Improved glycaemic control and reduced incidence of myocardial infarctions, strokes, and mortality in men with hypogonadism and type 2 diabetes, with and without long-term testosterone therapy

Introduction Guidelines by the ESC and EASD state that patients with diabetes have a two-fold excess risk of vascular outcomes. An increasing number of studies suggests that testosterone therapy (TTh) has cardiometabolic benefits in men with hypogonadism and type 2 diabetes (T2DM). Methods In a registry of men with hypogonadism in a urological office, 361 men had T2DM and received standard diabetes treatment including lifestyle recommendations and coaching in a diabetes center. 183 men received TTh with testosterone undecanoate injections 1000 mg/12 weeks following an initial 6-week interval (T-group). 178 men opted against TTh and served as controls (CTRL). Changes over time between groups were compared and adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups. 12-year analyses of 3149 patient-years are reported. Results Mean (median) follow-up 8.2±3.2 (8) years in the T-group, 9.2±2.8 (10) years in CTRL, baseline age: 60.6±5.4 (T-group) and 63.5±5.0 (CTRL) years (p<0.0001). All but 7 patients were overweight or obese. 70 patients (38.3%) in the T-group and 70 (39.3%) in CTRL had a history of cardiovascular disease (myocardial infarction MI, stroke, or coronary artery disease diagnosis) (p=0.8341). Baseline smoking prevalence was 41.0% (75 men) in the T-group and 38.2% (68 men) in CTRL (p=0.5161). The T-group had significantly worse baseline risk factor profile than CTRL: BMI (36.5±4.5 vs. 33.4±5.3 kg/m2), systolic blood pressure (163.0±13.5 vs. 145.6±14.6 mmHg), LDL (4.7±0.9 vs. 4.1±1.4 mmol/L), HbA1c 9.4±1.4 vs. 7.8±0.7% (p<0.0001 for all). HbA1c progressively decreased by 3.7±0.2% at 12 years in the T-group and increased in CTRL by 3.2±0.2%, estimated adjusted difference between groups: −6.9% [95% CI: −7.4; −6.4] (p<0.0001 for all). Fasting glucose decreased in the T-group by 1.9±0.1 and increased in CTRL by 1.8±0.1 mmol/L, estimated adjusted difference: −3.6 mmol/L [95% CI: −4.0; −3.3] (p<0.0001 for all). Men in the T-group lost 19.7±0.4% weight, men in CTRL gained 9.1±0.4%, estimated adjusted difference: −28.8% [95% CI: −30.2; −27.4] (p<0.0001 for all). During the observation period, 15 patients (8.2%) died in the T-group vs. 61 (34.3%) in CTRL (p<0.0001). In the T-group, there were no cases of MI or stroke. In CTRL, there were 56 cases of MI (31.5%) and 56 cases of stroke (31.5%). 35 patients (19.7%) suffered a MI and a stroke. Medication adherence to testosterone was 100% as all injections were administered in the medical office and documented. Conclusions Long-term treatment with TU in men with hypogonadism and T2DM significantly reduces mortality, compared to untreated controls. Improved glycaemic control and weight loss may have contributed to these outcomes. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG, Berlin, Germany

Effects of the Norfolk diabetes prevention lifestyle intervention (NDPS) on glycaemic control in screen-detected type 2 diabetes: a randomised controlled trial

