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Dapagliflozin: Cardiovascular Safety and Benefits in Type 2 Diabetes Mellitus.

ABSTRACT: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) such as dapagliflozin, canagliflozin, and empagliflozin, are a promising new therapy in the treatment of type 2 diabetes mellitus (T2DM). SGLT2is can effectively reduce hyperglycemia thus improving glycemic control and they offer some beneficial effects on the cardiovascular (CV) system which can benefit patients with heart failure in addition toT2DM. The United States Food and Drug Administration requires new diabetes mellitus therapies to show a CV safety profile. Empagliflozin was the first SGLT2i that, when added to the standard of care for patients withT2DM at high risk for CV events, showed improved CV outcomes including reduced deaths from CV causes. Evidence also exists in favor of dapagliflozin for use in patients with T2DM with CV risk factors and heart failure. This review focuses on the effects, safety, and benefits of dapagliflozin on the CV system. Clinical trials have shown that dapagliflozin improves glycemic control without variation. It is safe and well-tolerated in the general population including older patients and those with high-risk CV factors or preexisting CV disease. There may be a renal protective role by an unknown mechanism. Dapagliflozin also lowers blood pressure due to its natriuresis effect. It improves levels of visceral fat and reduces body weight, and thus ameliorates metabolic syndrome. Dapagliflozin reduces oxidative stress and may delay atherosclerosis. Recent findings indicate SGLT2is may also reduce the atrial natriuretic peptide levels. Additional trials are required to validate these benefits and further evaluate if these are class effects. Trials such as DECLARE-TIMI58 are ongoing to evaluate the CV outcomes of dapagliflozin. More research is needed to design better antihyperglycemic regimes with clinical benefits in addition to good glycemic control.

SUBMITTER: Saleem F

PROVIDER: S-EPMC5716679 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Dapagliflozin: Cardiovascular Safety and Benefits in Type 2 Diabetes Mellitus.

Saleem Fatima F

Cureus 20171005 10

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) such as dapagliflozin, canagliflozin, and empagliflozin, are a promising new therapy in the treatment of type 2 diabetes mellitus (T2DM). SGLT2is can effectively reduce hyperglycemia thus improving glycemic control and they offer some beneficial effects on the cardiovascular (CV) system which can benefit patients with heart failure in addition toT2DM. The United States Food and Drug Administration requires new diabetes mellitus therapies to sh ...[more]

PMID: 29226041

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Project description:IntroductionSodium-glucose co-transporter-2 (SGLT2) inhibitors moderately reduce glucose levels in type-2 diabetes mellitus (T2DM). Some cases of diabetic ketoacidosis (DKA) were reported with SGLT2 inhibitors. However, data on the long-term safety of dapagliflozin in Saudi Arabia are lacking. The present study aimed to monitor the safety of dapagliflozin in patients with T2DM and evaluate the change in HbA1c during the observation period compared to baseline.MethodsThis was a local, prospective, single-arm, non-interventional, regulatory post-marketing study. The study was conducted in Saudi Arabia from May 2017 to September 2019. Patients received either 5 or 10 mg dapagliflozin in conjunction with diet and exercise modifications to treat T2DM. The occurrence of adverse events was observed over the treatment duration and for 3 days after administering the last dose of dapagliflozin.ResultsA total of 527 patients were recruited in the study, 524 of which were eligible for the statistical analysis. About 62% were males. The median (IQR) age was 52.3 (14.8) years, while the median (IQR) body mass index was 31.6 (7.7) kg/m2. The median (IQR) duration since the patients were first diagnosed with T2DM was 8.78 (6.73) years. The most common comorbidities were hyperlipidemia (51.1%) and hypertension (41.1%). Almost three-quarters of the study population (73.7%) received other antidiabetic medications in addition to dapagliflozin. Over a period of 12 months, a total of 106 adverse events were experienced by 65 (12.33%) patients. Vulvovaginal pruritus (3.1%), dysuria (2.7%), polyuria (1.3%), urinary tract infections (1%), fatigue (0.8%), and hypoglycemia (0.8%) were among the reported adverse events. One case of DKA (0.2%) was reported. The mean (SD) HbA1c% level significantly decreased from 8.6 (1.6) % at baseline to reach 7.2 (1.2) % after 12 months of treatment (p < 0.0001).ConclusionDapagliflozin was found to be a well tolerated and effective treatment option for T2DM patients in Saudi Arabia. Vulvovaginal pruritus and dysuria were the most common adverse events.

