Earlier Use of Combination Therapy in the Management of Type 2 Diabetes
李美月 內分泌新陳代謝內科 小港醫院
Ideal Anti-hyperglycemia Agent DIABETES Decrease mortality and morbidity Insulin sensitivity Application Beta cell protection Efficacy Type of DM Efficiency ( cost and pleiotrophic effect) Safety and Side Effects
DCCT/EDIC: glycaemic control reduces the risk of nonfatal MI, stroke or death from CVD in type 1 diabetes
HbA1C (%)
9 Conventional treatment 8 Intensive treatment 7 0 Cumulative incidence of non-fatal MI, stroke or death from CVD
1
2
3
4
5
6
7
8
DCCT (intervention period
0.06
9
10
11 12 13 14 15 16 17 EDIC (observational follow-up)
57% risk reduction in non-fatal MI, stroke or CVD death* (P = 0.02; 95% CI: 12–79%)
0.04
0.02
Years
Conventional treatment Intensive treatment
0.00 0
1
2
3
4
5
6
7
8
DCCT (intervention period) DCCT. N Engl J Med 1993; 329:977–986. Med 2005; 353:2643–2653.
ON-SL-TW130406-1304 DCCT/EDIC.(28/Mar/2013 N Engl J MAR2015-ONGL-TW-13056
9 10 11 12 13 14 15 16 17 18 19 20 21 EDIC (observational follow-up) Years
Meta-analysis: improved glucose= reduction in macrovascular events Meta-analysis of randomized clinical trials: conventional vs intensive interventions Macrovascular T1DM (8 randomized studies) T2DM (6 randomized studies)
Combined Combined Incidence Incidence Any Any macrovascular macrovascular event event T1DM T1DM 0.38 0.38 (95% (95% CI, CI, 0.26–0.56) 0.26–0.56) T2DM T2DM 0.81 0.81 (95% (95% CI, CI, 0.73–0.91) 0.73–0.91)
Cardiovascular T1DM (8 randomized studies) T2DM (6 randomized studies)
Peripheral vascular T1DM (8 randomized studies) T2DM (6 randomized studies)
Cerebrovascular T1DM (8 randomized studies) T2DM (6 randomized studies)
T1DM N = 1800 T2DM N = 4472 Stettler C et al. Am Heart J. 2006;152:27–38.
0.1 0.2
0.5
1
2
10
Incidence ON-SL-TW130534-1305
4
4
Why do β-cells fail? Chronic hyperinsulinaemia
Glucotoxicity
Oxidative stress
Lipotoxicity (e.g. FFA) Adipokines and cytokines (IL-6, TNF alpha)
ER stress HIAPP oligomer toxicity Reduced gene transcription (epigenetics)
Chronic hyperamylinaemia
Apoptosis 73 2H
ER, endoplasmic reticulum; FFA, free fatty acids; HIAPP, human islet amyloid polypeptide; IL-6, interleukin 6; TNF, tumour necrosis factor. Boden G, Shulman GI. Eur J Clin Invest 2002;32:14‒23; Finegood DT, Topp BG. Diabetes Obes Metab 2001;3:20–7; Haataya L, et al. Endocrine Rev 2008;29:303‒16. 2008; 6 Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
100-year history of antihyperglycaemic therapeutics SGLTSGLT-2 inhibitor BromocriptineBromocriptine-QR
Number of classes of antihyperglycaemic agents
Bile acid sequestrant DPPDPP-4 inhibitor GLPGLP-1 receptor agonist Amylinomimetic Glinide
Basal insulin analogue
Thiazolidinedione Human insulin
Phenformin Sulphonylurea IntermediateIntermediate-acting insulin
Phenformin withdrawn
Soluble insulin
Year UGDP, DCCT and UKPDS studies.
AlphaAlpha-glucosidase inhibitor RapidRapid-acting insulin analogue Metformin
Options for Antidiabetic Treatment Insulin Resistance
Metformin Pioglitazone
Insulin Secretion
Glucose independent
Sulfonylurea Glinides Exogenous Insulin SGLT2-Inhibitors (Dapagliflozin, Canagliflozin, Empagliflozin)
Glucose dependent DPP-4 Inhibitors (Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin)
GLP-1 Mimetics (Exenatide, Liraglutide)
Inhibition of Glucose Resorption
Îą-Glucosidase Inhibitors (Acarbose, Miglitol, Voglibose)
Linagliptin: Mechanism of action Glucose-dependent insulin secretion β-cells
Food intake Pancreas
Increases glucose utilisation by muscle and adipose tissue
α-cells Glucose-dependent glucagon suppression
Intestine
Active GLP1 (7-36)
Linagliptin
Decreases hepatic glucose release improving overall glucose control
Inactive GLP1 (9-36) amide
DPP4
2 amino acids cleaved from amino terminus
DPP4, dipeptidyl peptidase 4; GLP1, glucagon-like peptide 1. Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12:87–100. Ahrén B. Curr Diab Rep. 2003;3:365–372.
Linagliptin increases active GLP1 and reduces glucagon levels in a glucose-dependent manner Active GLP-1 levels after 28 days of treatment after MTT intake Geometric mean (SE) over time, pmol/L
Glucagon levels after 28 days of treatment after MTT intake Geometric mean (SE) over time, pg/mL
Linagliptin Placebo
Linagliptin Placebo 130 120
25
Test meal administration
Plasma glucagon (pg/mL)
Plasma intact GLP1 (pmol/L)
30
20 15 10
100 90 80
5
75
0
60 0.0
0.5
1.0
1.5
2.0
2.5
Time (hours)
At peak, active GLP1 levels are ~ 2.5-fold higher in linagliptin group compared with placebo
3.0
Test meal administration
110
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Time (hours)
The AUC is reduced by 10% for linagliptin compared with placebo (-18.7 pg/h/mL placebo-adjusted change from baseline for linagliptin at Day 28)*
AUC, area under the curve; GLP1, glucagon-like peptide 1; MTT, meal tolerance test ; SE, standard error. *Baseline AUC 182.1 pg/h/mL. Rauch T, et al. Diabetes Ther. 2013;3:10.
Linagliptin has a very low rate of renal excretion Metabolism
Absorption Tablet intake: 5 mg once daily, independent of food
Absolute bioavailability: ~ 30%, with or without food
~ 10% (inactive) metabolite
~ 90% transferred unchanged
~ 95% bound to plasma proteins (in essence, DPP4)*
Excretion†
~ 95% of orally administered linagliptin is excreted via the bile and gut
~ 5% of orally administered linagliptin is excreted via the kidneys
DPP4, dipeptidyl peptidase 4. *Protein binding is concentration-dependent: 99% at 1 nmol/L to 75–89% at ≥ 30nmol/L, Trajenta® US prescribing information. †At steady state. Note that label statement describes single-dose analyses that do not add up to 100% (a common effect for this type of analysis): Following administration of an oral [14C]-linagliptin dose to healthy subjects, ~ 85% of the administered radioactivity is eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Tradjenta® US prescribing information. Boehringer Ingelheim Ltd. (Updated 22 May 2014).
