[GLP-1 Receptor Agonists: For Which Patients with Type-2 Diabetes?] / GLP-1-Rezeptor-Agonisten: Für welche Personen mit Diabetes mellitus Typ 2?

GLP-1 Receptor Agonists: For Which Patients with Type-2 Diabetes? Abstract: In the last few years, the cardiovascular outcome trials for SGLT-2 inhibitors and GLP-1 receptor agonists showed them to significantly lower the risk of cardiorenal endpoints in patients with type-2 diabetes when compared to other antidiabetics. This effect was independent of concurrent medication. This additional benefit is well established in the case of SGLT-2 inhibitors, leading to increased prescription. Following the current evidence, GLP-1 receptor agonists should also be prescribed early in the treatment course of type 2 diabetes. In patients with very high cardiovascular risk, a combination therapy of a GLP-1 receptor agonist with a SGLT-2 inhibitor is an attractive option.

Swiss recommendations of the Society for Endocrinology and Diabetes (SGED/SSED) for the treatment of type 2 diabetes mellitus (2023).

As a first step, the authors emphasise lifestyle changes (increased physical activity, stopping smoking), blood pressure control, and lowering cholesterol). The initial medical treatment should always be a combination treatment with metformin and a sodium-glucose transporter 2 (SGLT-2) inhibitor or a glucagon-like 1 peptide (GLP-1) receptor agonist. Metformin is given first and up-titrated, followed by SGLT-2 inhibitors or GLP-1 receptor agonists. In persons with type 2 diabetes, if the initial double combination is not sufficient, a triple combination (SGLT-2 inhibitor, GLP-1 receptor agonist, and metformin) is recommended. This triple combination has not been officially tested in cardiovascular outcome trials, but there is more and more real-world experience in Europe and in the USA that proves that the triple combination with metformin, SGLT-2 inhibitor, and GLP-1 receptor agonist is the best treatment to reduce 3-point MACE, total mortality, and heart failure as compared to other combinations. The treatment with sulfonylurea is no longer recommended because of its side effects and higher mortality compared to the modern treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. If the triple combination is not sufficient to reduce the HbA1c to the desired target, insulin treatment is necessary. A quarter of all patients with type 2 diabetes (sometimes misdiagnosed) require insulin treatment. If insulin deficiency is the predominant factor at the outset of type 2 diabetes, the order of medications has to be reversed: insulin first and then cardio-renal protective medications (SGLT-2 inhibitors, GLP-1 receptor agonists).

Accuracy of Flash Glucose Monitoring in Hemodialysis Patients With and Without Diabetes Mellitus.

AIMS: Glucose and insulin metabolism are altered in hemodialysis patients, and diabetes management is difficult in these patients. We aimed to validate flash glucose monitoring (FGM) in hemodialysis patients with and without diabetes mellitus as an attractive option for glucose monitoring not requiring regular self-punctures. METHODS: We measured interstitial glucose using a FreeStyle Libre device in eight hemodialysis patients with and seven without diabetes mellitus over 14 days and compared the results to simultaneously performed self-monitoring of capillary blood glucose (SMBG). RESULTS: In 720 paired measurements, mean flash glucose values were significantly lower than self-measured capillary values (6.17±2.52 vs. 7.15±2.41 mmol/L, p=1.3 E-86). Overall, the mean absolute relative difference was 17.4%, and the mean absolute difference was 1.20 mmol/L. The systematic error was significantly larger in patients without vs. with diabetes (- 1.17 vs. - 0.82 mmol/L) and on dialysis vs. interdialytic days (-1.09 vs. -0.90 mmol/L). Compared to venous blood glucose (72 paired measurements), the systematic error of FGM was even larger (5.89±2.44 mmol/L vs. 7.78±7.25 mmol/L, p=3.74E-22). Several strategies to reduce the systematic error were evaluated, including the addition of +1.0 mmol/L as a correction term to all FGM values, which significantly improved accuracy. CONCLUSIONS: FGM systematically underestimates blood glucose in hemodialysis patients but, taking this systematic error into account, the system may be useful for glucose monitoring in hemodialysis patients with or without diabetes.

[CME: Can Slim People Have Type-2 Diabetes?] / CME: Gibt es schlanke Patientinnen und Patienten mit Typ-2-Diabetes? CME-Fragen.

