당뇨병 억제제

최신 당뇨약 SGLT2억제제의 기대와 우려

체중·HbA1c·혈압 개선, 마른 당뇨에는 메트포르민 우선

신장에서 포도당이 재흡수되지 않도록 막아주는 나트륨/글루코스공수송체(SGLT)2 억제제 포시가(성분명 다파글리플로진, BMS-아스트라제네카 공동개발)가 최근 국내에서 승인됐다. SGLT2억제제는 신요세관에 발현해 소변 속 요당의 약 90%를 재흡수하는 단백질인 SGLT2의 기능을 억제해 체내 글루코스를 낮춰 혈당을 개선시키는 메커니즘을 갖고 있다. 인슐린저항성에 직접적인 저항을 주지 않으면서도 혈당조절과 함께 체중조절도 줄여주는 획기적인 신약이라는 평가도 받고 있다. 최근 동일 계열인 카나글리플로진(존슨앤존슨, 상품명 인보카나)의 일본인을 대상으로 한 12주간의 연구성적이 Diabetes, Obesity & Metabolism에 발표됐다. 대상자는 20~80세이고 당화혈색소(HbA1c) 6.9～9.9％인 2형 당뇨병환자. 총 543례 등록자 가운데 160례가 제외돼 최종 383례가 시험에 참가했다. 기존 복용하던 당뇨병 치료제를 8주 이상 워시아웃한 다음 5개군으로 무작위 배정했다. 위약군 75례(대조군), 카나글리플로진 50mg 1일 1회(82례), 100mg군(74례), 200mg군(77례), 300mg군(75례). 12주간 약물을 투여 후 HbA1c 변화치를 효과분석의 1차 평가항목(primary endpoint)으로 정했다. 아울러 500kcal 시험식 부하시험(meal tolerance test)도 실시했다. HbA1c, 체중, 혈압도 개선 4주마다 HbA1c를 확인한 결과, 대조군에서는 HbA1c에 별 변화가 없는 반면 카나글리플로진 투여군에서는 모두 HbA1c에 유의한 변화를 보였다. 또 HbA1c 7% 미만에 도달한 환자의 비율도 카나글리플로진 투여군에서 각각 유의하게 높았다(대조군 5.7%, 50mg군 21.0%, 100mg군 33.8%, 200mg군 29.2%, 300mg군 40.5%). 요중 글루코스/크레아티닌비(比), 공복혈당, 체중에 미치는 영향은 용량의존적이었지만, 시험식 부하시험 2시간 혈당에 미치는 효과는 50mg군에서 300mg군까지 큰 차이가 없었다. 혈압감소 효과도 유의했다. 결과적으로 카나글리플로진은 체중을 2~3kg 감량, HbA1c 약 0.8% 개선, 혈압 7～9/4～5mmHg 감소 등을 보였다. 한편 부작용으로는 중증인 경우는 적었고 50mg군에서 1례가 폐암이 발생했지만 인과관계는 확인되지 않고 있다. 또 시험약 복용을 중지할 만큼 심각한 부작용은 각 군에서 0~2례 정도이고, 폐암 외에 다른 부작용으로는 빈뇨, 구강내불쾌감, 가려움 등이었다. 지금까지 SGLT2억제제 시험에서 보고된 부작용 가운데 가장 많았던 요로·생식기계 감염증의 경우 100mg군에서 1례, 300mg군에서 1례 등 총 2례가 생식기감염증을 보였을 뿐이었다. 이번 결과에 대해 일본 기타사토연구소병원 당뇨병센터 야마다 사토루 교수는 "이번 연구 대상자에서 여성 비율이 30%로 적어 실제 임상에서는 요로 생식기계 감염증 발병빈도가 더 높을 수 있다. 그리고 75세 이상의 고령자 비율도 적어 고령자의 빈뇨 및 탈수 발병에 대한 안전성도 확인해야 한다"고 지적했다. 그러면서도 "적어도 장년층 남성에서 사구체 여과율이 유지된 증례로 대상을 한정하면 안전하게 당뇨병과 대사증후군 발병 요인을 확실하게 개선시킬 수 있는 것으로 보인다"고 설명했다. 이러한 SGLT2억제제의 안전성과 효과는 다파글리플로진에서도 이미 확인됐다. 이러한 결과는 이프라글리플로진, 엠파글리플로진, 토포글리플로진, 리세오글리플로진, 에르투글리플로진에 대해서도 같을 것이라고 야마다 교수는 예상하고 있다. SGLT2억제제의 특징은 기존 대부분의 당뇨병 치료제와 달리 인슐린분비와 인슐린 감수성이라는 인슐린 작용과 완전히 독립돼 혈당치를 개선시킨다는 점이다. 이론적으로 당뇨병 발병기전과 병태에 상관없이 혈당치 개선효과를 기대할 수 있는 것이다. 일본인을 대상으로 한 이번 연구와 다파글리플로진의 효과 보고는 단일 약제를 이용했지만, 서양에서는 다양한 약물과의 병용을 통해 효과를 검증하고 있다. 따라서 여러 당뇨병치료제로도 혈당 조절이 안 되는 비만형 2형 당뇨병에는 병합제를 검토해야 할 것이다. 한편으로 마른 당뇨병환자의 경우에는 SGLT2 억제제로 인한 체중감소가 문제가 될 수 있는 만큼 메트포르민 등의 일반적 제1선택제 보다 먼저 사용할 만큼 과학적 근거는 부족하다고 야마다 교수는 지적한다. 최대 우려사항은 고령자의 여름철 탈수 한편 SGLT2 억제제의 또 다른 우려 사항으로 여름철 고령자의 탈수증과 열 스트레스로 인한 고령장애(heat disorder) 등 생명에 관련한 합병증이다. 이밖에 이미 보고된 것처럼 요로·생식기계 감염증, 골대사에 미치는 영향, 혈중케톤체 농도의 상승 등을 들 수 있다. 야마다 교수는 "DPP-4억제제가 등장했을 당시 인크레틴 적정사용에 관한 권고가 있었던 것처럼 새로 등장한 약제인 만큼 안전성에 주의하면서 투약해야 할 것"이라고 강조했다.