Linagliptin is primarily excreted by the biliary system Share of renal excretion,* % Linagliptin1
No dose adjustment and/or no additional drug monitoring required
Sitagliptin2
Vildagliptin3
Saxagliptin4
Dose adjustment required in patients with renal impairment and/or drugrelated kidney monitoring
Alogliptin5
*Including metabolites and unchanged drug; excretion after single-dose administration of C14-labelled drug. 1. Tradjenta® US prescribing information. Boehringer Ingelheim Ltd. (Updated 22 May 2014). 2. Januvia® US prescribing information. MSD Ltd. (Updated 10 March 2015). 3. Galvus® EU summary of product characteristics. Novartis Pharmaceuticals. (Updated 28 November 2014). 4. Onglyza® US prescribing information. AstraZeneca Ltd. (Updated 24 May 2013). 5. Nesina® US prescribing information. Takeda Ltd. (Updated 15 August 2013).
Linagliptin: A DPP4 inhibitor with no need for dose adjustment, even in patients with renal impairment 2-fold increase in exposure Sitagliptin
Fold increase in exposure relative to normal renal function
Fold increase in exposure relative to normal renal function
Linagliptin
Creatinine clearance* (mL/min)
Normal
Mild
Moderate
Severe
ESRD
(n = 6) > 80
(n = 6) 50 to ≤ 80
(n = 6) 30 to ≤ 50
(n = 6) < 30
(n = 6) < 30 on HD
Renal impairment status
Normal Creatinine clearance* (mL/min)
Moderate
Severe
(n = 6) 30 to ≤ 50
(n = 6) < 30
ESRD (n = 6) on HD
Renal impairment status Vildagliptin (LAY151 metabolite)‡
Fold increase in exposure relative to normal renal function
Normal Creatinine clearance* (mL/min)
Mild (n = 6) 50 to ≤ 80
Fold increase in exposure relative to normal renal function
Saxagliptin (5-hydroxy saxagliptin metabolite)†
(n = 6) > 80
(n = 8) > 80
Mild
Moderate
(n = 8) (n = 8) > 50 to ≤ 80 > 30 to ≤ 50
Severe
ESRD
(n = 8) < 30
(n = 8) on HD
Normal
Mild
Moderate
Severe
Renal impairment status
Renal impairment status CI, confidence interval; DPP4, dipeptidyl peptidase 4; ESRD, end-stage renal disease; HD, haemodialysis. *Estimated creatinine clearance values were calculated using the Cockcroft–Gault formula. †90% CIs not available. ‡Patient numbers, 90% CIs and definitions of renal impairment according to creatinine clearance not available for vildagliptin. Graefe-Mody U, et al. Diabetes Obes Metab. 2011;13:939–946.
ESRD
Influence of hepatic impairment on pharmacokinetics: No dose adjustment of linagliptin in patients with hepatic impairment
Fold increase in exposure relative to normal hepatic function
Linagliptin exposure in patients with mild, moderate and severe hepatic impairment,* mean AUC Single dose 5 mg 1.00 Healthy (n = 8)
Mild (n = 7)
Moderate (n = 9)
Severe (n = 8)
Hepatic impairment group
Steady state† 1.00
Healthy (n = 8)
Mild (n = 7)
Moderate (n = 9) Severe‡ (n = 8)
Hepatic impairment group No dose adjustment for linagliptin is necessary for patients with mild, moderate or severe hepatic impairment AUC, area under the concentration curve. *Following Child–Pugh Classification. †Application of six oral doses of 5-mg linagliptin at 24-hour intervals. ‡Not measured; value estimated from single dose by pharmacokinetic modelling. Graefe-Mody U, et al. Br J Clin Pharmacol. 2012;74:75–85.
Demonstrated efficacy across complete range of diabetes therapies Linagliptin treatment effect across treatment lines Adjusted mean change from baseline HbA1c (%), placebo-corrected Monotherapy
Dual combination
Triple combination
Insulin
Initial combination therapies
OL: MET 1,000 mg BID*,8
BL HbA1c
11.8
-1.0
-2.0 p < 0.0001 for all studies vs baseline, for initial combination vs respective monotherapy OL arm (patients with poor glycaemic control at baseline)
-4.0
BID, twice daily; BL, baseline; HbA1c, glycosylated haemoglobin; MET, metformin; OL, open-label; SU, sulphonylurea. *24 weeks’ treatment duration. †18 weeks’ treatment duration. ‡12 weeks’ treatment duration. 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267. 2. Barnett AH, et al. Diabetes Obes Metab. 2012;14(12):1145–1154. 3. Kawamori R, et al. Diabetes Obes Metab. 2012;14:348–357. 4.Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74. 5. Lewin AJ, et al. Clin Ther. 2012;34:1909–1919.e15. 6. Owens DR, et al. Diabetic Med. 2011;28:1352-1361. 7. Yki-Järvinen H, et al. Diabetes Care. 2013;36:3875–3781. 8. Haak T, et al. Diabetes Obes Metab. 2012;14:565–575.
-3.7
HbA1c reductions sustained over 102 weeks with linagliptin monotherapy* Change from baseline HbA1c (%) Mean (SE) over time, % Placebo-controlled double-blind
Open-label extension
â&#x20AC;&#x201C;0.5% HbA1c reduction at 102 weeks
0
6
12
18
24
30
42
54
66
78
90
102
186
172
159
154
Treatment duration (weeks) n
296
284
278
275 266
234
214
191
. HbA1c, glycosylated haemoglobin; SE, standard error. *Open-label extension of double-blind, randomised, controlled trial over 24 weeks. Patients randomised to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set (observed cases). Gomis R, et al. Int J Clin Pract. 2012;66:731â&#x20AC;&#x201C;740.
HbA1c reductions sustained over 102 weeks with linagliptin as add-on to metformin* Change from baseline HbA1c (%) Mean (SE) over time, % Placebo-controlled double-blind
Open-label extension
â&#x20AC;&#x201C;0.7% HbA1c reduction at 102 weeks
0
6
12
18
24
30
42
54
66
78
90
102
298
276
252
244
Treatment duration (weeks) n
457
443
425
419 424
380
359
330
. . HbA1c, glycosylated haemoglobin; SE, standard error. *Open-label extension of double-blind, randomised, controlled trial over 24 weeks. Patients randomised to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set (observed cases). Gomis R, et al. Int J Clin Pract. 2012;66:731â&#x20AC;&#x201C;740.
