SGLT2抑制剂治疗2型糖尿病的能量代谢的相关研究进展

2型糖尿病是由胰岛素分泌不足和缺乏导致,SGLT2抑制剂在治疗2型糖尿病的能量代谢上有着明显作用。SGLT2抑制剂对于治疗2型糖尿病在能量代谢、血压、体重方面都有一定的促进作用,但是其也存在真菌感染、肾脏损害等不良反应,通过对SGLT2抑制剂治疗2型糖尿病的相关研究,探析其能量代谢的机理、效果,以期为糖尿病药物研究者提供参考。     

SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: A systematic review and meta-analysis

Background

Sodium–glucose co-transporter 2 (SGLT2) inhibitors may have renal protective effects in people with impaired kidney function. We assessed the use of SGLT2 inhibitors in people with type 2 diabetes with or without renal impairment [defined as estimated glomerular filtration rate (eGFR) of ≥30 and <60 ml/min/1.73 m² and/or UACR > 300 and ≤5000 mg/g] by conducting a systematic review and meta-analysis of available studies.

Peripheral Neuropathy as a Presenting Feature of Type 2 Diabetes: A Case-Controlled Study

The characteristics and outcome of 68 newly diagnosed Type 2 diabetic patients who presented with clinically evident peripheral neuropathy were compared with matched controls who had no neuropathy at diagnosis. All subjects (34 male) whose median age was 68 (range 47–89) yr were identified from a computerized diabetes register and presented in 1982–1990. The groups were compared at diagnosis for haemoglobin A₁, body mass index, blood pressure, smoking, and alcohol consumption, and for co-existent coronary and peripheral vascular disease. Mortality and morbidity were recorded to March 1991. Significantly more patients with neuropathy had co-existent peripheral vascular disease: 24(35%) compared to 6(9%) controls (p = 0.0021). Twenty (30%) of those with neuropathy and no controls had retinopathy at diagnosis, which was sight-threatening in 10. Seven (10%) with neuropathy but no controls presented with foot ulcers, one requiring limited amputation. Two more patients with neuropathy and one control subsequently developed foot ulcers resulting in one or more amputation in each group. Twenty-one (31%) of those with neuropathy and 14 (21%) controls died (p = 0.2109). In conclusion more diabetic patients with clinically evident peripheral neuropathy at diagnosis have peripheral vascular disease than matched patients without neuropathy. It is likely that macrovascular disease either exacerbates or causes the neuropathy in this group of patients. They are at high risk of developing foot ulceration and high priority should be given to foot care in planning their management.     

ESC 2019 DAPA-HF研究解读:SGLT2抑制剂的跨界演出

SGLT2抑制剂是近年来诞生的新型降糖药物,在糖尿病领域的几项大型临床研究中证实能减少心血管事件,但获益机制并不能完全归结于血糖的控制。近期ESC上公布的DAPA-HF研究(Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure)证实了SGLT2抑制剂对于未患2型糖尿病的射血分数减低的心力衰竭(HFrEF)患者依然可以显著降低心血管死亡和心力衰竭住院风险,这一里程碑式的研究将开启心力衰竭治疗新的时代。     

Pulse Pressure as a Risk Factor for Peripheral Vascular Disease in Type 2 Diabetic Patients

This study examined whether pulse pressure (PP) could be an independent predictor and associated with severity of peripheral vascular disease (PVD) in 396 type 2 diabetic patients (143 men and 253 women, aged 64.1 ± 11.2 years). Peripheral vascular disease was diagnosed by an ankle‐brachial index (ABI) < 0.90 and as severe PVD if ABI < 0.80. Association was evaluated before and after adjustment for age, sex, diabetes duration, hypertension, smoking, fasting plasma glucose (FPG), total cholesterol (TC), usage of insulin, and usage of angiotensin‐converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB); and for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), respectively. Results showed that PP increased from no (n = 348) to mild (n = 25) and severe (n = 23) PVD (one‐way ANOVA, p < 0.001; multiple comparisons, p < 0.05 for any two groups). The PP increase from no to mild PVD was due to SBP increase; while further increase to severe PVD was due to both DBP drop and an even higher SBP. Adjusted odds ratio (AOR) for PVD for every 1‐mmHg PP increment was 1.035 (1.012–1.058). When PP was categorized as tertiles (<50, 50–59 and ≥60 mmHg), respective AOR for PVD for second and third vs. first tertile was 2.605 (1.008–6.729) and 2.835 (1.123–7.156). Pulse pressure was also predictive for ABI independent of the effects of the confounders and the other parameters of blood pressure. In conclusion, PP was an independent predictor and correlated with severity of PVD in type 2 diabetic patients.     

钠葡萄糖协同转运子2抑制剂:糖尿病治疗的新选择

钠葡萄糖协同转运子2(SGLT2)是几乎仅在近曲小管表达的跨膜蛋白,介导了90%滤过葡萄糖的重吸收,SGLT2抑制剂可特异性抑制肾小管对滤过葡萄糖的重吸收,增加尿糖排泄,发挥降糖作用.SGLT2抑制剂还具有促进体重下降,间接改善肥胖的作用.根皮苷作为人类最早发现的SGLT2抑制剂,研究较为局限,随着T-1095、serglilozin、dapagliflozin等新型SGLT2抑制剂的开发,SCLT2抑制剂在治疗糖尿病上的有效性和安全性得到了进一步论证,为糖尿病治疗提供了新选择.     

SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: A systematic review and meta‐analysis

The effects of sodium‐glucose cotransporter 2 (SGLT2) inhibitors on risk of stroke have not been conclusively established. Therefore, we conducted a meta‐analysis to evaluate the effects of SGLT2 inhibitors on stroke risk in patients with type 2 diabetes mellitus (T2DM) by searching available randomized trials in PubMed, Embase, CENTRAL, Web of Science, Scopus and ClinicalTrials.gov databases. We identified 32 eligible trials involving 75 540 participants. The incidence of stroke in groups receiving SGLT2 inhibitor monotherapy or combination therapy did not differ significantly from that in control groups, with a relative risk (RR) of 1.01 and 1.0, respectively. Three SGLT2 inhibitors were tested, with similar RR values (canagliflozin [RR, 0.91], dapagliflozin [RR, 0.99] and empagliflozin [RR, 1.03]). Subgroup analyses showed that RR values were not affected by gender, age, diabetes duration, BMI or HbA1C levels, but Black patients had a lower incidence of stroke than White or Asian patients. This meta‐analysis indicated that SGLT2 inhibitor therapy did not increase stroke incidence, and no significant differences in stroke risk were observed among 3 SGLT2 inhibitors (class effect). However, the small racial disparity requires further study and confirmation.     

Blood pressure effects of sodium–glucose co-transport 2 (SGLT2) inhibitors

Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium–glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7–10 mm Hg of goal. It should be noted that the currently approved agents have side effects that include an increased incidence of genital infections, predominantly in women. The approved SGLT2 inhibitors have limited use based on kidney function and should be used only in those with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m² for dapagliflozin and ≥45 mL/min/1.73 m² for canagliflozin. Cardiovascular outcome trials are ongoing with these agents and will be completed within the next 4–5 years.     

SGLT2 inhibitor plus DPP‐4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta‐analysis

To assess the efficacy and safety of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors plus a dipeptidyl peptidase‐4 (DPP‐4) inhibitor in patients with type 2 diabetes mellitus (T2DM), we performed a systematic review and meta‐analysis of 14 randomized controlled trials (RCTs) involving 4828 patients. Compared with a DPP‐4 inhibitor, SGLT2 inhibitor/DPP‐4 inhibitor combination therapy was significantly associated with a decrease in glycaemic control (HbA1c, ?0.71%; fasting plasma glucose [FPG], ?25.62 mg/dL; postprandial plasma glucose, ?44.00 mg/dL), body weight (?2.05 kg) and systolic blood pressure (?5.90 mm Hg), but an increase in total cholesterol (TC) of 3.24%, high‐density lipoprotein of 6.15% and low‐density lipoprotein of 2.55%. Adding a DPP‐4 inhibitor to an SGLT2 inhibitor could reduce HbA1c by ?0.31%, FPG by ?8.94 mg/dL, TC by ?1.48% and triglycerides by ?3.25%. Interestingly, low doses of an SGLT2 inhibitor in the combination has similar or even better efficacy in some aspects than high doses. Similar adverse events were observed for the combination therapy, with the exception of genital infection vs DPP‐4 inhibitor (risk ratio [RR], 5.31) and consistent genital infection vs an SGLT2 inhibitor (RR, 0.61). Further studies are warranted to confirm these results.     

Dipeptidyl Peptidase-4 Inhibitors,Peripheral Arterial Disease,and Lower Extremity Amputation Risk in Diabetic Patients

Background

Recent studies have elucidated the vascular protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. However, to date, no large-scale studies have been carried out to determine the impact of DPP-4 inhibitors on the occurrence of peripheral arterial disease, and lower extremity amputation risk in patients with type 2 diabetes mellitus.

A Prospective Study of Painful Symptoms,Small-fibre Function and Peripheral Vascular Disease in Chronic Painful Diabetic Neuropathy

Fifty diabetic patients with chronic painful sensorimotor neuropathy were studied prospectively to clarify the natural history of this condition and the roles of small-fibre damage and concomitant peripheral vascular disease (PVD). Initially, 30 patients had no significant PVD (ankle:brachial Doppler ratio > 1.0). Pain was assessed using a visual analogue scale (0–10 cm), and small-fibre function by thermal limen (TL), heat-pain threshold (HPT), and weighted pinprick threshold (PPT). At follow-up, on average 3.6 years later (range 3.0–4.1), 11 patients had died (6 with PVD) and contact had been lost with 6. Pain scores fell in subjects without PVD (n = 24; median (range), from 4.8 (0.5–10.0) to 2.0 (0.0–9.2) cm, p < 0.001) and also in those with PVD (n = 9; from 5.1 (2.0–8.2) to 2.1 (0.0–8.0) cm, p < 0.05). Seven patients (5 without PVD) became pain-free; at presentation, these 7 patients had experienced pain for a shorter period of time. Despite this symptomatic improvement, small-fibre function generally deteriorated in both groups, with significant worsening (p < 0.05) of HPT and PPT in patients without PVD, and in HPT and TL in patients with PVD. Neuropathic pain therefore tends to improve with time and can resolve completely. By contrast, small-fibre function continues to deteriorate, indicating that these peripheral measures do not predict the evolution of painful symptoms. The presence or absence of PVD does not appear to affect the natural history of neuropathic pain or its symptomatology.