Abstract

 

Keywords:

• SGLT2 inhibitor

Aims

We examined the efficacy, safety and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Japanese patients with type 2 diabetes (T2DM) undergoing diet and exercise therapy.

어휘 ;

Tolerability : 내약성 / 내성이란 말로 정확히는 내약성(Tolerability)으로, 환자가 약을 반복하여 투여 받을 시 체내 효소가 약에 대한 분해능력이 증가해 약효가 저하되는 현상.

Co-transporter : 공수송체.

Canagliflozin : 인보카나 / 약 이름..

Methods

Patients aged 20–80 years with T2DM diagnosed ≥3 months previously, and HbA1c of 6.9–9.9% were randomized to 50, 100, 200 or 300 mg canagliflozin or placebo once daily for 12 weeks. The primary and secondary endpoints were changes in HbA1c, fasting plasma glucose (FPG), urinary glucose/creatinine and postprandial glycaemic parameters following a meal test. The safety assessments included adverse events (AEs) and clinical laboratory tests.

어휘

HbA1c : 당화혈색소 / Hb는 hemoglobin의 약자이며 A는 Adult의 약자입니다. Hb의 종류는 보통 Hb A, Hb A2 , Hb F 등이 있으며 이 중에서 성인들에게 많이 쓰이는 것은 Hb A입니다. 이것들을 크로마토그래피라는 방법으로 분석하면 Hb A1a, Hb A1b, Hb A1c로 나누어지는데 통틀어서 Hb A1라고 부릅니다. Hb A의 종류 중에서 Hb A1 이라는 것이 있고 이것을 나누기 위해 a, b, c를 붙였으며 Hb A1C는 Hb A1의 일종입니다

Endpoint : 평가항목.

Fasting plasma glucose : 공복 혈당(EPG).

Postprandial : 식후의 만찬 후의.

Glycaemic : 당, 혈당.