HbA1c reductions sustained over 102 weeks with linagliptin as add-on to metformin + SU* Change from baseline HbA1c (%) Mean (SE) over time, % Placebo-controlled double-blind
Open-label extension
â&#x20AC;&#x201C;0.7% HbA1c reduction at 102 weeks
0
6
12
18
24
30
42
54
66
78
90
102
380
347
334
311
Treatment duration (weeks) n
544
537
533
527 520
494
455
419
. HbA1c, glycosylated haemoglobin; SE, standard error; SU, sulphonylurea. *Open-label extension of double-blind, randomised, controlled trial over 24 weeks. Patients randomised to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set (observed cases). Gomis R, et al. Int J Clin Pract. 2012;66:731â&#x20AC;&#x201C;740.
HbA1c reductions were non-inferior to glimepiride over 104 weeks
Mean (± SE) of HbA1c, %
HbA1c change over 2 years Adjusted* mean (SE) over time, % Linagliptin
7.5
Glimepiride
7.0 -0.6 6.5
-0.6
6.0 Treatment duration (weeks) Completers cohort: linagliptin n = 233, glimepiride n = 271 (FAS: linagliptin n = 764, glimepiride n = 755) Mean baseline HbA1c: 7.17% (linagliptin), 7.31% (glimepiride) Completers cohort post-hoc analysis: All patients who completed the full 104 weeks on treatment in the FAS without important protocol violation who did not receive rescue medication and who did achieve defined HbA1c goals as described previously.† All observed cases were included. FAS, full analysis set; HbA1c, glycosylated haemoglobin; OAD, oral antidiabetic drug; SE, standard error. *Model includes treatment, baseline HbA1c and number of prior OADs. †As described previously by Seck T, et al. Int J Clin Pract. 2010; 64:562–576. Gallwitz B, et al. Lancet. 2012;380:475–483.
Linagliptin was more effective than glimepiride at achieving HbA1c target without unwanted AEs in completers cohort Percentage of patients achieving composite outcome of HbA1c < 7% with no hypoglycaemia and no weight gain over 2 years
(n = 271)
(n = 233)
AE, adverse event; CI, confidence interval; HbA1c, glycosylated haemoglobin; OR, odds ratio. Gallwitz B, et al. Int J Clin Pract. 2013;67:317â&#x20AC;&#x201C;321.
Linagliptin provides significant HbA1c reductions independent of duration of Type 2 Diabetes Change from baseline HbA1c (%) by time since diagnosis of Type 2 Diabetes Adjusted1 mean at 24 weeks’ treatment, % Linagliptin placebo-corrected
> 1 to ≤ 5 years p < 0.0001
> 5 years p < 0.0001
Adjusted* mean change in HbA1c (%) from baseline at Week 24
≤ 1 year p < 0.0001
BMI, body mass index; HbA1c, glycosylated haemoglobin. Pre-specified subgroup analysis on pooled data from 3 pivotal Phase III, randomised, placebo-controlled trials: treatment in monotherapy, add-on to metformin and add-on to metformin plus sulphonylurea. P-values for between-group differences (vs placebo). *ANCOVA adjusted for continuous HbA1c, BMI group, washout phase, treatment group, study, age group, sex, time since diagnosis of diabetes, race and age × treatment or Type 2 Diabetes × treatment interactions. Patel S, et al. EASD 2011. Poster P832.
Linagliptin provides significant HbA1c reductions independent of patient age Change from baseline HbA1c (%) by age Adjusted1 mean at 24 weeks’ treatment, %
Adjusted* mean change in HbA1c (%) from baseline at Week 24
Linagliptin placebo-corrected
≤ 50 years
51–64 years
65–74 years
p < 0.0001
p < 0.0001
p < 0.0001
≥ 75 years† p = 0.0013
BMI, body mass index; HbA1c, glycosylated haemoglobin. Pre-specified subgroup analysis on pooled data from 3 pivotal Phase III, randomised, placebo-controlled trials: treatment in monotherapy, add-on to metformin and add-on to metformin plus sulphonylurea. P-values for between-group differences (vs placebo). *ANCOVA adjusted for continuous HbA1c, BMI group, washout phase, treatment group, study, age group, sex, time since diagnosis of diabetes, race and age × treatment or Type 2 Diabetes × treatment interactions. †Linagliptin should be used with caution when treating patients aged > 80 years, as experience in this patient group is limited. Patel S, et al. EASD 2011. Poster P832.
Linagliptin shows favourable safety and tolerability Organ-specific AE rate for AEs previously associated with the DPP4 inhibitor class* in a pooled analysis of 23 randomised, placebo-controlled, Phase III trials
Linagliptin
Placebo
5488
3290
Thyroid AEs (%)
0.1
0.0
Hepatic AEs (%)
1.4
Pancreatitis (%) Pancreatic cancer (%)
0.1 0.0
0.1 0.0
Acute renal failure (%)
0.5
0.7
Cutaneous AEs (%)
0.1
0.0
Drug hypersensitivity (%)
0.8
0.9
Patients, n
AE, adverse event; DPP4, dipeptidyl peptidase 4. *Categories of organ-specific AEs described if mentioned in the labels of currently marketed DPP4 inhibitors in the USA. Schernthaner G, et al. EASD 2014. Poster P885.
1.6
Linagliptin can be used with no dose adjustment in various patient populations Hepatic function
Adult age group (including geriatric patients*)
Renal function Use is independent of…. Weight/BMI
Ethnicity
Disease duration
No dose adjustment BMI, body mass index. *Clinical experience in patients aged > 80 years is limited and caution should be exercised when treating this population. Sources: Tradjenta® US prescribing information. Boehringer Ingelheim Ltd. (Updated 22 May 2014). Trajenta® EU summary of product characteristics. Boehringer Ingelheim Ltd. (Updated 29 October 2014).
商品名
Trajenta®
Januvia®
Onglyza®
Galvus®
Nesina®
主要代謝器官
無
無
肝臟
腎臟
無
主要排除途徑
膽汁及腸道
腎臟
腎臟
腎臟
腎臟
一天一次
一天一次
一天一次
一天兩次
一天一次
100mg QD
5mg QD
50mg BID
25mg QD
50mg QD
2.5mg QD
50mg QD
12.5mg QD
重度腎功能不全
25mg QD
2.5mg QD
50mg QD
6.25mg QD
肝功能不全限制
無
重度肝功能不全須小 心 謹 慎 使 用
無
歲以上研究數據證 70歲以上研究數據證 實療效及安全性
無
無
無
無
藥物相關監測
無
腎功能
腎功能
腎功能及肝功能
腎功能及肝功能
藥物交互作用
無
無
3A4強效抑制劑， 2.5mg QD
無
CYP2D6, 3A4代謝
一般療程、 一般療程、用法 輕度腎功能不全 中度腎功能不全
老年人族群使用試驗
5mg QD
給予治療前先進行肝功能 肝功能監測須在開始 檢查並評估患者。重度肝 使用前進行，肝功能 功能不全須小心謹慎使 不全患者不建議使用 用 。
In patients with moderate to severe renal impairment, linagliptin significantly lowered HbA1c
HbA1c (%) change from baseline adjusted* mean ± SE
Adjusted* mean (SE) change in HbA1c (%) from baseline at Week 12 Linagliptin 5 mg (n = 113) Baseline 8.08 0.0
Placebo (n = 120) 8.03
-0.2 –0.11 -0.4
-0.6 –0.53 Treatment difference: -0.42 (95% CI -0.60, -0.24); p < 0.0001
Mean HbA1c change from baseline of -0.5% after 12 weeks in patients with moderate to severe renal impairment (primary endpoint) CI, confidence interval; HbA1c, glycosylated haemoglobin; SE, standard error. The dosage(s) of background anti-diabetes drugs had to remain stable for the first 12 weeks: for insulin, the adjusted mean change from baseline for the first 12 weeks to Week 12 was -2.6 and -0.6 IU/day in the linagliptin (n = 105) and placebo (n = 94) groups, respectively (difference of -2.1; p = 0.0613). *ANCOVA model includes baseline HbA1c, treatment, renal impairment category and prior use of anti-diabetes drugs. Sources: Laakso M, et al. Diabetes Care. 2015;38(2):e15–17. Laakso M, et al. ADA 2013. Poster 1090-P.
