary Glucose Excretion (g/d)
Below RTG minimal glucosuria occurs Above RTG glucosuria occurs
150 125
SGLT2i- SGLT2itreated treated healthy T2DM
100 75
Untreated T2DM
RTG
RTG
50
Untreated healthy
25 0
0
40
70
100
140
180
200
240
Plasma Glucose (mg/dl)
Canagliflozin decreases RTG to the levels that have low potential to cause hypoglycaemia SGLT2, sodium glucose co-transporter 2; RTG, renal threshold for glucose excretion; UGE, urinary glucose excretion. Polidori D et al. 2010. Abstract 2186-PO. Presented at. ADA 2010. Polidori D et al. 2010. Abstract 875. Presented at EASD 2010
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HbA1c change from baseline Placebo-controlled Phase 3 Studies Add-on combinations with Monotherapy Metformin (DIA3005) N =584
Placebo-subtracted LS Mean Change in HbA1c (%) (95% CI)
BL Mean HbA1c (%)
(DIA3006) N = 1284
8.0
7.9
SU
Met/SU
Met/Pio
Insulin
(DIA3008) N = 127
(DIA3002) N = 469
(DIA3012) N = 342
(DIA3008) N = 1718
8.4
8.1
7.9
All at 26 weeks except 18 weeks DIA3008 Insulin, SU sub-studies
8.3
* p<0.001 Based on ANCOVA models, data prior to rescue (LOCF)
Assessment report EMA/718531/2013
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Dapagliflozin Versus Sulfonylurea as Add-on to Metformin: Incidence of Hypoglycemia
•
The proportion of patients experiencing hypoglycemia was significantly lower with dapagliflozin than glipizide
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Nauck M, et al. Diabetes Care. 2011;34(9):2015–2022.
DAPA + MET
Glipizide + MET
ME732BE13NP01160 NS SK-2841-03-2013
Percent with 95% CI
P<0.0001
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Body weight percent change from baseline Placebo-controlled Phase 3 Studies Add-on combinations with Metformin
SU
Met/SU
Met/Pio
Insulin
(DIA3005) N =584
(DIA3006) N = 1284
(DIA3008) N = 127
(DIA3002) N = 469
(DIA3012) N = 342
(DIA3008) N = 1718
86.8
87.2
83.0
92.8
94.1
97.0
Placebo-subtracted LS Mean % Change in Body Weight (95% CI)
BL Mean Weight (kg)
Monotherapy
*p
<0.001; † p <0.05 Based on ANCOVA models, data prior to rescue (LOCF)
Assessment report EMA/718531/2013 29
Summary of Systolic Blood Pressure Change from Baseline Placebo-controlled Phase 3 Studies
Add-on combinations with Monotherapy Metformin 127.7
(DIA3006) N = 1284
Pulse rate (bpm) LS mean change
SU
Met/SU
(DIA3008) N = 127
(DIA3002) N = 469
128.2
Placebo-subtracted LS Mean Change in Systolic BP (mmHg) (95% CI)
BL Mean SBP (mmHg)
(DIA3005) N =584
136.2
CANA 100 mg -1.33 -0.70
-0.95
-0.24
-4.03
-3.75
130.5
Met/Pio
Insulin
(DIA3012) N = 342
(DIA3008) N = 1718
127.2
137.8
CANA 300 mg -0.16
-0.53
1.02
-0.08
-1.11
-0.22
No clinically meaningful changes in pulse rate
Assessment report EMA/718531/2013
*p<0.001; **p<0.05
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Based on ANCOVA models, data prior to rescue (LOCF)
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Summary of Adverse Drug Reactions
≥2% in Four Placebo-controlled 26-week Studies (n=2313) Placebo N=646 (%)
CANA 100 mg N=833 (%)
CANA 300 mg N=834 (%)
Constipation
0.9
1.8
2.3
Thirst
0.2
2.8
2.3
Nausea
1.4
2.2
2.2
Polyuria or pollakiuria
0.8
5.3
4.6
Urinary tract infection (UTI)
4.0
5.9
4.3
Balanitis or balanoposthitis
0.6
4.2
3.7
Vulvovaginal candidiasis
3.2
10.4
11.4
Gastrointestinal Disorders
Renal and Urinary Disorders
Reproductive System Disorders
The most commonly reported AEs overall were vulvovaginal candidiasis, UTI and polyuria or pollakiuria. When CANA was used in combination with insulin or insulin secretagogues the most commonly reported AEs included hypoglycaemia
Janssen Briefing Materials for the January 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334551.pdf