Parameter : 한계, 조건, 매개변수. 변수(variable)

 

Results(결과)

Overall, 383 patients were randomized to receive either placebo (n = 75), or 50 mg (n = 82), 100 mg (n = 74), 200 mg (n = 77) or 300 mg canagliflozin (n = 75). At week 12, significant reductions in HbA1c were observed in all canagliflozin groups relative to placebo (−0.61, –0.80, –0.79 and −0.88% for 50, 100, 200 and 300 mg, respectively, versus +0.11% for placebo; all, p < 0.01). FPG and postprandial glycaemic parameters improved significantly in the canagliflozin groups. Body weight was significantly decreased by canagliflozin. No deaths or drug-related serious AEs were reported. There was no dose-dependent increase in the incidence of AEs in the canagliflozin groups. The incidence of hypoglycaemia was low; episodes were not severe or dose dependent. Canagliflozin did not affect serum creatinine levels or the urinary albumin/creatinine ratio.

어휘

Dose-dependent : 용량 의존적, 복용량에 따라 달라지는, 복용량에 따른, 복용량에 의한.

Conclusions(결론)

Treatment with canagliflozin for 12 weeks significantly improved glycaemic control and reduced body weight in Japanese patients with T2DM. Canagliflozin was well tolerated.

어휘

Tolerate : 내성(내약성, 항독성)이 있다. 소화 흡수 할 수 있다. 받아들이다. (여기선 별다른 부작용이 없었다)

Introduction(소개)

There are an estimated 366 million patients with diabetes worldwide, including 10.7 million in Japan. The prevalence of type 2 diabetes worldwide is expected to increase significantly over the next 20 years. Current treatment recommendations focus on improving diet and exercise, followed by monotherapy with an antihyperglycaemic drug.

Numerous studies, including the ADOPT trial, have shown that β-cell function continues to decline and that type 2 diabetes progressively worsens over time. Many existing treatments exert their effects by stimulating insulin secretion or by improving insulin action. However, such effects may be limited in patients with progressively deteriorating β-cell function. Other limitations of current therapies include hypoglycaemia, weight gain, peripheral oedema and gastrointestinal side effects, while many patients wish to avoid the side effects and inconvenience of injectable agents. Therefore, new therapeutic targets are needed to overcome or avoid the limitations associated with current drugs.

 

어휘

Monotherapy ; 단일 요법, 단일 치료.

Hypoglycaemia : 저혈당.

Oedema : edema 부종, 수종.

ADOPT ; A Diabetes Outcome Progression Trial

peripheral oedema ; 말단 부종, 혹은 하지 부종?

Gastrointestinal : 위장의, 위장 내의

 

In healthy humans, virtually all of the filtered glucose is re-absorbed at plasma glucose (PG) levels of up to ∼10 mmol/l—the renal threshold for glucose (RT_G)—at which point glucose transport reaches saturation. Above the RT_G, the urinary glucose concentration increases proportionally to PG.

Sodium glucose co-transporter 2 (SGLT2) is a glucose transporter expressed in the proximal renal tubules, and is responsible for the majority of glucose re-absorption from urine. Its activity is also independent of insulin. Enhanced ｅxpression of SGLT2 and increased glucose uptake were reported in animal models of diabetes and in patients with diabetes, suggesting that the kidney plays important roles in the maintenance and progression of hyperglycaemia. Accordingly, inhibitors of SGLT2 were developed to lower the RT_G and enhance urinary glucose excretion (UGE).

Canagliflozin (TA-7284 and JNJ-28431754; Mitsubishi Tanabe Pharma Corporation/Janssen Research & Development, LLC) is a potent, selective inhibitor of SGLT2.

 

어휘

Renal threshold : 신장 역치

proximal ; [의학] […의] 기부(基部)에 가까운, 기부의[to ‥].

Tubule : 작은 관, 세관

Uptake : 섭취

Excretion : 배설물, 분비물.

One phase 1 study in healthy men showed that a single dose of canagliflozin (in the morning) of up to 800 mg per day significantly and dose-dependently increased 24-h UGE and dose-dependently reduced RT_G. The incidence of adverse events (AEs) was low, with the majority of AEs being mild in severity.