In patients with moderate to severe renal impairment, HbA1c reduction with linagliptin is sustained over 52 weeks HbA1c (%) change from baseline adjusted* mean ± SE
Adjusted mean (SE) change in HbA1c (%) over time Linagliptin (n = 113) (baseline HbA1c 8.08%) Placebo/glimepiride† (n = 120) (baseline HbA1c 8.03%)
0.0
-0.2
-0.4 –0.50%
-0.6
Over time, HbA1c reduction was sustained with linagliptin, but attenuated with glimepiride
–0.64%
-0.8
-1.0 0
4
8
12
16
20
24
28
34
40
46
2.2
2.2
2.2
52
Week Mean glimepiride dose, mg/day
1.0
1.5
1.8
2.2
2.2
Mean change from baseline in insulin dose, IU/day, measured in patients receiving background insulin Linagliptin
-0.11 -1.46 -1.61 -1.90 -3.17 -2.45 -3.55
-4.68
-4.53
-5.18
-6.16
Placebo/glimepiride
0.00
-4.94
-5.14
-5.83
-5.10
0.19 0.44 0.17 -1.83 -2.43 -4.40
HbA1c, glycosylated haemoglobin; SE, standard error. *ANCOVA on FAS, LOCF, adjusted for baseline HbA1c, background anti-diabetes drugs at baseline, renal impairment category and treatment. †Placebo patients were switched to glimepiride at Week 12 while maintaining double blinding. Glimepiride was initiated at 1 mg/day and could be up-titrated to a maximal dose of 4 mg/day if fasting home blood glucose monitoring values were > 110 mg/dL. Laakso M, et al. Diabetes Care. 2015;38(2):e15–17.
In patients with moderate to severe renal impairment, there was a lower incidence of hypoglycaemia with linagliptin than placebo/glimepiride Linagliptin Glimepiride
Placebo/glimepiride
Hypoglycaemia,* patients with â&#x2030;Ľ 1 event (%)
Placebo
vs placebo
vs glimepiride
*Data for Period 2 and Period 1 + 2 are for investigator-reported hypoglycaemia, which includes hypoglycaemic events and events attributed to hypoglycaemia. Laakso M, et al. Diabetes Care. 2015;38(2):e15â&#x20AC;&#x201C;17.
In patients with moderate to severe renal impairment, linagliptin was well tolerated Period 1 Patients (%)
Any AE Drug-related AEs AEs leading to discontinuation Serious AEs* Drug-related Death Drug-related Cardiovascular event† Renal AE Pancreatitis
Period 2
Period 1 + 2
Linagliptin n = 113
Placebo n = 122
Linagliptin n = 107
Glimepiride n = 114
Linagliptin 5 mg n = 113
Placebo/ Glimepiride n = 122
76.1
73.8
90.7
96.5
95.6
98.4
23.9
24.6
38.3
46.5
45.1
49.2
3.5
4.9
4.7
9.6
8.0
13.9
7.1 1.8 0 0
8.2 0.8 0 0
22.4 1.9 0.9 0
26.3 0 0.9 0
24.8 1.8 0.9 0
29.5 0.8 0.8 0
n/a
n/a
2.8
6.1
2.7
6.6
n/a
n/a
3.7
5.3
4.4
8.2
0
0
0
0
0
0
AE, adverse event; n/a, not available. *AE that resulted in death, was immediately life-threatening, resulted in persistent or significant disability/incapacity, required/prolonged patient hospitalisation, or was a congenital anomaly/birth defect, or any other serious medical event based on clinical judgment that might have jeopardised the patient and might have required medical or surgical intervention to prevent 1 of these outcomes. †Cardiovascular death, myocardial infarction, stroke or hospitalisation due to unstable angina adjudicated in a blinded manner by an external, independent committee of cardiologists and neurologists. Sources: Laakso M, et al. Diabetes Care. 2015;38(2):e15–17. Laakso M, et al. ADA 2013. Poster 1090-P.
What issues need to be considered for elderly Type 2 Diabetes? A) Comorbidities and geriatric syndromes •Cognitive dysfunction •Functional impairment •Fall and fracture •Polypharmacy •Others
B) Age-specific aspects of pharmacotherapy •Older patients are at increased risk of adverse drug events due to agerelated pharmacokinetics (in particular reduced renal clearance) and pharmacodynamics (increased sensitivity to certain medications) affecting drug disposition C) Vulnerability to hypoglycaemia •Age-related reduced counterregulatory response to hypoglycemia •Reduced renal clearance
Kirkman MS, et al. J Am Geriatr Soc. 2012;60:2342–2356.
Anti-hyperglycaemic medication use in elderly patients Understanding the advantages and disadvantages of each OAD is critical Useful for post-prandial control DPP4 inhibitors? Impart little risk for hypoglycaemia Well tolerated No weight loss Relatively safely used even with decreased RI High cost
DPP4, dipeptidyl peptidase 4; OAD, oral anti-diabetes drug; RI, renal impairment. Kirkman MS, et al. J Am Geriatr Soc. 2012;60:2342â&#x20AC;&#x201C;2356.
In elderly (≥ 70 years) patients with Type 2 Diabetes, linagliptin significantly reduced HbA1c and FPG* Change from baseline, placebo-corrected Adjusted mean (SE) change in HbA1c (%) and FPG (mmol/L) at 24 weeks’ treatment Placebo HbA1c, %
n p-value
Linagliptin
Linagliptin placebo-corrected FPG, mmol/L
78
160
78 < 0.0001
FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin; SE, standard error. *Full analysis set. Barnett AH, et al. Lancet. 2013;382:1413–1423.
