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Prevalence of sodium-glucose transporter 2 inhibitor-associated diabetic ketoacidosis in real-world data: A systematic review and meta-analysis

Al-Hindi B, Mohammed MA, Mangantig E, Martini ND

J Am Pharm Assoc (2003), 2023 Oct 14.
PMID: 37844733 DOI: 10.1016/j.japh.2023.10.010

BACKGROUND: The U.S. Food and Drug Administration revised the labels of sodium-glucose transporter 2 (SGLT2) inhibitors in December 2015 to inform users regarding the risk of diabetic ketoacidosis (DKA). As more drugs of this class are approved and their indications are expanded, this serious adverse effect has been increasingly reported.
OBJECTIVE: This review evaluated observational studies to inform the prevalence of SGLT2-inhibitor-associated DKA compared with other antihyperglycemic agents.
METHODS: A systematic review was conducted in PubMed and EMBASE until 19 July 2022 (PROSPERO: CRD42022385425). We included published retrospective cohort active comparator/new user (ACNU) and prevalent new user studies assessing SGLT2-inhibitor-associated DKA prevalence in adult patients with type 2 diabetes mellitus (T2DM) against active comparators. We excluded studies which lacked 1:1 propensity score matching. The JBI Checklist for Cohort Studies guided the risk-of-bias assessments. Meta-analysis was conducted based on the inverse variance method in R software.
RESULTS: Sixteen studies with a sample of 2,956,100 non-unique patients met the inclusion criteria. Most studies were conducted in North America (n = 9) and adopted the ACNU design (n = 15). Meta-analysis of 14 studies identified 33% higher DKA risk associated with SGLT2 inhibitors (HR = 1.33, 95% CI: 1.14-1.55, p < 0.01). Meta-regression analysis identified the study location (p = 0.02), analysis principle (p < 0.001), exclusion of chronic comorbidities (p = 0.007), and canagliflozin (p = 0.04) as significant moderator variables.
CONCLUSIONS: Despite limitations related to heterogeneity, generalisability, and misclassification, the results of this study show that SGLT2 inhibitors increase the prevalence of DKA among adult T2DM patients in the real world. The findings supplement evidence from randomised controlled trials and call for continued vigilance.
Fulltext Acute and Sub-Acute Toxicity Evaluation of the Methanolic Extract of Alstonia scholaris Stem Bark

Bello I, Bakkouri AS, Tabana YM, Al-Hindi B, Al-Mansoub MA, Mahmud R, et al.

Med Sci (Basel), 2016 Mar 08;4(1).
PMID: 29083368 DOI: 10.3390/medsci4010004

Alstonia scholaris has been used by traditional medicine practitioners since the medieval ages for the treatment of diseases. The aim of this research was to evaluate the acute and sub-acute oral toxicity of its methanolic extract. The acute toxicity test was conducted using Sprague Dawley (SD) rats. The methanolic extract of Alstonia scholaris stem bark (ASME) was administrated in a single dose of 2000 mg/kg via oral gavage; and the animals were observed for any behavioral changes or mortality. In the sub-acute toxicity study, SD rats received three doses of ASME (250, 500 and 1000 mg/kg) for 28 days via oral gavage. During these 28 days of treatment, the rats were observed weekly for toxicity symptoms. Following the 28-day treatment, the rats were sacrificed for hematological, biochemical and histopathology studies. In the acute toxicity study, Alstonia scholaris was found to be non-toxic at a dose of 2000 mg/kg b.w. In the sub-acute toxicity study, significant variations in body weight, hematological and biochemical parameters were observed in the experimental groups at the dose of 500 and 1000 mg/kg with the death of two female rats being recorded at the highest dose (1000 mg/kg b.w.). Histopathological studies revealed slight degeneration (lesion) and centrilobular necrosis in the liver, which was most expressed in the highest-dose group. These results demonstrate that, while a single dose and short term oral intake of Alstonia scholaris bark extract caused no toxicity up to a dose of 2000 mg/kg b.w., toxic effects manifested in the long term treatment at the highest dose (500 and 1000 mg/kg). The long-term toxic effect was found to be associated with alterations in hematological compositions and end-organ damage to the liver. Thus, prolonged use of high doses of ASME orally should be discouraged and lower doses encouraged.
Fulltext Aqueous Extract of Nypa fruticans Wurmb. Vinegar Alleviates Postprandial Hyperglycemia in Normoglycemic Rats

Yusoff NA, Ahmad M, Al-Hindi B, Widyawati T, Yam MF, Mahmud R, et al.

Nutrients, 2015 Aug;7(8):7012-26.
PMID: 26308046 DOI: 10.3390/nu7085320

Nypa fruticans Wurmb. vinegar, commonly known as nipa palm vinegar (NPV) has been used as a folklore medicine among the Malay community to treat diabetes. Early work has shown that aqueous extract (AE) of NPV exerts a potent antihyperglycemic effect. Thus, this study is conducted to evaluate the effect of AE on postprandial hyperglycemia in an attempt to understand its mechanism of antidiabetic action. AE were tested via in vitro intestinal glucose absorption, in vivo carbohydrate tolerance tests and spectrophotometric enzyme inhibition assays. One mg/mL of AE showed a comparable outcome to the use of phloridzin (1 mM) in vitro as it delayed glucose absorption through isolated rat jejunum more effectively than acarbose (1 mg/mL). Further in vivo confirmatory tests showed AE (500 mg/kg) to cause a significant suppression in postprandial hyperglycemia 30 min following respective glucose (2 g/kg), sucrose (4 g/kg) and starch (3 g/kg) loadings in normal rats, compared to the control group. Conversely, in spectrophotometric enzymatic assays, AE showed rather a weak inhibitory activity against both α-glucosidase and α-amylase when compared with acarbose. The findings suggested that NPV exerts its anti-diabetic effect by delaying carbohydrate absorption from the small intestine through selective inhibition of intestinal glucose transporters, therefore suppressing postprandial hyperglycemia.
Fulltext Safety assessment of the ethanolic extract of Gongronema latifolium Benth. leaves: a 90-day oral toxicity study in Sprague Dawley rats

Al-Hindi B, Yusoff NA, Ahmad M, Atangwho IJ, Asmawi MZ, Al-Mansoub MA, et al.