In patients with type 2 diabetes, treatment with canagliflozin (100 mg once daily or 300 mg twice daily) for 28 days as an add-on to insulin reduced RT_G, increased UGE, and reduced HbA1c, fasting plasma glucose (FPG) and body weight compared with placebo. In a subsequent 12-week study, canagliflozin as an add-on to metformin significantly improved glycaemic control, with a low incidence of hypoglycaemia and with significant weight loss compared with placebo in patients with type 2 diabetes. In another study, treatment with 100 or 300 mg canagliflozin once daily for 26 weeks in patients with type 2 diabetes who were on diet and exercise therapy alone significantly reduced HbA1c, FPG, 2-h postprandial PG, body weight and systolic blood pressure compared with placebo.

However, these three studies were conducted mainly in obese Caucasian patients. Therefore, studies are needed to assess the efficacy and safety profiles of canagliflozin in other ethnic groups. The aim of this study was to determine the efficacy, safety and optimal doses of canagliflozin for the treatment of type 2 diabetes in Japanese patients.

 

어휘

Metformin : 제 1형 당뇨병 치료제.

Systolic blood pressure : 수축기 혈압. 

 

Patients(환자)

Patients aged 20–80 years who were diagnosed with type 2 diabetes at least 3 months before the run-in period and who had HbA1c levels of 6.9–9.9% at the start of the run-in period were eligible for this study. Patients were to have undergone diet and exercise therapy, with no change in their regimen for ≥8 weeks before the study. Patients previously treated with antihyperglycaemic drugs were also eligible if their treatment was discontinued during a washout period after they had provided informed consent. Exclusion criteria included history of or current serious diabetic complications (e.g. proliferative diabetic retinopathy, stage 3 or later overt nephropathy, diabetic ketoacidosis or serious diabetic neuropathy), FPG ≥270 mg/dl (1 mg/dl FPG = 0.0555 mmol/l), indication for insulin therapy, hereditary glucose-galactose malabsorption or renal glycosuria. Additional inclusion/exclusion criteria are listed in the Supporting Information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, the Pharmaceutical Affairs Law of Japan, Good Clinical Practice (GCP), and the approved study protocol. The study was approved by institutional review boards at each participating site. All patients provided written informed consent before entering the washout or the run-in period.

 

어휘

Run in period : 고혈압 환자를 대상으로 하는 임상연구에서 피험자에게 통상적으로 1-2주간의 휴약기(washout period)에 연이어 2-4주 내외의 치료 전 단계(run-in period)를 두는 경우가 있다. 휴약기란 피험자가 기존의 치료방법을 바꾸기 전에, 이전에 복용했던 약물의 영향이 완전히 소실될 때까지 일정한 기간 약을 먹지 않는 것을 말한다. ‘run-in period’는 피험자를 연구 대상군에 무작위 배정하기 전, 일정한 준비기간 동안 위약(가짜 약)을 투여하면서 순응도를 평가하는 기간이다. 그런 점에서 ‘run-in period’ 역시 일종의 휴약기라고 할 수 있다. 굳이 ‘washout period’ 외에 ‘run-in period’를 두는 것은 안정적인 상황에서는 잘 드러나지 않는 부적절한 피험자나 순응도가 낮은 피험자를 걸러내는(screening)데 중요한 역할을 하기 때문이다. ‘run-in period’는 연구자/의뢰자(제약회사)들이 순응도가 일정 수준 이상이 되는 피험자들만을 최종 연구 대상으로 선정하기 위한 용도로 종종 사용된다.

proliferative diabetic retinopathy : 증식성 당뇨 망막변증

nephropathy ; 신장 장애

diabetic ketoacidosis ; 당뇨병성 케토산증

malabsorption ; 흡수불량

[출처] ‘Run-in period’의 윤리|작성자 taekhan2

 

Study Design, Treatments and Blinding 연구 설계, 치료 그리고 눈가림.