Dapaglifozin: genital and urinary tract infections GTI
UTI
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Johnsson K, et al. J Diab Complic 2013 dx.doi.org/10.1016/j.jdiacomp.2013.04.012 en dx.doi.org/10.1016/j.jdiacomp.2013.05.004
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Genital mycotic infections: consideration and management Placebo N=646 %
CANA 100 mg N=833 %
CANA 300 mg N=834 %
Balanitis or balanoposthitis
0.6
4.2
3.7
Vulvovaginal candidiasis
3.2
10.4
11.4
Consideration
Management
Risk factors • History of GMI • More common in females than males
Conventional treatment Topical antifungal treatments either prescribed by a healthcare professional or self-treated while continuing therapy
Highest rate of occurrence observed during the first four months of treatment, followed by an attenuation in the rate of increase
Low discontinuation rate Only 0,7 % for men and 0,5% for women Majority: no recurrence after treatment
Invokana SmPC (Nov 2013) Available at: http://www.medicines.org.uk/emc/medicine/28400/SPC/Invokana+100+mg+filmcoated+tablets/#PRODUCTINFO
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individualiseren
•
metformine +
•
DPP-4 inhibitor of SGLT2 inhibitor
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nierinsufficiëntie ® DPP4i
MDRD sitagliptine vildagliptine saxagliptine linagliptine alogliptine (ml/min) (Januvia) (Galvus) (Onglyza) (Trajenta) (Vipidia) > 50
1x 100 mg
2x 50 mg
1x 5 mg
1x 5 mg
1x 25 mg
30-50
1x 50 mg
1x 50 mg
1x 2,5 mg
1x 5 mg
1x 12,5 mg
< 30
1x 25 mg
1x 50 mg
1x 2,5 mg
1x 5 mg
1x 6,25 mg
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onvoldoende controle met 2 OAD Jan is 50j. Hij heeft overgewicht. Hij slaagt er niet in om te vermageren. Hij neemt Metformine 850 mg 1-1-1 en Uni-Diamicron 60 mg 1,5. Hij heeft lang een A1c tussen 7 en 7.5% gehad, maar die is geleidelijk opgelopen tot 9,2%. Hij ziet erg op tegen spuitjes. Normale nierfunctie.
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onvoldoende controle met 2 OAD Jan is 76. Hij heeft licht overgewicht. Hij neemt Metformine 850 mg 1-0-1 en Uni-Diamicron 60 mg 1,5. Hij heeft lang een A1c tussen 7 en 7.5% gehad, maar die is geleidelijk opgelopen tot 9,2%. Hij ziet erg op tegen spuitjes. Normale nierfunctie. Hij is een maaglijder (makkelijk misselijk)
MF + SU + … • 3de OAD
= glitazone of DPP4i of SGLT2i
• GLP1 analoog • basale insuline
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Add-on to MET + SU vs DPP4 inhibitor: Change in HbA1c (LOCF) Triple therapy Baseline (%)
8.1
8.1
0.2
LS mean change (±SE) from baseline (%)
0 –0.2
LS mean change
–0.4 –0.6
–0.66%
–0.8
–0.37% (95% CI: –0.50, –0.25)
–1.0
–1.03%
–1.2 –1.4 0
6
12
18
26
34
42
52
Time point (wk)
CANA provided a greater reduction in HbA1c compared with SITA (upper limit of 95% CI < 0.0%) LOCF, last observation carried forward ; SITA, sitagliptin; CANA, Canagliflozin; LS, least squares; SE, standard error; CI, confidence interval. Adapted from Schernthaner G. et al. Data presented at EASD 2012 Berlin, Germany, (OP43) Schernthaner G et al. Diabetes Care. 2013 Apr 5. [Epub ahead of print]
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Add-on to MET + SU vs DPP-4 inhibitor: Percent Change in Body Weight (LOCF) Triple therapy
LS mean % change (±SE) from baseline
Baseline (kg) 1.0
89.6
87.6
0
LS mean % change 0.3% (0.1 kg)
40
–2.8% (–2.4 kg) P <0.001
–1.0
–2.0 –2.5% (–2.3 kg)
–3.0
–4.0 0
6
12
18
26
34
42
52
Time point (wk) LOCF, last observation carried forward; SITA, sitagliptin; CANA, Canagliflozin; LS, least squares; SE, standard error.
