Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

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OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes. RESEARCH DESIGN AND METHODS Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to &lt;75 mL/min/1.73 m2, and treated with optimized renin–angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c &lt;7.5% (58 mmol/mol) or ≥7.5%. RESULTS Of 5,674 patients, 3,637 (64.1%) received insulin at baseline. Overall, 5,663 patients were included in the analysis for HbA1c; 2,794 (49.3%) had baseline HbA1c &lt;7.5% (58 mmol/mol). Finerenone significantly reduced risk of the kidney composite outcome independent of baseline HbA1c level and insulin use (Pinteraction = 0.41 and 0.56, respectively). Cardiovascular composite outcome incidence was reduced with finerenone irrespective of baseline HbA1c level and insulin use (Pinteraction = 0.70 and 0.33, respectively). Although baseline HbA1c level did not affect kidney event risk, cardiovascular risk increased with higher HbA1c level. UACR reduction was consistent across subgroups. Adverse events were similar between groups regardless of baseline HbA1c level and insulin use; few finerenone-treated patients discontinued treatment because of hyperkalemia. CONCLUSIONS Finerenone reduces kidney and cardiovascular outcome risk in patients with CKD and T2D, and risks appear consistent irrespective of HbA1c levels or insulin use.

 îáçîðå îòðàaeåíû îñíîâíûå íàïðàâëåíèè ôàðìàêîãåíåòè÷åñêèõ èññëåäîâàíèé ïðèìå-íåíèÿ ìåòôîðìèíà ó áîëüíûõ ñàõàðíûì äèàáåòîì 2 òèïà. Ïðèâåäåíû ðåçóëüòàòû èçó÷åíèÿ ïîëèìîðôèçìîâ ãåíîâ áåëêîâ, ó÷àñòâóþùèõ â ôàðìàêîêèíåòèêå ïðåïàðàòà, à òàêaeå ñäåëà-íû ïðåäïîëîaeåíèÿ îòíîñèòåëüíî äðóãèõ ãåíîâ, êîòîðûå ìîãóò îáóñëàâëèâàòü îñîáåííîñòè ôàðìàêîäèíàìèêè ïðåïàðàòà.Êëþ÷åâûå ñëîâà: ôàðìàêîãåíåòèêà; ïåðñîíèôèêàöèÿ; ìåòôîðìèí; ôàðìàêîêèíåòèêà; ôàðìàêîäèíàìèêà.Àêòèâíîå èññëåäîâàíèå ãåíîòèïà â ñâÿçè ñ âîçìîaeíî-ñòüþ ïðîãíîçèðîâàíèÿ äåéñòâèÿ îïðåäåë¸ííûõ ïðåïàðà-òîâ íàñ÷èòûâàåò îêîëî 10 ëåò.  ïîñëåäíåå âðåìÿ ïðåä-ïðèíÿòû îïðåäåëåííûå óñèëèÿ â ýòîì íàïðàâëåíèè è íà-ðÿäó ñ èçâåñòíûìè ãåíîòèïàìè âûÿâëÿþòñÿ íîâûå ãå-íû-êàíäèäàòû, ìîäèôèêàöèè êîòîðûõ ìîaeíî ñâÿçàòü ñ ýôôåêòèâíîñòüþ èëè íåóäà÷åé ïðè èñïîëüçîâàíèè òåõ èëè èíûõ ïðåïàðàòîâ.