Saxagliptin som tilläggsbehandling till sulfonylurea eller tiazolidinedion förbättrade viktiga parametrar för blodsockerkontroll hos patienter med otillräckligt kontrollerad typ 2-diabetes

Resultaten från två 24-veckors studier av saxagliptin i fas 3 har presenterats vid 44th European Association for the Study of Diabetes. Saxagliptin visades ge reduktion av alla viktiga parametrar för blodsockerkontroll som studerades - glykosylerat hemoglobin (HbA1C), fasteblodsocker (FPG) och blodsockernivå efter måltid (PPG), när saxagliptin användes som tillägg till sulfonylurea (SU) eller tiazolidinedion (TZD) hos patienter med otilläckligt kontrollerad typ 2-diabetes, jämfört med placebo som tillägg till antingen en ökad dos SU eller en stabil dos TZD. Saxagliptin som tillägg till SU och TZD tolererades väl under studiernas gång och fler patienter kunde uppnå behandlingsmålet HbA1C på mindre än 7 procent jämfört med jämförelsesubstanserna.

Saxagliptin är en selektiv hämmare med bindning till enzymet DPP-4, och utvecklas gemensamt av AstraZeneca och Bristol-Myers Squibb för behandling av typ 2-diabetes.

"Ett stort antal patienter med typ 2-diabetes har svårigheter att hantera sin sjukdom och får inte tillräcklig behandling med dagens befintliga läkemedel. Eftersom antalet diabetespatienter ökar runt om i världen är det viktigt att undersöka nya behandlingsmetoder för att bekämpa denna kroniska sjukdom", kommenterar professor Anthony Barnett, vid University of Birmingham och Heart of England NHS Foundation Trust.

AstraZeneca och Bristol-Myers Squibb inlämnade registreringsansökningar den 30 juni till amerikanska FDA och den 1 juli till EMEA. Dessa är för närvarande under handläggning. Ansökningarna i USA och inom EU för saxagliptin baseras på resultaten från ett brett kliniskt prövningsprogram, som omfattat både användning av produkten som komplement till standardbehandling och användning som monoterapi för ej tidigare behandlade patienter. Det kliniska prövningsprogrammet omfattade doseringar på upp till 80 gånger den terapeutiska kliniska dosen på 5 mg en gång om dagen. De sex centrala läkemedelsprövningarna i fas 3 för fastställande av säkerhet och effekt hos saxagliptin omfattade över 4 000 patienter, varav 3 000 behandlades med saxagliptin.

Bakgrund:

STUDIERESULTATEN I DETALJ


1. Phase III - Poster Presentation: Saxagliptin added to sulphonylurea provided clinically important improvement of glycemic control, compared with up-titrated sulphonylurea, without increasing adverse events

This study was designed to assess the addition of saxagliptin to a submaximal dose of sulphonylurea versus increasing the dose of sulphonylurea. The data represent findings from a 24-week, randomized, double-blind, placebo-controlled, three-arm, parallel-group, multi-center international study of 768 people with type 2 diabetes (ages 18-77) whose A1C level was greater than or equal to 7.5 percent and less than or equal to 10 percent after at least two months on a submaximal dose of a sulphonylurea at enrolment. After a four-week, open-label, lead-in phase, where all individuals received glyburide (GLY) 7.5 mg, individuals were randomized to one of three separate treatment arms: saxagliptin 2.5 mg + GLY 7.5 mg (n=248), saxagliptin 5 mg + GLY 7.5 mg (n=253), or placebo + GLY 10 mg (n=267), given daily. In the placebo + GLY 10 mg group, blinded up-titration of GLY was allowed to a maximum total daily dose of 15 mg (UP-GLY). Approximately 92 percent of individuals in the UP-GLY group reached the maximum total daily dose during the study.

The primary endpoint of the study was the change from baseline to week 24 in A1C. The secondary endpoints of the study included changes from baseline to week 24 in FPG, PPG response, as indicated by PPG area under the curve (AUC) from 0-180 minutes during an oral glucose tolerance test (OGTT) and the proportion of individuals achieving the American Diabetes Association recommended A1C target of less than 7 percent.

Study results
After 24 weeks, individuals in the saxagliptin + GLY treatment arms demonstrated a significant adjusted mean change in A1C from baseline of -0.5 percent for saxagliptin 2.5 mg + GLY and -0.6 percent for saxagliptin 5 mg + GLY, compared to +0.1 percent for UP-GLY (p-value less than 0.0001 for both treatment arms). Reductions were observed at four weeks, the earliest assessment point in the study. More than twice as many individuals receiving saxagliptin + GLY achieved A1C of less than 7 percent compared to UP-GLY: 22.4 percent for saxagliptin 2.5 mg + GLY and 22.8 percent for saxagliptin 5 mg + GLY, compared to 9.1 percent for UP-GLY (p-value less than 0.0001 for both treatment arms).

Individuals treated with saxagliptin + GLY demonstrated a significant adjusted mean change in FPG from baseline to week 24: -7.1 mg/dL for saxagliptin 2.5 mg + GLY and -9.7 mg/dL for saxagliptin 5 mg + GLY, compared to +0.7 mg/dL for UP-GLY (p-value less than or equal to 0.0218 for both treatment arms). Reductions were observed at two weeks, the earliest assessment point in the study. The two saxagliptin + GLY treatment arms also demonstrated adjusted mean decreases in PPG from baseline to week 24, compared to UP-GLY (p-value less than 0.0001 for both treatment arms).