160 < 0.0001
In elderly (≥ and < 75 years) patients with Type 2 Diabetes, linagliptin significantly reduced HbA1c* Change from baseline HbA1c by age, placebo-corrected Adjusted mean (SE) change in HbA1c at 24 weeks’ treatment (%) < 75 years
n p-value
42
≥ 75 years
90
36 < 0.0001
HbA1c, glycosylated haemoglobin; SE, standard error. *Full analysis set. Barnett AH, et al. Lancet. 2013;382:1413–1423.
70 < 0.0001
In elderly (≥ 70 years) patients with Type 2 Diabetes, linagliptin significantly reduced HbA1c regardless of disease duration* Change from baseline HbA1c by time since diagnosis of T2D, placebo-corrected Adjusted mean (SE) change in HbA1c at 24 weeks’ treatment (%)
n p-value
> 1 to ≤ 5 years
> 5 to ≤ 10 years
7
29
20 0.0042
48
> 10 years
42 0.0005
HbA1c, glycosylated haemoglobin; SE, standard error; T2D, Type 2 Diabetes. *Full analysis set. Barnett AH, et al. Lancet. 2013;382:1413–1423.
89 < 0.0001
In elderly (≥ 70 years) patients with Type 2 Diabetes, linagliptin significantly reduced HbA1c regardless of background therapy* Change from baseline HbA1c by background therapy Adjusted mean (SE) change in HbA1c at 24 weeks’ treatment (%)
n p-value
Metformin only
SU ± metformin
21
42
44 0.0024
81
Insulin ± OAD
15
35
< 0.0001
HbA1c, glycosylated haemoglobin; OAD, oral anti-diabetes drug; SE, standard error; SU, sulphonylurea. *Full analysis set. Barnett AH, et al. Lancet. 2013;382:1413–1423.
0.0005
Investigator-defined hypoglycaemia (% patients with ≥ 1 episode)†
In elderly (≥ 70 years) patients with Type 2 Diabetes, hypoglycaemic AEs were comparable between linagliptin and placebo*
Overall
Without SU
With SU
Patients with hypoglycaemia
13 39
6
10
7
29
Total number of patients
79 162
36
67
43
95
With MET 0
2
22 45
AE, adverse event; CI, confidence interval; INS, insulin (with or without metformin); MET, metformin only; SU, sulphonylurea (with or without other anti-diabetes drugs). *Treatment set. †Confirmed plasma glucose concentration of ≤ 3.9 mmol/L, or symptoms attributed to hypoglycaemia, or both. Barnett AH, et al. Lancet. 2013;382:1413–1423
With INS 6
8
14 22
Meaningful efficacy across complete range of diabetes therapies in the Asian subgroup Linagliptin treatment effect across treatment lines Adjusted mean change from baseline HbA1c (%), placebo-corrected Monotherapy
Global1* Baseline HbA1c
8.00
Dual combination with MET
Chinese2* Japanese3† Global4*
7.95
8.07
8.09
Triple combination With MET+SU
Pooled
Chinese5*
Global6*
Chinese7*
Global8‡
Asian9*
Global10*
Asian11*
7.99
8.15
8.14
NC
8.2
8.31
8.5
HbA1c, glycosylated haemoglobin; MET, metformin; NC, not calculated; SU, sulphonylurea. *24 weeks’ treatment duration. †12 weeks’ treatment duration. ‡18 weeks’ treatment duration. 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267. 2. Chen Y, et al. J Diabetes Invest. In press. 3. Kawamori R, et al. Diabetes Obes Metab. 2012;14:348–357. 4.Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74. 5. Wang W, et al. J Diabetes 2015; In press. 6. Owens DR, et al. Diabetic Med. 2011;28:1352–1361. 7. Zeng Z, et al. Curr Med Res Opin. 2013;29:921–929. 8. Singh-Franco D, et al. Diabetes Obes Metab. 2012;14:694–708. 9. Ning G, et al. IDF 2013. Poster P-1046. 10. Yki-Järvinen H, et al. Diabetes Care 2013;36:3875–3881. 11. Sheu WH, et al. Curr Med Res Opin. 2015;31:503–512.
Initial combination of linagliptin and metformin in patients with marked hyperglycemia in the Asian subgroup Global
Global Asian Global Asian (BL HbA1c ≥ 9.5%) (BL HbA1c ≥ 9.5%)*(BL HbA1c < 9.5%) (BL HbA1c < 9.5%)*
LINA
LINA/ MET
LINA
LINA/ MET
LINA
LINA/ MET
LINA
LINA/ MET
9.69
9.73
–
–
10.46
10.49
–
–
LINA
LINA/ MET
LINA
LINA/ MET
8.73
8.76
–
–
Adjusted mean change from baseline in HbA1c (%)
Baseline HbA1c
Asian
HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; PPCC, per-protocol completers cohort. Unless stated otherwise, data are for the PPCC (all randomised patients who received ≥ 1 dose of study drug, had a baseline HbA1c measurement, had no important protocol violations, completed 24 weeks’ treatment without receiving glycaemic rescue and had an HbA1c measurement at week 24.
*Data use last observation carried forward for the full analysis set (all randomised patients who received ≥ 1 dose of study drug, had a baseline HbA1c measurement and ≥ 1 on-treatment HbA1c measurement. Sources: Ross S, et al. ADA 2014. Oral 150-OR. Ma CWR, et al. AASD 2014. Oral 1188.
Meaningful HbA1c reduction with linagliptin in elderly patients (â&#x2030;Ľ 65 years) â&#x20AC;&#x201C; a pooled analysis of Asian subgroup
Adjusted mean change from baseline in HbA1c, % (SE)
Adjusted change in HbA1c at Week 24 Baseline HbA1c 8.21 (0.83)
Baseline HbA1c 8.22 (0.85)
Between-group difference: -0.82 (0.10); 95% CI: -1.02, -0.62; p < 0.0001 Linagliptin (n = 239)
Placebo (n = 108)
Difference
HbA1c, glycosylated haemoglobin; OAD, anti-diabetes drug; SE, standard error. Data are from the full analysis set (last observation carried forward). Model included treatment, baseline HbA1c, prior OADs and study. Sheu WH, et al. AASD 2013. Oral 170.
Linagliptin shows favourable tolerability and safety in Asian patients: Pooled analysis of 10 clinical trials* Linagliptin 5 mg (n = 1037)
Placebo (n = 440)
Any AE
601 (58.0)
256 (58.2)
Drug-related AEs
125 (12.1)
37 (8.4)
AEs leading to discontinuation
21 (2.0)
15 (3.4)
Serious AEs
25 (2.4)
12 (2.7)
Serious AEs leading to discontinuation
6 (0.6)
1 (0.2)
Patients, n (%)
AE, adverse event. *Pooled data from: 1. NCT00328172 (ClinicalTrials.gov). 2. Forst T, et al. Diabet Med. 2010;27:1409–1419. 3. Gomis R, et al. Diabetes Obes Metab. 2011;13:653–661. 4. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258–267. 5. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74. 6. Owens DR, et al. Diabet Med. 2011;28:1352–1361. 7. Gallwitz B, et al. Lancet. 2012;4;380:475–483. 8. Kawamori R, et al. Diabetes Obes Metab. 2012;14:348–357. 9. Gomis R, et al. Int J Clin Pract. 2012;66:731–740. 10. Barnett AH, et al. Diabetes Obes Metab. 2012;14(12):1145–1154. Zeng Z, et al. ADA 2012. Abstract 1163-P.