This was a multicentre, randomized, placebo-controlled, parallel-group study. After giving informed consent, patients treated with diet and exercise entered a single-blind 4-week placebo run-in period (with visits at weeks 2 and 4). Patients who were previously treated with one or more antihyperglycaemic drugs discontinued these agents after providing informed consent and entered a washout period of ≥8 weeks before starting the single-blind run-in period. Eligibility criteria were checked at the start and end of the run-in period. At the end of this period, eligible patients were randomized using a block allocation method into one of five groups (ratio 1 : 1 : 1 : 1 : 1) to receive placebo or one of four doses of canagliflozin (50, 100, 200 or 300 mg once daily) for 12 weeks. Randomization was conducted by a central committee, which provided the investigators at each site with randomization codes stored in sealed envelopes. The randomization code was not to be broken until data entry had been completed or unless needed in an emergency. Investigators and patients were blinded to the study drug received during the treatment phase. Visits were scheduled at weeks 4, 8 and 12 in the treatment phase, with a follow-up visit 2 weeks after the treatment phase. The patients did not receive the study drug during the follow-up phase. In terms of concomitant treatments, antihyperglycaemic drugs were prohibited after randomization until the end of the follow-up period. Diet and exercise interventions were to be continued without modification after randomization until the end of the follow-up period. This trial was registered at ClinicalTrials.gov (NCT01022112).

Efficacy Outcomes 유효성 결과

The primary endpoint(일차 평가 항목) was the change in HbA1c from the last day of the run-in period (baseline) to the end of the treatment period. Secondary endpoints(이차 평가 항목) included change in FPG, percentages of patients with HbA1c <7.0%, changes in urinary glucose/creatinine ratio, body weight, body mass index (BMI), waist circumference, lipid levels, blood pressure, insulin and proinsulin(인간 전구 인슐린) levels, homeostasis model assessment of β-cell function (HOMA-β) and meal tolerance-related parameters.

Meal Tolerance Test(시험식 부하 시험)

At baseline and week 12, patients underwent a meal tolerance test after a ≥10-h fast (water and calorie-free drinks were permitted). After basal blood sampling and completely emptying their bladder, the patients consumed (within 10 min) a standard test meal (approximately 500 kcal; 60% carbohydrate, 25% fat and 15% protein). Blood samples were obtained at 30, 60, 90 and 120 min after starting the meal, and urine samples were also collected. At 120 min, the patients were asked to completely empty their bladder.

Treatment Compliance(치료 순응도)

To examine treatment compliance, the number of tablets remaining at each visit was counted, and the investigator verbally discussed treatment adherence with the patient.

Safety(안전성)

AEs and safety assessments, including vital signs, 12-lead electrocardiography(12 유도 심전도), clinical laboratory tests (blood chemistry, haematology, coagulation, bone markers(골표지자 검사) and urinalysis(검뇨, 소변 검사)), and hypoglycaemic symptoms, were recorded throughout the study. AEs were classified according to system organ class and preferred term (MedDRA/J version 13.0) and were evaluated in terms of their potential relationship with the study drug (no causal relationship or possible causal relationship) and severity (mild, moderate or severe).

Statistical Methods(통계 방법)

The sample size calculation is described in the Supporting Information online. Primary and secondary analyses were conducted in the full analysis set (FAS), defined as all allocated patients, excluding patients who did not receive any study drug or who did not have any efficacy data after entering the treatment phase. In the event of missing data for efficacy variables, the last observation carried forward (LOCF) approach was used to impute missing values in the FAS analyses. Safety parameters were evaluated in the safety analysis set, defined as all patients, except those who did not receive any study drug during the treatment phase or who did not have any safety data during the treatment phase. The primary and secondary endpoints were examined descriptively and by analysis of covariance (ancova) with treatment group as a fixed factor and value at baseline as a covariate. Comparisons between canagliflozin and placebo at week 12 (with LOCF) and significance tests were performed based on the differences between the least squares (LS) means (the adjusted mean change from baseline obtained from ancova) for each treatment. For categorical variables, the percentage of patients was determined with 95% CIs (confidence intervals). The incidences of AEs and adverse drug reactions (ADRs) were determined descriptively as the number and proportion of patients. According to the closed testing procedures, the analysis of multiple comparisons of the primary endpoint was performed with a two-sided significance level of 0.05. Because the significance level was not controlled in multiple comparisons of data other than the primary endpoint, the p values for these comparisons are nominal. For baseline imbalances in patient characteristics, the significance level was set at 0.15 (two-sided).