CME: Can Slim People Have Type-2 Diabetes? Abstract. Most patients with type-2 diabetes mellitus are obese or overweight. In slim patients with suspected type 2 diabetes mellitus the possibility of other types of diabetes must be considered. In addition to type-1 diabetes in adulthood and genetic forms of diabetes (MODY, mitochondrial diabetes), it could also be diabetes due to a disease of the exocrine pancreas, a condition which is generally underdiagnosed.

Association of pre- and postoperative αKlotho levels with long-term remission after pituitary surgery for acromegaly.

Soluble αKlotho (sKl) is a disease-specific biomarker that is elevated in patients with acromegaly and declines after surgery for pituitary adenoma. Approximately 25% of patients do not achieve remission after surgery, therefore a risk stratification for patients early in the course of their disease may allow for the identification of patients requiring adjuvant treatment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) have been assessed as biomarker for disease activity, however the value of sKl as a predictive biomarker of surgical success has not been evaluated yet. In this study, we measured serum biomarkers before and after transsphenoidal pituitary surgery in 55 treatment-naïve patients. Based on biochemical findings at follow-up (7-16 years), we divided patients into three groups: (A) long-term cure (defined by normal IGF-1 and random low GH (< 1 µg/l) or a suppressed GH nadir (< 0.4/µg/l) on oral glucose testing); (B) initial remission with later disease activity; (C) persistent clinical and/or biochemical disease activity. sKl levels positively related to GH, IGF-1 levels and tumor volume. Interestingly, there was a statistically significant difference in pre- and postoperative levels of sKl between the long-term cure group and the group with persistent disease activity. This study provides first evidence that sKl may serve as an additional marker for surgical success, decreasing substantially in all patients with initial clinical remission while remaining high after surgery in patients with persistent disease activity.

Switching the basal insulin to insulin glargine 300 U/ml in people with type 2 diabetes under basal insulin supported oral therapy: Observational trial on effectiveness and safety.

AIMS: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D). MATERIALS AND METHODS: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target. RESULTS: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged. CONCLUSIONS: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain.

[CME: Primary and Secondary Hypercholesterolemia]. / CME: Primäre und sekundäre Hypercholesterinämie.

CME: Primary and Secondary Hypercholesterolemia Abstract. In patients with hypercholesterolemia and an LDL-cholesterol level >5 mmol/l, familial hypercholesterolemia (primary hypercholesterolemia) should be considered. This genetically determined illness should lead to medical therapy and screening for hypercholesterinemia in close relatives. Beside the superelevated LDL-cholesterol levels, additional clinically diagnostic findings and family anamnesis can support the diagnosis of familial hypercholesterolemia. The likelihood of familial hypercholesterolemia can be estimated using the Lipid Clinic Network Score. Additionally, a variety of exogenous factors may have an impact on lipoprotein metabolism and may lead to secondary hypercholesterolemia. Hypothyroidism, cholestasis, nephrotic syndrome or specific medications, among others, should be considered as potential factors leading to high cholesterol levels before familial hypercholesterolemia is suspected or lipid-lowering treatment is started.

Distinct mechanisms of hypoglycaemia in patients with somatostatin-secreting neuroendocrine tumours.

INTRODUCTION: Somatostatin-secreting neuroendocrine tumours may present with diabetes, cholelithiasis and steatorrhoea. In addition, hypoglycaemia has been associated with somatostatinomas. However, the mechanism of hypoglycaemia in patients with somatostatinomas has not been well characterized. METHODS: We describe two patients with recurrent neuroglycopenic episodes caused by somatostatin-secreting neuroendocrine tumours in the liver, detected by abdominal CTs and whole-body octreotide scintigraphy scans and confirmed by biopsy. RESULTS: Pancreatic islet hyperplasia and co-secretion of insulin (in addition to somatostatin) from tumour cells, respectively, have been characterized as completely distinct mechanisms of hypoglycaemia at both the functional and morphological levels in these two patients. CONCLUSIONS: Hypoglycaemia may be caused by different mechanisms in patients with somatostatinomas.

Soluble delta-like 1 homolog decreases in patients with acromegaly following pituitary surgery: A potential mediator of adipogenesis suppression by growth hormone?