Linagliptin shows favourable tolerability and safety in Asian patients Organ-specific AE rate for AEs previously associated with the DPP4 inhibitor class*
Linagliptin Placebo Patients, n
440
2.5%
3.4%
%
8.9%
Nasopharyngitis
6.9%
5.0%
Cough
2.1%
1.1%
Hepatic enzyme increase
0.2%
0.2%
Serum creatinine increase 0.1%
0
Headache
Pancreatitis was not reported in either the linagliptin or placebo Asian patient groups
1037
Upper respiratory tract infection
Urinary tract infection
2.3%
3.4%
Blood and lymphatic system disorders
1.5%
1.6%
Hypersensitivity
0.2%
0
AE, adverse event; DPP4, dipeptidyl peptidase 4. *Reported as of 16 February 2012. Categories of organ-specific AEs described if mentioned in the labels of currently marketed DPP4 inhibitors in the USA. Ning G, et al. IDF 2013. Poster P-1046.
Which of the following is your preferred second-line therapy as add-on to metformin?
1. DDP-4 inhibitor 2. GLP-1 receptor agonist 3. Insulin 4. SGLT-2 inhibitor 5. Sulfonylurea 6. Thiazolidinedione 7. Other
10
Currently, what is your major area of concern regarding the safety of novel therapies?
1. Cardiovasular disease 2. Pancreatitis/pancreatic cancer 3. Thyroid disorders 4. Renal safety 5. Immune system abnormalities 6. Other
10
An alternative approach to managing Type 2 diabetes
Early use of combination therapies
73 2H
10
Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
“Cellular pathways operate more like webs than superhighways. There are multiple redundancies, or alternate routes, that may be activated in response to the inhibition of a pathway.” “For this reason, combination therapies are often needed to effectively treat many tumours and infectious diseases.” 73 2H
W 8 Woodcock J, et al. N Engl J Med 2011;364:985‒7. Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
Early use of combination therapy is well established in several therapeutic areas
• Cancer1 • HIV/AIDS2 • Hypertension3 • Asthma4 • Rheumatoid arthritis5 • Tuberculosis6
73 2H
1. NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, 2010; 2. World Health Organization HIV/AIDS Prevention, Treatment and Care in the Health Q Sector 2009 www.who.int/hiv/pub/priority_interventions_web.pdf (Accessed Feb 2010); 3. Chobanian AV, et al. Hypertension 2003;42:1206–52; 4. British 12 9 nes on the management of asthmas www.sign.ac.uk/pdf/org101.pdf (Accessed Feb 2010); 5. Saag KG, et al. Arthritis Rheum 2008;59:762–84; guideli N Confidential. Containsguidelines unpublished2003. data. For training purpose only. Not to be distributed. 6. World Health Organization Treatment for tuberculosis P 14
Specific reasons why early combination therapy may be beneficial in Type 2 diabetes
Rationale for early combination therapy in Type 2 diabetes • Early, robust lowering of HbA1C • Avoidance of clinical inertia associated with a stepwise approach to therapy • Potential for early combination therapy to improve β-cell function • Initiation of a therapeutic intervention with a complimentary mechanism of action • Potential to use less than maximal doses of individual agents, minimising side effects 11 Zinma n B. Am J Med 2011;124:S19‒34.
Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
73 2H Q 12 N P 14
The vast majority of patients with Type 2 diabetes eventually require combination therapy
100
Patients (%)
80
75% 60 40
50%
20 0 3 Years
9 Years
73 2H
12 Tur Turner RC, et al. for the UKPDS GroupConfidential. (UKPDS 49). JAMA 1999;281:2005â&#x20AC;&#x2019;12. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
73 2H
13 Shah Shah BR, et al. Diabetes Care 2005;28:600â&#x20AC;&#x2019;6. Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
There is significant clinical inertia in response to inadequate glycaemic control (HbA1C >8%)
73 2H
14 Shah Shah BR, et al. Diabetes Care 2005;28:600â&#x20AC;&#x2019;6. Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
73 2H
15 Brown JB, et al. Diabetes Care 2010;33:501â&#x20AC;&#x2019;6.
Confidential. Contains unpublished data. For training purpose only. Not to be distributed.
Q 12 N P 14
Secondary failure of metformin monotherapy is increased when initial HbA1C is ≥8% 1.0 <7%
0.9 12.3% per year
(10.5–14.4)
0.8
7–7.9% 17.8% per year (15.7–20.1)
Proportion not experiencing secondary failure
0.7 0.6 0.5 0.4
8–8.9% 19.2% per year (16.2–22.8)
0.3 ≥9.0% 0.2
19.4% per year (16.8–22.4)
0.1 0 0 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 58 Months on metformin
73 2H
Figure shows a Kaplan–Meier plot of secondary failure of metformin monotherapy by categories of HbA1C at metformin initiation adjusted for age and diabetes duration at initiation and the percent per year (95% CIs) experiencing secondary failure. 16 Confidential. Contains unpublished data. For training purpose only. Not to be distributed. Brown JB, et al. Diabetes Care 2010;33:501‒6.
Q 12 N P 14
2.0
1.5
1.0
30 20
0.5 10 0
0 500
1000
1500
2000
2500
Dose (mg/day) Garber AJ et al. Am J Med 1997;102:491 Riddle M Am J Med. 2000;108(6A):15Sâ&#x20AC;&#x201C;22S.
GI distress, patients (%)
Reduction vs. placebo, HbA1c (%)
Metformin Dose-Response Curve
FOR INTERNAL USE
Synergistic effects: Metformin and linagliptin Metformin
AMPK activation
Linagliptin
↑ GLP1 production
Gut
↓ GLP1 Inactivation
DPP4 inhibition ↑ GIP Pancreas
Liver
↑ GLP1
↑ Insulin
↓ Gluconeogenesis ↓ Hyperglycaemia (fasting and post-prandial)
↓ Glucagon (Glucose dependent)
AMPK, AMP-activated protein kinase; DPP4, dipeptidyl peptidase; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1. Scheen AJ. Expert Opin Drug Metab Toxicol. 2013;9:363–377.
Overview: Studies supporting SPC use • • •
Efficacy of linagliptin 5 mg QD versus 2.5 mg BID (1218.62) Initial combination with metformin (1218.46) Initial combination with metformin versus linagliptin monotherapy in newly diagnosed patients (1218.83)
BID, twice daily; QD, once daily; SPC, single-pill combination.