 

어휘

Least square : 최소 자승법, 최소 제곱법.

Nominal : 이름뿐인, 아주 적은.

Significance level : 유의 수준.

 

Patients(환자)

The disposition(기질, 처분, 성향, 배치, 배열) of patients is summarized in Figure 1. Five-hundred and forty-three patients consented to participate, 493 entered the run-in period and 383 were randomized and treated with either placebo (n = 75), or 50 mg (n = 82), 100 mg (n = 74), 200 mg (n = 77) or 300 mg canagliflozin (n = 75). Overall, 160 patients withdrew from the study before randomization for the following reasons: patient's request (n = 23), did not meet eligibility criteria (n = 97), FPG decreased below the specified range (n = 10), worsening of diabetes (n = 2), experienced an AE (n = 1) or other reasons (n = 27). Twenty-two patients withdrew after randomization because the FPG was beyond the level specified in the exclusion criteria (n = 8), at the patient's request (n = 6), because of an AE (n = 4), worsening of diabetes (n = 2) or other reasons (n = 2). The full analysis and safety analysis sets consisted of 382 and 383 patients, respectively.

Figure 1. Patient disposition.

Patient characteristics(환자의 인적 사항?) were generally well balanced among the five groups, with no marked differences among treatment groups (Table 1) except for height, body weight and presence/absence of neuropathy(신경장애) or hypertension, which were unbalanced among the five groups at p < 0.15. Ancova was performed using baseline HbA1c and these imbalanced factors as covariates and showed that the changes in HbA1c were unaffected by adjustment for any of these variables. Of the 382 patients included in the full analysis set, 260 (68.1%) were male, and their mean ± standard deviation age(평균나이 및 표준편차 나이) was 57.4 ± 10.6 years, BMI was 25.70 ± 4.23 kg/m² and HbA1c was 8.09 ± 0.82%. Just under half of the patients (44.0%) had previously received antidiabetic drugs, including sulfonylureas (16.8%) and biguanides (14.9%); these patients entered a washout period of ≥8 weeks after providing informed consent and before starting the run-in period.

Glycaemic Control(당 조절)

Figure 2A, B shows the changes in HbA1c over time and the change from baseline to week 12 (with LOCF) in each of the five groups. HbA1c levels measured at each time are shown in figure S1A. Improvements in HbA1c were observed as early as week 4 in the canagliflozin groups. The mean changes in HbA1c in the 50, 100, 200 and 300 mg canagliflozin groups (−0.61, –0.80, –0.79 and −0.88%, respectively) differed significantly from that in the placebo group (+0.11%; all, p < 0.01). The changes in HbA1c from baseline to week 12 (with LOCF) were significantly greater in the 100, 200 and 300 mg groups than in the 50 mg group (all, p < 0.05). More patients in the 50, 100, 200 and 300 mg canagliflozin groups achieved HbA1c < 7% at week 12/LOCF compared with the placebo group; specifically, HbA1c < 7% at week 12/LOCF was achieved by 17 (21.0%), 24 (33.8%), 21 (29.2%), 30 (40.5%) and 4 (5.7%) patients in these groups, respectively.

 

Other Efficacy Variables(기타 효과 변수들)

Figure 2D and figure S1C show the effects of canagliflozin on urinary glucose/urinary creatinine ratio (i.e. UGE) from baseline to week 12. All four doses of canagliflozin elicited significant increases in UGE compared with placebo (all, p < 0.01), and these increases were maximal at the first on-treatment visit (week 4), with UGE reaching a plateau thereafter. The increases in UGE also showed a dose-dependent trend, with the greatest increases observed in the 300 mg canagliflozin group.

As indicated in figures 2E and S1D, treatment with canagliflozin for 12 weeks (with LOCF) resulted in significantly greater reductions in body weight compared with placebo. These reductions in body weight were also dose dependent and were accompanied by small, but significant, reductions in waist circumference (Table 2).