Ïðåïàðàòîì âûáîðà äëÿ èíèöèàöèè òåðàïèè áîëüíûõ ñàõàðíûì äèàáåòîì 2 òèïà (ÑÄ2) ñ÷èòàþò ìåòôîðìèí. Îñíîâíûì ìåõàíèçìîì äåéñòâèÿ (ïðåïàðàò èç ãðóïïû áè-ãóàíèäîâ, ïîâûøàþùèé ïå÷åíî÷íóþ è ïåðèôåðè÷åñêóþ ÷óâñòâèòåëüíîñòü ê ýíäîãåííîìó èíñóëèíó, íå âëèÿÿ íà åãî ñåêðåöèþ) ÿâëÿåòñÿ ñíèaeåíèå ïðîäóêöèè ãëþêîçû ïå-÷åíüþ, ïîâûøåíèå çàõâàòà ãëþêîçû ìûøöàìè è aeèðîâîé òêàíüþ ïóòåì óñèëåíèÿ ñâÿçûâàíèÿ èíñóëèíà ñ ðåöåïòî-ðàìè è ïîâûøåíèÿ àêòèâíîñòè òðàíñïîðòåðîâ ãëþêîçû ÃËÞÒ-1 è ÃËÞÒ-4. Ñíèaeåíèå óðîâíÿ ãëèêèðîâàííîãî ãåìîãëîáèíà â ðåçóëüòàòå ïðèìåíåíèÿ ìåòôîðìèíà íà-áëþäàåòñÿ â ïðåäåëàõ 1 -2 % [1, 3].22 íîÿáðÿ 2010 ã. â aeóðíàëå "The Year in Diabetes and Obesity" áûëà îïóáëèêîâàíà ñòàòüÿ Liana K. Billings è Jose C. Florez "The genetics of type 2 diabetes: what have we learned from GWAS?", â êîòîðîé áûëà îáîáùåíà èí-ôîðìàöèÿ î ãåíàõ, ðàçëè÷íûì îáðàçîì ñâÿçàííûõ ñ ðàç-âèòèåì ÑÄ2 [12]. Ê 2011 ã. ïîÿâèëàñü ñâîäíàÿ èíôîðìàöèÿ î âîçìîaeíûõ ãåíàõ-êàíäèäàòàõ, îòâåòñòâåííûõ çà ýôôåêòèâíîñòü ïå-ðîðàëüíûõ ñàõàðîñíèaeàþùèõ ïðåïàðàòîâ (ÏÑÑÏ), â ÷à-ñòíîñòè, ìåòôîðìèíà (ðèñ. 1).  îáøèðíîì èññëåäîâàíèè GoDARTS (5 386 ïàöèåíòîâ ñ ÑÄ2) ñ ïîìîùüþ GCTA ìå-òîäà (êàðòèðîâàíèå ãåíîâ) áûëî âûÿâëåíî, ÷òî îñîáåííî-ñòè ôàðìàêîëîãè÷åñêîãî îòâåòà íà ìåòôîðìèí ÿâëÿþòñÿ íàñëåäñòâåííûì ïðèçíàêîì è ìîãóò âàðüèðîâàòü â çàâè-ñèìîñòè îò ãåíîòèïà ëîêóñà ãåíà àòàêñèè-òåëåàíãèýêòà-çèè (ÀÒÌ) [58]. íàñòîÿùåå âðåìÿ âñ¸áîëüøèé èíòåðåñ âûçûâàþò ïîëèìîðôèçì ãåíîâ, ó÷àñòâóþùèõ êàê â ôàðìàêîêèíåòè-êå, òàê è â ôàðìàêîäèíàìèêå ïåðîðàëüíûõ ñàõàðîñíè-aeàþùèõ ïðåïàðàòîâ [21]. Îäíàêî ìíîãèå èññëåäîâàòåëè îòìå÷àþò âûñîêóþ âåðîÿòíîñòü âëèÿíèÿ è äðóãèõ ãåíîâ, òàêèõ, êàê, íàïðèìåð, ôàêòîð òðàíñêðèïöèè ãåïàòîöèòîâ 4-a [24].  ñâÿçè ñ ýòèì ïîèñê íîâûõ ðåãóëÿòîðíûõ è äðóãèõ ãåíîâ-ìèøåíåé è èõ ïîëèìîðôèçìà, îòâå÷àþùèõ çà ýôôåêòèâíîñòü ÏÑÑÏ, îñòà¸òñÿ àêòóàëüíîé ïðîáëå-ìîé.Îñîáûé èíòåðåñ, êàê âèäíî èç äèàãðàììû, ïðåäñòàâ-ëÿåò ôàðìàêîãåíåòè÷åñêîå èññëåäîâàíèå ïðèìåíåíèÿ ìåòôîðìèíà èç-çà òîãî, ÷òî äàííûé ïðåïàðàò èñïîëüçóåò-ñÿ â ìåäèöèíñêîé ïðàêòèêå áîëåå ïîëóâåêà è ÿâëÿåòñÿ ïåðâûì ýòàïîì ìåäèêàìåíòîçíîé òåðàïèè ÑÄ2. Ýôôåêò ìåòôîðìèíà çàâèñèò îò âñàñûâàíèÿ, òðàíñïîðòèðîâêè, ðàñïðåäåëåíèÿ è âûâåäåíèÿ âåùåñòâà. Ïðè ýòîì ñóùåñò-âóþò ðàçíî÷òåíèÿ ïî ïîâîäó âëèÿíèÿ ïîëèìîðôèçìà òðàí...

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