BMC Complement Altern Med, 2019 Jun 28;19(1):152.
PMID: 31253153 DOI: 10.1186/s12906-019-2573-x

BACKGROUND: The leaves of Gongronema latifolium Benth. have long been recognized traditionally as a remedy for a variety of ailments in Africa. This study was conducted to evaluate the safety profile of the ethanolic extract of G. latifolium (GLES) leaves through a repeated dose 90-day oral toxicity study in male and female of Sprague Dawley rats.
METHODS: GLES was orally administered at doses of 250, 500 and 1000 mg/kg/day consecutively for 90 days.
RESULTS: No behavioral or physiological changes and mortality were observed. GLES did not have a marked impact on general hematological parameters and did not precipitate nephrotoxicity. However, compared to the control, serum triglycerides, total cholesterol and low-density lipoprotein levels were lower and white adipose tissue paired retroperitoneal fat depots were depleted in male rats treated with GLES3 by the end of the experiment. The liver was significantly enlarged in GLES-treated rats of both sexes. Negative gender-specific alterations were observed with the highest dose. Adverse risk was evident in the female rats mainly due to marked body weight gain and cerebrum weight reduction.
CONCLUSION: Further research is needed to reach more specific conclusions about to the safety of ingesting high doses of GLES for long periods of time.
Fulltext Nypa fruticans Wurmb. Vinegar's Aqueous Extract Stimulates Insulin Secretion and Exerts Hepatoprotective Effect on STZ-Induced Diabetic Rats

Yusoff NA, Lim V, Al-Hindi B, Abdul Razak KN, Widyawati T, Anggraini DR, et al.

Nutrients, 2017 Aug 23;9(9).
PMID: 28832548 DOI: 10.3390/nu9090925

BACKGROUND: An aqueous extract (AE) of vinegar made from Nypa fruticans Wurmb. can improve postprandial glucose levels in normoglycaemic rats. The aim of this study was to evaluate its antihyperglycaemic activity further using in vivo and in vitro approaches.
METHODS: AE was administered to streptozotocin (STZ)-induced diabetic rats twice daily at three doses (1000, 500, and 250 mg/kg b.w.) for 12 days p.o. Several biochemical analyses and a histological study of the pancreas and liver were performed, accompanied by a cell culture assay.
RESULTS: As compared to diabetic control (DC), AE at the doses of 500 and 1000 mg/kg b.w. caused significant reduction (p < 0.05) of blood glucose, total cholesterol and triglycerides levels, with positive improvement of serum insulin levels. Interestingly, immunohistochemical staining of the pancreas suggested no β-cell regeneration, despite significant increase in insulin production. AE-treated groups, however, showed overall restoration of the hepatic histoarchitecture of STZ-induced liver damage, suggesting a possible hepatoprotective effect. The pancreatic effect of AE was further studied through RIN-5F cell culture, which revealed a positive stimulatory effect on insulin release at a basal glucose concentration (1.1 mM).
CONCLUSION: Nypa fruticans Wurmb. vinegar's aqueous extract exerts its antihyperglycaemic activity, at least in part, through insulin stimulatory and hepatoprotective effects.
Mutagenicity and preclinical safety assessment of the aqueous extract of Clinacanthus nutans leaves

Farsi E, Esmailli K, Shafaei A, Moradi Khaniabadi P, Al Hindi B, Khadeer Ahamed MB, et al.

Drug Chem Toxicol, 2016 Oct;39(4):461-73.
PMID: 27033971 DOI: 10.3109/01480545.2016.1157810

CONTEXT: Clinacanthus nutans (CN) is used traditionally for treating various illnesses. Robust safety data to support its use is lacking.
OBJECTIVE: To evaluate the adverse effects of aqueous extract of CN leaves (AECNL).
MATERIALS AND METHODS: The oral toxicity of the AECNL was tested following Organisation for Economic Co-operation and Development (OECD) guidelines. Mutagenicity (Ames test) of AECNL was evaluated using TA98 and TA100 Salmonella typhimurium strains.
RESULTS: No mortality or morbidity was found in the animals upon single and repeated dose administration. However, significant body weight loss was observed at 2000 mg/kg during sub-chronic (90 d) exposure. In addition, increased eosinophil at 500 mg/kg and decreased serum alkaline phosphatase levels at 2000 mg/kg were observed in male rats. Variations in glucose and lipid profiles in treated groups were also observed compared to control. Ames test revealed no evidence of mutagenic or carcinogenic effects at 500 μg/well of AECNL.
CONCLUSION: The median lethal dose (LD50) of the AECNL is >5000 mg/kg and the no-observed-adverse-effect level is identified to be greater than 2000 mg/kg/day in 90-d study.