Meal Tolerance Test(시험식 부하 시험)

Meal tolerance tests were performed at baseline and week 12 (Table 2). Glucose levels measured immediately before and at the specified times after consuming the meal are shown in figure S2. All four doses of canagliflozin provided significant reductions from baseline to week 12 (with LOCF) in 2-h PPG (figure 2F) and 2-h postmeal insulin levels, and in the areas under the glucose and insulin concentration curves for 0–2 h (AUC_0–2h). By contrast, 2-h postmeal UGE increased in the canagliflozin-treated groups from baseline to week 12 (with LOCF).

 

Safety(안전성)

AEs(부작용)

Overall, 266 AEs occurred in 169 patients, including 43 AEs in 26 (34.7%) patients in the placebo group, 52 AEs in 37 (45.1%) patients in the 50 mg group, 60 AEs in 34 (45.9%) patients in the 100 mg group, 61 AEs in 38 (49.4%) patients in the 200 mg group and 50 AEs in 34 (45.3%) patients in the 300 mg group. There were no deaths. AEs leading to study discontinuation occurred only in 0–2 patients across the groups (lung adenocarcinoma, pollakiuria, oral discomfort and pruritus) (Table 3). Table 4 summarizes the most common treatment-emergent(치료 후 발생한) AEs in each group. Most of the AEs were mild; only one serious AE occurred (lung adenocarcinoma in one patient in the 50 mg group). Five patients with treatment-emergent AEs withdrew from the study although, in one of these, the primary reason for withdrawal was disease progression. The AEs reported in >3% patients were nasopharyngitis, increased blood ketone bodies, hypoglycaemia unawareness, hypoglycaemia, gastritis, periodontitis, upper respiratory tract infections and malaise, but there was no dose-dependent trend. Two vulvovaginal infections were reported in the canagliflozin group (one each of vulvovaginal candida infection in the 100 and 300 mg groups). Volume-related AEs (dry mouth, dehydration, dizziness and palpitation) were reported in 0–3 patients in the canagliflozin groups and in 1 patient in the placebo group. Pollakiuria was reported in three patients in the canagliflozin groups and in none of the patients in the placebo group. No urinary tract infections were reported in any group.

No clinically meaningful changes in electrocardiograms were observed. Although canagliflozin was associated with a decrease in blood pressure, no postural hypotension(기립성 저혈압, 체위성 저혈압) was reported. No clinically meaningful changes in serum electrolytes(전해질) were observed in any of the groups. Small increases in haemoglobin, haematocrit and blood urea nitrogen(혈중 요소질소) were observed in the canagliflozin-treated groups. The change in blood total ketone body concentration peaked at week 4, showing a trend towards a dose-dependent increase. Thereafter, the mean changes in the 200- and 300-mg groups decreased, and the mean changes at week 12 of the treatment period were similar at all doses of canagliflozin. There were no remarkable changes in serum creatinine or the urinary albumin/creatinine ratio, suggesting that canagliflozin did not impair kidney function. No cardiovascular events occurred in this study.

There were small increases in urinary N-terminal cross-linked telopeptide of type I collagen levels and serum C-terminal cross-linked telopeptide of type I collagen levels together with slight decreases in bone-specific alkaline phosphatase and 1,25-(OH)₂ vitamin D levels from baseline to week 12 in the canagliflozin groups. The clinical relevance of these small changes is unknown and there were no AEs suggestive of changes in bone-related markers.

 

어휘

Cross linked : 교차 결합의, 가교 결합의

Hypoglycaemia

As expected based on the mechanism of action, the incidence rates of hypoglycaemic symptoms and hypoglycaemia reported as an AE (including hypoglycaemia unawareness) were low in all of the canagliflozin-treated groups (Table 4); no patient in the placebo group experienced hypoglycaemia. There were no major differences in the incidence of these symptoms/events among the four canagliflozin-treated groups (Table 4). All episodes of hypoglycaemia were mild.

