Dapagliflozin: a sodium glucose cotransporter 2 inhibitor in development for type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic. Patients face lifelong therapy to control hyperglycemia and prevent the associated complications. There are many medications, with varying mechanisms, available for the treatment of T2DM, but almost all target the declining insulin sensitivity and secretion that are associated with disease progression. Medications with such insulin-dependent mechanisms of action often lose efficacy over time, and there is increasing interest in the development of new antidiabetes medications that are not dependent upon insulin. One such approach is through the inhibition of renal glucose reuptake. Dapagliflozin, the first of a class of selective sodium glucose cotransporter 2 inhibitors, reduces renal glucose reabsorption and is currently under development for the treatment of T2DM. Here, we review the literature relating to the preclinical and clinical development of dapagliflozin

Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort

__Objective:__ Previous studies suggest that androgens have a sexually dimorphic impact on metabolic dysfunction. However, the sex-specific link between circulating androgens and risk of type 2 diabetes mellitus (T2DM) has not been examined in a large scale, longitudinal cohort, a task we undertook in this study. __Design:__ A retrospective cohort study in a UK primary care database. __Patients:__ We included men and women with available serum testosterone and sex hormone-binding globulin (SHBG) results. __Measurements:__ We categorized serum concentrations according to clinically relevant cut-off points and calculated crude and adjusted T2DM Incidence Rate Ratios (IRRs and aIRRs). __Results:__ Serum testosterone concentrations were available in 70 541 men and 81 889 women; serum SHBG was available in 15 907 men and 42 034 women. In comparison to a reference cohort with serum testosterone ≥20 nmol/L, men with lower serum testosterone had a significantly increased risk of T2DM, with the highest risk in those with serum testosterone <7 nmol/L (aIRR 2.71, 95% CI 2.34-3.14, P < 0.001). In women, the risk of T2DM started to increase significantly when serum testosterone concentrations exceeded 1.5 nmol/L, with the highest risk in women with serum testosterone ≥3.5 nmol/L (aIRR 1.98, 95% CI 1.55-2.52, P < 0.001). These observations were verified in a continuous rather than categorized analysis. The risk of T2DM increased in men and women with serum SHBG <40 and <50 nmol/L, respectively. __Conclusions/Interpretation:__ In this longitudinal study, we found sexually dimorphic associations between serum testosterone and risk of incident T2DM. Androgen deficiency and excess should be considered important risk factors for diabetes in men and women, respectively

Increased risk of non-alcoholic fatty liver disease in women with gestational diabetes mellitus: A population-based cohort study, systematic review and meta-analysis

Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the leading causes of liver transplantation in the West. This study seeks to examine whether women with gestational diabetes mellitus (GDM) are at increased risk of developing NAFLD compared to women without GDM. Methods: We conducted a population-based retrospective matched-controlled cohort study utilising The Health Improvement Network (THIN), a large primary care database representative of the United Kingdom population, between 01/01/1990 to 31/05/2016 followed by systematic review of available literature. The study population included 9640 women with GDM and 31,296 controls without GDM, matched for age, body mass index (BMI) and time of pregnancy. All study participants were free from NAFLD diagnosis at study entry. Patients with GDM and patients developing NAFLD were identified by clinical codes. Results: The median (range) follow-up duration was similar in women with and without GDM (2.95 (1.21–6.01) vs 2.85 (1.14–5.75) years respectively). Unadjusted incidence rate ratio (IRR) for NAFLD development in women with vs without GDM was 3.28 (95% CI 2.14–5.02), which remained significant after adjustment for wide range of potential confounders (IRR 2.70; 95% CI 1.744–4.19). The risk of NAFLD in GDM remained high (IRR 2.46: 95% CI 1.51–4.00) despite women being censored after they developed type 2 diabetes. The meta-analysis of 3 studies (including the current study) showed increased NAFLD risk in women with vs without GDM (OR 2.60; 95% CI 1.90–3.57, I2 = 0%). As our study is based on routine clinical diagnosis of NAFLD, this study could potentially have underestimated the risk of NAFLD development. Conclusions: Women with GDM are at increased risk of developing NAFLD in their later life compared to women without GDM regardless of the development of type 2 diabetes. Clinicians should have a low threshold to investigate women with history of GDM for the presence of NAFLD. Further studies to identify screening strategies are needed. © 2019 Elsevier Inc

Increased risk of non-alcoholic fatty liver disease in women with gestational diabetes mellitus: A population-based cohort study, systematic review and meta-analysis

Aims: Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the leading causes of liver transplantation in the West. This study seeks to examine whether women with gestational diabetes mellitus (GDM) are at increased risk of developing NAFLD compared to women without GDM. Methods: We conducted a population-based retrospective matched-controlled cohort study utilising The Health Improvement Network (THIN), a large primary care database representative of the United Kingdom population, between 01/01/1990 to 31/05/2016 followed by systematic review of available literature. The study population included 9640 women with GDM and 31,296 controls without GDM, matched for age, body mass index (BMI) and time of pregnancy. All study participants were free from NAFLD diagnosis at study entry. Patients with GDM and patients developing NAFLD were identified by clinical codes. Results: The median (range) follow-up duration was similar in women with and without GDM (2.95 (1.21–6.01) vs 2.85 (1.14–5.75) years respectively). Unadjusted incidence rate ratio (IRR) for NAFLD development in women with vs without GDM was 3.28 (95% CI 2.14–5.02), which remained significant after adjustment for wide range of potential confounders (IRR 2.70; 95% CI 1.744–4.19). The risk of NAFLD in GDM remained high (IRR 2.46: 95% CI 1.51–4.00) despite women being censored after they developed type 2 diabetes. The meta-analysis of 3 studies (including the current study) showed increased NAFLD risk in women with vs without GDM (OR 2.60; 95% CI 1.90–3.57, I2 = 0%). As our study is based on routine clinical diagnosis of NAFLD, this study could potentially have underestimated the risk of NAFLD development. Conclusions: Women with GDM are at increased risk of developing NAFLD in their later life compared to women without GDM regardless of the development of type 2 diabetes. Clinicians should have a low threshold to investigate women with history of GDM for the presence of NAFLD. Further studies to identify screening strategies are needed. © 2019 Elsevier Inc

Drug evaluation: vildagliptin-metformin single-tablet combination.

The single-tablet combination of vildagliptin and metformin addresses key defects of type 2 diabetes for improved glycemic control. By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, vildagliptin raises the levels of the active incretin hormones, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. This leads to increased synthesis and release of insulin from the pancreatic beta cells and decreased release of glucagon from the pancreatic alpha cells. The combination tablet also contains metformin, which addresses insulin resistance. The complementary mechanisms of action of the two agents in combination have been shown to provide additive and sustained reductions in hemoglobin A(1c) compared with metformin monotherapy. In active-controlled trials, the vildagliptin-metformin combination has been shown to produce equivalent reductions in hemoglobin A(1c) to pioglitazone-metformin and glimepiride-metformin combinations, without significant risk of hypoglycemia and without causing weight gain. In clinical trials, the overall incidence of any adverse event was similar in patients randomized to vildagliptin plus metformin and placebo plus metformin. Available data support the use of vildagliptin in combination with metformin as a promising second-line treatment for the management of type 2 diabetes and this is reflected in the latest UK National Institute for Health and Clinical Excellence draft guideline for consultation on new agents for blood glucose control in type 2 diabetes