OBJECTIVE: GH excess in acromegaly leads to lower fat mass and insulin resistance; both reverse following pituitary surgery. Soluble delta like-1 homolog (sDlk1) inhibits adipocyte differentiation and may mediate the antiadipogenic effects of GH. It is released into the circulation by ectodomain shedding through 'A Disintegrin And Metalloproteinase domain 17' (ADAM17), which also sheds soluble α-Klotho (sKlotho). Klotho is a transmembrane protein, which influences life span. sKlotho inhibits insulin signalling, and is markedly elevated in acromegaly and decreases after surgery. Therefore, we examined if sDlk1 parallels the course of sKlotho, which could explain the well-known changes in fat mass in patients with acromegaly after surgery. DESIGN: We measured serum levels of GH, IGF-1, sDlk1 and sKlotho (both by ELISA) in 42 treatment-naïve acromegaly patients (20 females/22 males) before and 1-3 months after transsphenoidal surgery. Data are presented as median(interquartile range). RESULTS: GH decreased in all patients postoperatively (in 32/42 to <1 ng/ml during oral glucose tolerance testing). Likewise, IGF-1 and sKlotho decreased in all patients, from 587 (432-708) to 195 (133-270) ng/ml, and from 4.0 (2.7-5.9) to 0.7 (0.6-1.2) ng/ml, respectively; sDlk1 fell in 40/42 subjects, from 10.7 (5.8-13.4) to 7.1 (3.7-10.4) ng/ml following pituitary surgery. P < 0.0001 for all parameters. CONCLUSIONS: sDlk1 declined after pituitary surgery in our patients with acromegaly, but to a lesser extent than sKlotho. It remains to be seen whether this may contribute to the well-known postoperative changes in body composition. Our findings may extend beyond the scope of acromegaly, and thus further elucidate mechanisms in the fields of obesity and anti-ageing.

Improved Glycemic Control with Insulin Glargine 300 U/mL (Toujeo®) in Patients with Type 2 Diabetes: Real-World Effectiveness in Switzerland.

INTRODUCTION: Insulin glargine 300 U/mL (Gla-300, Toujeo®) is a long-acting, once-daily basal insulin with improved-more stable and smoother-pharmacokinetic and pharmacodynamic profiles compared to insulin glargine 100 U/mL (Gla-100) and insulin degludec (IDeg). These properties have been shown to translate into an effective HbA1c reduction with the advantage of a lower risk of hypoglycemia in randomized controlled trials of Gla-300 versus Gla-100. In this study, we assessed the effectiveness and safety of Gla-300 under real-world conditions in Switzerland. METHODS: The prospective, observational, open-label, multicenter study TOP-2 explored the effectiveness of Gla-300 in adult patients with type 2 diabetes (T2D) uncontrolled (HbA1c 7.5-10%) on their previous basal insulin in Germany, Austria, and Switzerland. The primary endpoints were the percentages of patients achieving a fasting plasma glucose (FPG) of ≤ 6.1 mmol/L after 6 and 12 months. Secondary endpoints included changes in HbA1c, FPG, body weight, and insulin dose as well as hypoglycemia incidence and safety. Here we report the results for the Swiss patient cohort after 12 months of treatment with insulin glargine 300 U/mL. RESULTS: The 62 patients (33 men) had a mean age of 65 years, a mean diabetes duration of 14 years, a mean body mass index (BMI) of 31 kg/m2, and were mainly switched from Gla-100 (44%) to Gla-300. The most common concomitant oral anti-diabetes therapy was metformin (65%). The mean individual HbA1c target chosen by the investigators was 7.4%. After 12 months of therapy, Gla-300 significantly reduced mean HbA1c from 8.2% to 7.6% (p < 0.0001). Likewise, Gla-300 significantly reduced mean FPG from 9.1 mmol/L to 7.4 mmol/L (p < 0.0001). At study end, 32% of patients achieved FPG ≤ 6.1 mmol/L, 55% achieved FPG ≤ 7.2 mmol/L , and 57% achieved their individual HbA1c target. Gla-300 was uptitrated to a mean dose of 40 units per day. Symptomatic hypoglycemia incidence after 12 months was low at 9.7% and a rate of 0.23 events per patient year. Body weight remained stable and was not significantly altered during the study. CONCLUSION: Upon switching basaI insulin to Gla-300, overall glucose control significantly improved and glycemic targets were achieved with a low rate of hypoglycemia in T2D patients under real-world conditions in Switzerland. FUNDING: Sanofi-Aventis (Suisse) SA.