In this study, treatment with canagliflozin for 12 weeks significantly improved glycaemic control in terms of HbA1c, FPG and 2-h PPG, as well as other clinically relevant parameters (e.g. body weight, blood pressure and lipid levels) in patients with type 2 diabetes undergoing diet and exercise therapy. The changes, particularly glycaemic control, were dose dependent, with greater improvements with higher doses (≥100 mg) of canagliflozin compared with 50 mg canagliflozin.

AEs occurred in less than half of the patients, and were mostly mild in severity, with only one serious AE that was judged unrelated to the study drug. Furthermore, the incidence of hypoglycaemia and vulvovaginal infections was low, with no evidence for a dose-dependent effect on AEs.

Several other clinical studies of canagliflozin have been published recently. In the first of these, a 28-day study involving 29 patients with type 2 diabetes, 100 mg canagliflozin once daily and 300 mg canagliflozin twice daily significantly reduced RT_G and increased UGE, HbA1c, FPG and body weight compared with placebo. The second study, a 12-week study, showed that doses of 50, 100, 200 or 300 mg canagliflozin once daily, or 300 mg twice daily, achieved significant changes in HbA1c of −0.79, −0.76, −0.70, −0.92 and −0.95%, respectively, compared with −0.22% for placebo (all p < 0.001) and −0.74% for 100 mg sitagliptin once daily. The changes in HbA1c, FPG and body weight observed in that study were similar to those observed in this study, and were associated with significant increases in the urinary glucose/creatinine ratio. In those studies, patients either continued insulin therapy or metformin. Canagliflozin as monotherapy was tested in the study by Stenlöf et al., who reported that HbA1c decreased significantly by −0.77 and −1.03% in patients treated with 100 and 300 mg canagliflozin, respectively, compared with 0.14% in patients treated with placebo (both, p < 0.001). As observed in the study by Stenlöf et al., a significant increase in HDL-C, a decrease in triglycerides and a small increase in LDL-C were observed in our study. The LDL-C/HDL-C ratio decreased slightly in both studies. The clinical relevance of these small changes in lipids needs to be assessed in a long-term study.

Dapagliflozin is another SGLT2 inhibitor currently in clinical development. Several studies of ≥12 weeks in duration have been reported. Patients in those studies received dapagliflozin or placebo alone; dapagliflozin, metformin or placebo alone; or dapagliflozin or placebo in combination with oral antihyperglycaemic drugs plus insulin. The results of those studies were generally similar to those for canagliflozin in this study.

The RT_G was reported to be increased in patients with type 2 diabetes, supporting the rationale for using SGLT2 inhibitors to treat this disease. Canagliflozin substantially reduced RT_G in both animal models and humans, favouring glucose excretion rather than re-absorption. Indeed, in the clinical studies performed to date, canagliflozin significantly enhanced UGE adjusted for urinary creatinine levels.

This study revealed that canagliflozin improves β-cell function in terms of HOMA-β and proinsulin/insulin ratio. The study by Rosenstock et al. also revealed that canagliflozin improves β-cell function, estimated by HOMA2-%B. In an animal study, SGLT2 deletion was found to preserve β-cell function by increasing β-cell mass in mice fed a high-fat diet for 4 weeks. Further studies are needed to examine the precise mechanisms and the role of glucose toxicity in influencing β-cell function in humans. Studies evaluating the long-term effects of canagliflozin on β-cell function, including after cessation of treatment, will be of particular interest.

Some limitations of this study warrant mention. First, the study was relatively short (12 weeks), which may limit the extent of HbA1c lowering. Second, the number of patients enrolled may have been too small to detect significant differences among the higher dose groups. Finally, this study was conducted in Japanese patients, limiting generalizability to other patient populations.

The results of this study show favourable efficacy and safety profiles of canagliflozin monotherapy in Japanese patients with type 2 diabetes, particularly at doses ≥100 mg per day. Additional clinical studies of canagliflozin are warranted and are now underway to extend these findings, including the use of canagliflozin instead of or in combination with other antihyperglycaemic drugs. The results of such studies will help establish the indications(징후, 적응, 바람직한 요법, 적응증)for canagliflozin.