Linagliptin 5 mg QD and 2.5 mg BID: Equally superior to placebo for HbA1c reduction from baseline to Week 12 Placebo-corrected change in HbA1c from baseline to Week 12
Baseline HbA1c, %
LINA 2.5 mg BID + MET
LINA 5 mg QD + MET
7.96
7.98
Adjusted* mean (SE) HbA1c change from baseline (%)
Treatment difference 0.06 (95% CI -0.07, 0.19)‡ BID, twice daily; HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; QD, once daily; SE, standard error. *ANCOVA model includes treatment, continuous baseline HbA1c and number of prior oral anti-diabetes agents in addition to background metformin; †p < 0.0001 vs placebo; ‡Non-inferiority in treatment effect is established, as pre-specified, based on an upper bound of < 0.35% for the 95% CI of the treatment difference (linagliptin 2.5 mg BID – linagliptin 5 mg QD). Ross SA, et al. Curr Med Res Opin. 2012;28:1465–1474.
Overview: Studies supporting SPC use • • •
Efficacy of linagliptin 5 mg QD versus 2.5 mg BID (1218.62) Initial combination with metformin (1218.46) Initial combination with metformin versus linagliptin monotherapy in newly diagnosed patients (1218.83)
BID, twice daily; QD, once daily; SPC, single-pill combination.
Initial combination of linagliptin and metformin: Superior to the respective monotherapy arms Open-label arm†
Randomised arm* (placebo-corrected)
Baseline HbA1c, % Patients, n
LINA 2.5 mg BID LINA 2.5 mg BID LINA 2.5 mg BID + MET 500 mg + MET 1000 mg + MET 1000 mg BID‡ BID‡ BID
LINA 5 mg QD
MET 500 mg BID
MET 1000 mg BID
8.7 135
8.7 141
8.5 138
8.7 137
-0.6
-0.8
-1.2
-1.3
8.7 140
11.8 66
Change in HbA1c from baseline, %
0 -0.5 -1.0
-1.0
-1.7 -3.7
-1.5 -2.0
-2.0 -3.0
-3.0 -4.0
-3.5 Both combination regimens were superior to the respective metformin monotherapy arms BID, twice daily; HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; LOCF, last observation carried forward; MET, metformin; QD, once daily; SE, standard error. *Randomised arm: mean (SE); full analysis set, LOCF; †Open-label arm in patients with poor glycaemic control: mean (SE); full analysis set, observed cases (n = 48); ‡p < 0.0001, combination therapy vs respective monotherapy. Haak T, et al. Diab Obes Metab. 2012;14:565–574.
Initial combination of linagliptin and metformin: Superior in patients with higher baseline HbA1c levels (Week 24) Open-label arm†
Randomised arm* (placebo-corrected)
MET 500 mg BID
MET 1000 mg BID
66 69
68 73
74 64
63 74
LINA 2.5 mg BID + MET 1000 mg BID
66 74
Mean (SE) change in HbA1c from baseline, %
Patients, n
LINA 5 mg QD
LINA 2.5 mg BID LINA 2.5 mg BID + MET 500 mg + MET 1000 mg BID BID
66
3.7
HbA1c reductions with combination regimens were greater in patients with high baseline levels
BID, twice daily; HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; QD, once daily; SE, standard error. *Randomised arm: mean (SE); full analysis set, last observation carried forward. †Open-label arm in patients with poor glycaemic control: mean (SE); full analysis set, observed cases (n = 48). Haak T, et al. Diabetes Obes Metab. 2012;14:565–574.
Overview: Studies supporting SPC use • • •
Efficacy of linagliptin 5 mg QD versus 2.5 mg BID (1218.62) Initial combination with metformin (1218.46) Initial combination with metformin versus linagliptin monotherapy in newly diagnosed patients (1218.83)
BID, twice daily; QD, once daily; SPC, single-pill combination.
1218.83: A randomised controlled trial of linagliptin monotherapy versus initial combination with linagliptin and metformin in newly diagnosed Type 2 Diabetes patients
Objective: To investigate the efficacy and safety of combination therapy compared with linagliptin monotherapy
Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Study design 24 weeks 1 week
Assessment of eligibility
Placebo run-in period
INITIAL COMBINATION THERAPY LINA 5 mg QD + MET BID n = 159
Randomisation (n = 316)
DPP4 MONOTHERAPY LINA 5 mg QD + placebo BID n = 157
Primary endpoint: •Change from baseline in HbA1c after 24 weeks PPCC* Inclusion criteria (not exhaustive) •Age ≥ 18 years •Recently diagnosed (≤ 12 months) uncontrolled T2D •No glucose-lowering therapy in previous 12 weeks •HbA1c 8.5–12.0% (69–108 mmol/mol) •BMI ≤ 45 kg/m2
Exclusion criteria (not exhaustive) •Cardiovascular event within the previous 3 months •Hepatic disease (alanine transaminase, aspartate transaminase and/or alkaline phosphatase > 3× ULN) •Kidney disease (creatinine clearance < 60 mL/min as calculated by Cockcroft–Gault equation)
BID, twice daily; BMI, body mass index; DPP4, dipeptidyl peptidase 4; HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; PPCC, per protocol completers cohort; QD, once daily; T2D, Type 2 Diabetes; ULN, upper limit of normal. *All randomised patients who received ≥ 1 dose of study drug; did not have important protocol violations; had 1 HbA1c measurement at baseline, ≥ 1 on treatment and 1 at Week 24; and completed 24 weeks of treatment without receiving glycaemic rescue therapy. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44
Baseline demographics and clinical characteristics (1/2)
LINA 5 mg + MET (n = 159)
LINA 5 mg (n = 157)
49.0 ± 10.9
48.6 ± 11.2
Male, %*
43.4
49.0
Diabetes duration < 1 year, %*
100.0
98.7
No previous anti-diabetes agents, %*
100.0
100.0
BMI, kg/m2*
29.8 ± 5.8
29.6 ± 5.4
HbA1c,%†
9.8 ± 1.2
9.9 ± 1.1
FPG, mg/dL†
196 ± 54
198 ± 61
Age, years*
BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; SD, standard deviation. Values are mean ± SD or % of patients. *Treated set: linagliptin + metformin, n = 159; linagliptin, n = 157. †Full analysis set: linagliptin + metformin, n = 153; linagliptin, n = 150. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Baseline demographics and clinical characteristics (2/2) LINA 5 mg + MET (n = 159)
LINA 5 mg (n = 157)
White
61.0
54.1
Asian
35.8
40.8
Black/African American
3.1
3.8
American Indian/Alaskan Native
0.0
1.3
Normal
54.7
57.3
Mild impairment
43.4
40.8
Moderate impairment
1.9
1.9
Severe impairment
0.0
0.0
Ethnicity, %*
Renal function, %*â&#x20AC;