Background The purpose of this trial was to test if the Norfolk Diabetes Prevention Study (NDPS) lifestyle intervention, recently shown to reduce the incidence of type 2 diabetes in high-risk groups, also improved glycaemic control in people with newly diagnosed screen-detected type 2 diabetes. Methods We screened 12,778 participants at high risk of type 2 diabetes using a fasting plasma glucose and glycosylated haemoglobin (HbA1c). People with screen-detected type 2 diabetes were randomised in a parallel, three-arm, controlled trial with up to 46 months of follow-up, with a control arm (CON), a group-based lifestyle intervention of 6 core and up to 15 maintenance sessions (INT), or the same intervention with additional support from volunteers with type 2 diabetes trained to co-deliver the lifestyle intervention (INT-DPM). The pre-specified primary end point was mean HbA1c compared between groups at 12 months. Results We randomised 432 participants (CON 149; INT 142; INT-DPM 141) with a mean (SD) age of 63.5 (10.0) years, body mass index (BMI) of 32.4 (6.4) kg/m2, and HbA1c of 52.5 (10.2) mmol/mol. The primary outcome of mean HbA1c at 12 months (CON 48.5 (9.1) mmol/mol, INT 46.5 (8.1) mmol/mol, and INT-DPM 45.6 (6.0) mmol/mol) was significantly lower in the INT-DPM arm compared to CON (adjusted difference −2.57 mmol/mol; 95% CI −4.5, −0.6; p = 0.007) but not significantly different between the INT-DPM and INT arms (−0.55 mmol/mol; 95% CI −2.46, 1.35; p = 0.57), or INT vs CON arms (−2.14 mmol/mol; 95% CI −4.33, 0.05; p = 0.07). Subgroup analyses showed the intervention had greater effect in participants < 65 years old (difference in mean HbA1c compared to CON −4.76 mmol/mol; 95% CI −7.75, −1.78 mmol/mol) than in older participants (−0.46 mmol/mol; 95% CI −2.67, 1.75; interaction p = 0.02). This effect was most significant in the INT-DPM arm (−6.01 mmol/mol; 95% CI −9.56, −2.46 age < 65 years old and −0.22 mmol/mol; 95% CI −2.7, 2.25; aged > 65 years old; p = 0.007). The use of oral hypoglycaemic medication was associated with a significantly lower mean HbA1c but only within the INT-DPM arm compared to CON (−7.0 mmol/mol; 95% CI −11.5, −2.5; p = 0.003). Conclusion The NDPS lifestyle intervention significantly improved glycaemic control after 12 months in people with screen-detected type 2 diabetes when supported by trained peer mentors with type 2 diabetes, particularly those receiving oral hypoglycaemics and those under 65 years old. The effect size was modest, however, and not sustained at 24 months. Trial registration ISRCTN34805606. Retrospectively registered 14.4.16

A qualitative exploration of attitudes towards physical activity, exercise and sport participation in people living with type one diabetes (T1D).

Regular exercise has many benefits such as increasing energy levels, reducing depressive symptoms, improving sleep quality and reducing the risk of chronic diseases. For people living with Type 1 diabetes (T1D) there are additional benefits such as increased insulin sensitivity, improved glycaemic control and a reduced risk of diabetes complications. Little research has been published which investigates attitudes towards exercise and sport in those with T1D and who are already active. Seven interviews were undertaken with already active people living with T1D, aged 24-81 years. The aim of the interviews were to explore the attitudes and beliefs that influenced already active people living with T1D towards physical activity, exercise and sport participation. Thematic analysis identified four themes: Motivations, Influences, Deterrents and Normalising participation. Latent analysis of the themes suggests that the factors that influence the attitudes of already active people living with T1D towards physical activity and sport participation are focused around the influence of peers, parents and the media, as stated in the Tripartite Model, motivation and level of diabetes management knowledge

Sulphonylurea responsive monogenic diabetes in an Insulin treated 8-year old child in West Africa; of more than academic interest and one of many?

We describe the case and identification of monogenic diabetes mellitus in a Togolese girl at the age of eight years, previously treated as Type 1 Diabetes following diagnosis at the age of two months. She has since been transitioned from insulin to oral sulphonylurea therapy, with improved glycaemic control and greater therapeutic security. We believe many more such cases must exist in Africa amongst those with a history of neonatal diabetes. Free genomic testing is available (see below) in suitable cases. The case highlights the value of personalized medicine and international cooperation.

Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart

Aims Emipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i). However, at resting intracellular pH (pHi), NHE1 activity is very low and its pharmacological inhibition is not expected to meaningfully alter steady-state [Na+]i. We re-evaluate this putative EMPA target by measuring cardiac NHE1 activity. Methods and results The effect of EMPA on NHE1 activity was tested in isolated rat ventricular cardiomyocytes from measurements of pHi recovery following an ammonium pre-pulse manoeuvre, using cSNARF1 fluorescence imaging. Whereas 10 µM cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30 µM). Intracellular acidification by acetate-superfusion evoked NHE1 activity and raised [Na+]i, reported by sodium binding benzofuran isophthalate (SBFI) fluorescence, but EMPA did not ablate this rise. EMPA (10 µM) also had no significant effect on the rate of cytoplasmic [Na+]i rise upon superfusion of Na+-depleted cells with Na+-containing buffers. In Langendorff-perfused mouse, rat and guinea pig hearts, EMPA did not affect [Na+]i at baseline nor pHi recovery following acute acidosis, as measured by 23Na triple quantum filtered NMR and 31P NMR, respectively. Conclusions Our findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i’s) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i’s in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+].