さまよう薬剤師のブログ

学位を持っても、センスのない、感染制御専門薬剤師のブログ.  I have Ph.D. but less sense ID pharmacist.

SGLT2阻害薬の復習

Empagliflozinが、大きなインパクトを出しました。詳細は以前のブログにて…

そこで、SGLT2阻害薬の復習を


SGLT2阻害薬のkey word
 (ここが知りたい糖尿病ハンドブックver2より引用)

  1. 尿糖排泄
  2. 体重減少
肥満型で若者〜中年の腎機能が保たれている症例によい適応

特徴

  • 内臓脂肪減少 SGLT2阻害薬により、1日100g程度のブドウ糖が尿中排泄。よって、400キロカロリー減。
  • 血糖降下はインスリン作用を介さない
  • 血糖値依存性、腎機能依存性
  • 他の糖尿病薬との併用効果がある。

日本糖尿病学会からもrecommendation


  • インスリンやSU薬等インスリン分泌促進薬と併用する場合には、低血糖に十分留意して、それらの用量を減じる(方法については下記参照)。インスリンとの併用は治験で安全性が検討されていないことから特に注意が必要である。患者にも低血糖に関する教育を十分行うこと。
  • 高齢者への投与は、慎重に適応を考えたうえで開始する。発売から3ヶ月間に65歳以上の患者に投与する場合には、全例登録すること。
  • 脱水防止について患者への説明も含めて十分に対策を講じること。利尿薬との併用は推奨されない。
  • 発熱・下痢・嘔吐などがあるときないしは食思不振で食事が十分摂れないような場合(シックデイ)には必ず休薬する。
  • 本剤投与後、薬疹を疑わせる紅斑などの皮膚症状が認められた場合には速やかに投与を中止し、皮膚科にコンサルテーションすること。また、必ず副作用報告を行うこと。
  • 尿路感染・性器感染については、適宜問診・検査を行って、発見に努めること。問診では質問紙の活用も推奨される。発見時には、泌尿器科、婦人科にコンサルテーションすること。
  • 原則として、本剤は当面他に2剤程度までの併用が推奨される。

平成27年9月15日、添付文書の改訂
  
UpToDate より

SGLT2 inhibitors

Given the absence of long-term efficacy and safety data, we do not recommend sodium-glucose co-transporter 2 (SGLT2) inhibitors for routine use in patients with type 2 diabetes. SGLT2 inhibitors may play a role as a third-line agent in patients with inadequate glycemic control on two oral agents (eg, metformin and sulfonylurea) if for some reason combination metformin and insulin is not a therapeutic option.

The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and A1C levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. The glucose-lowering effect is independent of insulin (beta cell function and insulin sensitivity).

Glycemic efficacy 

SGLT2 inhibitors have been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, sitagliptin, and insulin. Dapagliflozin, canagliflozin, and empagliflozin are available in Europe and the United States,and other SGLT2 inhibitors are in development. In meta-analyses of clinical trials comparing SGLT2 inhibitors with placebo or active comparators (metformin, sulfonylurea, dipeptidyl peptidase-4 [DPP-4] inhibitors, insulin), SGLT2 inhibitors reduced A1C by approximately 0.5 to 0.7 percentage points (mean difference versus active comparators -0.06 percent), making them relatively weak glucose-lowering agents, similar in potency to the DPP-4 inhibitors.

Adverse effects 

In clinical trials, side effects of SGLT2 inhibitors include an increased incidence of vulvovaginal candidiasis, reported in 10 to 15 percent of women. Similarly, in meta-analyses of dapagliflozin trials (10 mg), there was a higher rate of vulvovaginal candidal infections (9.5 versus 2.6 percent in the control groups).In addition, there was a small but significant increase in the rate of urinary tract infections (8.8 versus 6.1 percent). There were 10 cases of bladder cancers diagnosed among dapagliflozin users in clinical trials, five of which occurred in the first six months of dapagliflozin, a much shorter time interval than would be expected if dapagliflozin promoted tumorigenesis. However, these findings have prompted the US Food and Drug Administration (FDA) to recommend postmarketing surveillance studies. There are no long-term safety data with regard to the effects of chronic glucosuria on the urinary tract. In addition, there are no data on microvascular or cardiovascular outcomes.

“Euglycemic” (usually meaning plasma glucose <250 mg/dL) diabetic ketoacidosis has been reported in patients with type 2 diabetes taking SGLT2 inhibitors. In these individuals, the absence of substantial hyperglycemia delays recognition of the problem by both the patients and the clinicians. Serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed. Off-label use in type 1 diabetes is discouraged in the absence of enough data to know if such therapy is safe.

Dosing

Canagliflozin is taken orally before the first meal of the day.The initial dose is 100 mg once daily, and it can be increased to 300 mg daily to achieve glycemic goals. In patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 45 to 59 mL/min), the dose should not exceed 100 mg daily. Canagliflozin should not be given to patients with eGFR <45 mL/min or in patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment.Dapagliflozin (10 mg once daily) can be taken any time of day, with or without food. It is not recommended for use in patients with eGFR <60 mL/min or in patients with active bladder cancer. For patients with severely reduced liver function, a starting dose of 5 mg is recommended. There is limited experience with either drug in patients with severe hepatic impairment.