Countries included in the study Asia: India, Israel, Malaysia, Philippines, Sri Lanka, Thailand Europe: Russia, Ukraine North America: Canada, Mexico, USA
LINA, linagliptin; MET, metformin. *Treated set: linagliptin + metformin, n = 159; linagliptin, n = 157. â&#x20AC; According to estimated glomerular filtration rate by the Modification of Diet in Renal Disease (MDRD) study equation. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Change from baseline to Week 24 in HbA1c FAS (LOCF)
PPCC (OC) LINA 5 mg + MET (n = 132) 9.73
9.69
LINA 5 mg + MET (n = 153) BL HbA1c, %
LINA 5 mg (n = 150)
9.79
9.88
HbA1c (%) change from baseline Adjusted* mean (SE)
HbA1c (%) change from baseline Adjusted* mean (SE)
BL HbA1c, %
LINA 5 mg (n = 113)
Treatment difference -0.79 95% CI -1.13, -0.46; p < 0.0001
Treatment difference -0.99 95% CI -1.33, -0.64; p < 0.0001
BL, baseline; CI, confidence interval; FAS, full analysis set; HbA1c, glycosylated haemoglobin; LINA, linagliptin; LOCF, last observation carried forward; MET, metformin; OC, observed cases; PPCC, per protocol completers cohort; SE, standard error. *ANCOVA model includes continuous baseline HbA1c and treatment. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Change over time in HbA1c PPCC (OC)
HbA1c (%), mean Âą SE
LINA 5 mg LINA 5 mg + MET
0 Patients, n LINA 5 mg + MET LINA 5 mg
6
12
18
24
131 112
132 113
Week 132 113
131 110
132 113
HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; OC, observed cases; PPCC, per protocol completers cohort; SE, standard error. The analysis was performed using a mixed model repeated measurements (MMRM) method. 1218.83 Clinical Trial Report. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Change at Week 24 in baseline HbA1c Adjusted mean change from baseline in HbA1c at Week 24 (PPCC)*
Adjusted† mean (SE) change from baseline in HbA1c (%)
< 9.5% (< 80 mmol/mol)
≥ 9.5% (≥ 80 mmol/mol)
Treatment difference: -0.69% (95% CI: -1.23, 0.15)
Treatment difference: -0.84% (95% CI: -1.32, -0.35)
CI, confidence interval; HbA1c, glycosylated haemoglobin; PPCC, per protocol completers cohort; SE, standard error. *All randomised patients who received ≥ 1 dose of study drug; did not have important protocol violations; had 1 HbA1c measurement at baseline, ≥ 1 on treatment and 1 at Week 24; and completed 24 weeks of treatment without receiving glycaemic rescue therapy; †ANCOVA model includes categorical baseline HbA1c, treatment and treatment by categorical baseline HbA1c interaction. Ross S, et al. ADA 2014. Oral 150-OR; Gallwitz B, et al. EASD 2014, Poster 894.
Responders: Proportion of patients with HbA1c < 7.0% at Week 24
Patients with HbA1c < 7.0% at Week 24 (%)
PPCC Odds ratio* = 2.45 95% CI 1.45, 4.12; p = 0.0008 LINA 5 mg + MET LINA 5 mg
Clinically significant improvements in HbA1c were seen in both treatment groups
HbA1c, glycosylated haemoglobin; LINA, linagliptin; MET, metformin; PPCC, per protocol completers cohort. *Logistic regression model includes continuous baseline HbA1c and treatment. The results were confirmed by sensitivity analysis on the full analysis set (last observation carried forward). Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Safety: Clinical AEs (treated set) LINA 5 mg + MET (n = 159)
LINA 5 mg (n = 157)
Any AE
56.0
61.1
Drug-related AE
8.8
5.7
AE leading to discontinuation
1.3
1.3
Serious AE
1.9
1.3
Death
0.0
0.0
Requiring hospitalisation
1.9
1.3
Drug-related
0.0
0.0
Severe AE
1.3
1.9
Pancreatitis
0.0
0.0
Pancreatic cancer
0.0
0.0
Heart failure
0.0
0.0
Dyslipidaemia
8.8
14.0
Headache
6.3
4.5
Urinary tract infection
6.3
8.9
Gastrointestinal disorders Diarrhoea
14.5 5.7
13.4 1.9
Hyperglycaemia
3.1
12.7
Patients (%)
AEs occurring in â&#x2030;Ľ 5% of patients
AE, adverse event; LINA, linagliptin; MET, metformin. Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Investigator-defined hypoglycaemia, patients (%)
Safety: Frequency of investigator-defined hypoglycaemia (treated set)
LINA (5 mg) + MET
LINA (5 mg)
Similar proportions of patients in the 2 treatment groups had investigator-defined hypoglycaemic events; there were no severe hypoglycaemic events (requiring assistance) in either treatment group
LINA, linagliptin; MET, metformin. *No episodes of severe hypoglycaemia occurred (i.e., an episode requiring third-party assistance to administer carbohydrate, glucagon, or other resuscitative action). Ross SA, et al. Diabetes Obes Metab. 2015;17:136-44.
Fixed-dose Combinations of Antidiabetics Advantages: •Reduce the pill burden •Increase adherence •Improve glycemic control •Reduce side effects associated with high dose Disadvantages: •Require special vigilance on the contraindications, precautions and monitoring of both agents •May have a higher hypoglycemic risk when use combination •Concern about lack of flexibility for dose titration Bailey CJ & Day C., Diabetes, Obesity and Metabolism, Published Online: 19 Jan 2009
糖尿病患者的困擾： 一天要吃好幾次藥！ 一次要吃好幾種藥！！ 每種藥的劑量又都不一樣！！！
Strategy in Prescribing OAD • 1. Earlier glycemic control ( HbA1c >6.5, start with Metformin) • 2. Earlier combination ( HbA1c >8.0) • 3. Choose appropriate OAD based on efficacy and onset of medication ( SU + Met + DPP4 I on HbA1c >9.0 , SU + Met on HbA1c > 8.5, Met + DPP4 I on HbA1c >8.0 4. SU Dose titration depends on patient’s HbA1c and +/hypoglycemia symptoms and timing 0.5# qd , 0.5# bid , 1/0.5# bid , 1# bid ,….) 5. Lastly , choose an appropriate SU!!!
• SU + Metformin = 水煮意麵 “ Flexible in dose titration to achieve HbA1c without hypoglycemia individually” • DPP4 I + Metformin = 煮泡麵 “ Convenient and without hypoglycemia but with limitation in dose titration to achieve HbA1c individually”
DPP4 FDC in renal impairment patients
CKD
30 50
60
30
Limitation for DPP4i FDC
Trajenta Duo
Janumet
中重度腎功能不全病患不得使用Janumet 中重度腎功能不全病患不得使用
Galvusmet
Kombiglyze
KombiglyzeXR 顆粒大， 顆粒大，對於年紀大老人 或是吞嚥困難病人可能降低服藥順服性
Trajenta Duo 500mg: 1.5cm*0.6cm 850mg: 2.0cm*0.8cm
Kombiglyze 1000mg: 2.2cm*1cm
Thank you for your attention.