Project description:Aims/hypothesisPeople with diabetes have an increased cardiovascular risk with an accelerated development of atherosclerosis and an elevated mortality rate after myocardial infarction. Therefore, cardioprotective effects of glucose-lowering therapies are of major importance for the pharmacotherapy of individuals with type 2 diabetes. For sodium-glucose cotransporter 2 inhibitors (SGLT2is), in addition to a reduction in blood glucose, beneficial effects on atherosclerosis, obesity, renal function and blood pressure have been observed. Recent results showed a reduced risk of worsening heart failure and cardiovascular deaths under dapagliflozin treatment irrespective of the diabetic state. However, the underlying mechanisms are yet unknown. Platelets are known drivers of atherosclerosis and atherothrombosis and disturbed platelet activation has also been suggested to occur in type 2 diabetes. Therefore, the present study investigates the impact of the SGLT2i dapagliflozin on the interplay between platelets and inflammation in atherogenesis.MethodsMale, 8-week-old LDL-receptor-deficient (Ldlr-/-) mice received a high-fat, high-sucrose diabetogenic diet supplemented without (control) or with dapagliflozin (5 mg/kg body weight per day) for two time periods: 8 and 25 weeks. In a first translational approach, eight healthy volunteers received 10 mg dapagliflozin/day for 4 weeks.ResultsDapagliflozin treatment ameliorated atherosclerotic lesion development, reduced circulating platelet-leucocyte aggregates (glycoprotein [GP]Ib+CD45+: 29.40 ± 5.94 vs 17.00 ± 5.69 cells, p < 0.01; GPIb+lymphocyte antigen 6 complex, locus G+ (Ly6G): 8.00 ± 2.45 vs 4.33 ± 1.75 cells, p < 0.05) and decreased aortic macrophage infiltration (1.31 ± 0.62 vs 0.70 ± 0.58 ×103 cells/aorta, p < 0.01). Deeper analysis revealed that dapagliflozin decreased activated CD62P-positive platelets in Ldlr-/- mice fed a diabetogenic diet (3.78 ± 1.20% vs 2.83 ± 1.06%, p < 0.01) without affecting bleeding time (85.29 ± 37.27 vs 89.25 ± 16.26 s, p = 0.78). While blood glucose was only moderately affected, dapagliflozin further reduced endogenous thrombin generation (581.4 ± 194.6 nmol/l × min) × 10-9 thrombin vs 254.1 ± 106.4 (nmol/l × min) × 10-9 thrombin), thereby decreasing one of the most important platelet activators. We observed a direct inhibitory effect of dapagliflozin on isolated platelets. In addition, dapagliflozin increased HDL-cholesterol levels. Importantly, higher HDL-cholesterol levels (1.70 ± 0.58 vs 3.15 ± 1.67 mmol/l, p < 0.01) likely contribute to dapagliflozin-mediated inhibition of platelet activation and thrombin generation. Accordingly, in line with the results in mice, treatment with dapagliflozin lowered CD62P-positive platelet counts in humans after stimulation by collagen-related peptide (CRP; 88.13 ± 5.37% of platelets vs 77.59 ± 10.70%, p < 0.05) or thrombin receptor activator peptide-6 (TRAP-6; 44.23 ± 15.54% vs 28.96 ± 11.41%, p < 0.01) without affecting haemostasis.Conclusions/interpretationWe demonstrate that dapagliflozin-mediated atheroprotection in mice is driven by elevated HDL-cholesterol and ameliorated thrombin-platelet-mediated inflammation without interfering with haemostasis. This glucose-independent mechanism likely contributes to dapagliflozin's beneficial cardiovascular risk profile.

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Dapagliflozin: Cardiovascular Safety and Benefits in Type 2 Diabetes Mellitus.

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Dapagliflozin: Cardiovascular Safety and Benefits in Type 2 Diabetes Mellitus.

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