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Schernthaner G. et al. Poster presented at CODHy 2012 Barcelona, Spain, (P70). Schernthaner G et al. Diabetes Care. 2013 Apr 5. [Epub ahead of print]
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Metabolisme van GLP-1 Meal GLP-1 analoog
Intestinal GLP-1 release
Byetta, Lyxumia, Victoza, Bydurion (spuiten)
Active GLP-1
DPP-4 Januvia, Galvus, DPP-4 Onglyza, Trajenta, inhibitor Vipidia (tabletten)
GLP-1 inactive
Rothenberg P, et al. Diabetes 2000;49(suppl 1):A39 Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39. olv
GLP1 analogen - exenatide:
Byetta®
2x /d
- liraglutide:
Victoza®
1x /d
- lixisenatide:
Lyxumia®
1x /d
- exenatide LA: Bydurion®
1x /wk
- (albiglutide:
Eperzan®
1x /wk)
- (dulaglutide:
Trulicity®
1x /wk)
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Exenatide LA vs glargine MF ± SU HbA1c 8,3 ± 1,1 %
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Diamant M, et al. Lancet 2010;375:2234–43
Exenatide LA vs glargine
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Diamant M, et al. Lancet 2010;375:2234–43
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Exenatide LA vs glargine
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Diamant M, et al. Lancet 2010;375:2234–43
Exenatide LA vs glargine
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Diamant M, et al. Lancet 2010;375:2234–43
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GLP1 analogen product
naam
structuur
T½
eliminatie
frequentie
reconstitutie / naald
HbA1c ¯ vs lira
HbA1c ¯ vs sita
exenatide
Byetta
exendin-4 analoog
3-4u
renaal
2/d
- / dun
<
?
liraglutide
Victoza
humaan analoog ~ VVZ
11-13u
mutipel
1/d
- / dun
lixisenatide
Lyxumia
exendin-4 analoog
3-4u
renaal
1/d
- / dun
?
=
exenatide LA
Bydureon
exendin-4 analoog polymeer microsferen
steady-state 6-7 w
renaal
1/w
+ / dik
<
>
albiglutide
Eperzan
humane analoog ~albumine
5d
multipel
1/w
+ / dun
<
=
dulaglutide
Trulicity
2 humane analogen ~ IgG4 Fc fragment
5d
multipel
1/w
- / dun
=
>
>
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individualiseren
•
metformine + SU +
•
DPP4i of SGLT2 inhibitor of GLP1 analoog of insuline
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conclusies
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Anno 2015 • geïndividualiseerde aanpak • verschuiving naar nieuwe producten met beter profiel dan SU • DPP4i: effectief, meer en meer gerust over veiligheid • SGLT2i: effectief, ook bij gevorderde diabetes (maar niet bij nierinsufficiëntie), breed effect (G, BD) • GLP1a: meer en meer vóór insuline of in combinatie met basale insuline
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ADA-EASD position statement. Inzucchi S, et al. Diabetes Care 2015;38:140
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