Over 24 weeks, the reported hypoglycemic events were: 13.3 percent for saxagliptin 2.5 mg + GLY, 14.6 percent for saxagliptin 5 mg + GLY and 10.1 percent for UP-GLY (p-value equals NS). The occurrence of confirmed hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL) was: 2.4 percent for saxagliptin 2.5 mg + GLY, 0.8 percent for saxagliptin 5 mg + GLY and 0.7 percent for UP-GLY.

Incidence of adverse events was: 75.0 percent for saxagliptin 2.5 mg + GLY, 72.3 percent for saxagliptin 5 mg + GLY and 76.8 percent for UP-GLY. The percentages of the most commonly reported (greater than or equal to 5 percent) adverse events for the saxagliptin 2.5 mg + GLY, saxagliptin 5 mg + GLY and UP-GLY treatment arms, respectively, were: urinary tract infection [5.2, 10.7, 8.2]; nasopharyngitis [5.6, 5.9, 6.7]; upper respiratory tract infection [4.4, 6.3, 6.7]; influenza [5.2, 4.0, 6.0]; diarrhoea [5.6, 4.0, 5.2]; back pain [4.8, 5.9, 4.5]; pain in extremity [4.4, 3.6, 5.6]; headache [7.7, 7.5, 5.6]; cough [5.2, 4.0, 4.9]; and hypertension [3.6, 6.3, 2.2].

2. Phase III - Poster Presentation: Saxagliptin added to thiazolidinedione provided clinically important improvement of glycemic control, compared with thiazolidinedione monotherapy, without increasing adverse events


This study was designed to assess the addition of saxagliptin to thiazolidinedione versus the addition of placebo to TZD. The data represent findings from a 24-week, multinational, randomized, placebo-controlled, three-arm, parallel group, double-blind study of 565 people with type 2 diabetes (ages 18-77), whose A1C level was greater than or equal to 7 percent and less than or equal to 10.5 percent and who were receiving stable TZD monotherapy (pioglitazone 30 mg or 45 mg, or rosiglitazone 4 mg or 8 mg, total daily dose) for at least 12 weeks prior to screening. After a two-week lead in period during which all individuals continued on their previous pioglitazone or rosiglitazone dose individuals were randomized to one of three treatment arms: saxagliptin 2.5 mg (n=195), saxagliptin 5 mg (n=186) or placebo (n=184), given once daily, in addition to continuing on their previously prescribed TZD dose.

The primary endpoint of the study was the change from baseline to week 24 in A1C. The secondary endpoints of the study included changes from baseline to week 24 in FPG, response as indicated by PPG area under the curve (AUC) from 0-180 minutes during an oral glucose tolerance test (OGTT), and the proportion of individuals achieving the American Diabetes Association recommended A1C target of less than 7 percent.

After 24 weeks, individuals in the saxagliptin + TZD treatment arm demonstrated an adjusted mean change in A1C from baseline of -0.7 percent for saxagliptin 2.5 mg + TZD and -0.9 percent for and saxagliptin 5 mg + TZD compared with -0.3 percent for placebo + TZD (p-value less than or equal to 0.0007 for both treatment arms). A greater percentage of individuals treated with saxagliptin + TZD achieved an A1C of less than 7 percent at week 24: 42.2 percent for saxagliptin 2.5 mg + TZD and 41.8 percent for saxagliptin 5 mg + TZD compared with 25.6 percent for placebo + TZD (p-value less than or equal to 0.0013 for both treatment arms).

Individuals treated with saxagliptin + TZD demonstrated an adjusted mean change from baseline in FPG: -14.3 mg/dL for saxagliptin 2.5 mg + TZD and -17.3 mg/dL for saxagliptin 5 mg + TZD, compared to -2.8 mg/dL for placebo + TZD (p-value less than or equal to 0.0053 for both treatment arms). Both saxagliptin + TZD treatment arms also demonstrated adjusted mean decreases from baseline in PPG, compared with placebo + TZD (p-value less than 0.0001 for both treatment arms).

One confirmed case of hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL) was reported in the saxagliptin 2.5 mg + TZD treatment arm. There were no cases of confirmed hypoglycemia in the saxagliptin 5 mg + TZD or placebo + TZD treatment arms. Reported hypoglycemic events were: 4.1 percent for the saxagliptin 2.5 mg + TZD, 2.7 percent for saxagliptin 5 mg + TZD, and 3.8 percent for placebo + TZD.

Over 24 weeks, the incidence of adverse events was: 62.1 percent for saxagliptin 2.5 mg + TZD, 74.2 percent for saxagliptin 5 mg + TZD and 66.8 percent for placebo + TZD. The percentages of the most commonly reported (greater than or equal to 5 percent) adverse events from the saxagliptin 2.5 mg + TZD, saxagliptin 5 mg + TZD and placebo + TZD treatment arms, respectively, were: upper respiratory tract infection [7.7, 9.1, 7.1]; urinary tract infection [3.6, 6.5, 6.5]; nasopharyngitis [3.1, 4.8, 6.0]; arthralgia or joint pain [5.6, 2.7, 2.7]; headache [4.6, 5.4, 3.8]; dizziness [2.6, 3.2, 5.4]; peripheral edema [3.1, 8.1, 4.3]; and hypertension [5.6, 4.3, 4.9].

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