Gender dependence of serum soluble Klotho in acromegaly.

OBJECTIVES: In acromegaly, disease activity is biochemically assessed by growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. However, they are often discrepant, as several factors including gender influence their relationship. We recently found excessively high serum levels of soluble Klotho (sKl) in acromegalic patients, which depended on GH to a comparable extent as IGF-1. To further elucidate the relationship between GH and sKl, we examined the effect of gender on sKl in patients with untreated acromegaly. PATIENTS AND DESIGN: We determined GH, IGF-1 and sKl in sera of 62 consecutive patients with newly diagnosed acromegaly (31 females/31 males, aged 20-85 years). RESULTS: For their given GH excess at presentation with acromegaly, females had lower IGF-1 (490 ± 33 vs 604 ± 33 ng/ml, P = 0·02), but higher sKl [5171 ± 590 vs 3439 ± 431 pg/ml (mean ± SE), P = 0·02] levels than males. In multiple regression analysis, IGF-1 was closely associated with logGH (estimate 139, SE 47, P = 0·005) and BMI (estimate 14·2, SE 4·8, P = 0·005). sKl was closely associated with logGH (estimate 3088, SE 652, P = 0·0001) and gender (estimate 2034, SE 612, P = 0·002), and to a lesser extent with BMI (estimate 174, SE 66, P = 0·01). CONCLUSIONS: For a given GH status, sKl concentrations are higher and IGF-1 concentrations are lower in women than in men. GH is the strongest predictor for both sKl and IGF-1, but gender needs to be considered when using these parameters for monitoring acromegalic patients.

Impact of Growth Hormone on Cystatin C.

BACKGROUND: Cystatin C (CysC) is an alternative marker to creatinine for estimation of the glomerular filtration rate (GFR). Hormones such as thyroid hormones and glucocorticoids are known to have an impact on CysC. In this study, we examined the effect of growth hormone (GH) on CysC in patients with acromegaly undergoing transsphenoidal surgery. METHODS: Creatinine, CysC, GH and insulin-like growth factor-1 (IGF-1) were determined in 24 patients with acromegaly before and following transsphenoidal surgery. Estimated GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. RESULTS: In all patients, surgical debulking resulted in decreased clinical disease activity and declining GH/IGF-1 levels. Postoperatively, biochemical cure was documented in 20 out of 24 patients. Creatinine levels (mean ± SEM) increased from 72 ± 3 to 80 ± 3 µmol/l (p = 0.0004) and concurrently, estimated GFR decreased from 99 ± 3 to 91 ± 3 ml/min (p = 0.0008). In contrast to creatinine, CysC levels decreased from 0.72 ± 0.02 to 0.68 ± 0.02 mg/l (p = 0.0008). CONCLUSIONS: Our study provides strong evidence for discordant effects of GH on creatinine and CysC in patients with acromegaly undergoing transsphenoidal surgery, thus identifying another hormone that influences CysC independent of renal function.

Prognostic factors for impaired plasma sodium homeostasis after transsphenoidal surgery.

OBJECTIVE: Surgical manipulation of the pituitary stalk, neurohypophysis or the hypothalamus may disturb control of the plasma sodium level. The factors that might predict the risk of postoperative sodium imbalance are not clear, and were investigated in this study. METHODS: A retrospective survey of 129 surgical records for the occurrence of plasma sodium levels outside the normal range, following transsphenoidal procedures. Median patient age was 49 (range 20-78) years, 65 female. 73 of the operated lesions were non-functioning pituitary adenomas. Patients were considered to have impaired plasma sodium balance if the range of 135-145 mmol/L was not maintained. RESULTS: Of all 129 surgical cases, 68 (53%) experienced an imbalance in sodium levels. Severe sodium imbalance (≥ 149 or ≤ 131 mmol/L) was observed in 28 patients (22%). 13 showed hypernatraemia (median day 1), and 15 hyponatraemia (median day 6). Tumour size was associated with an increased incidence of sodium imbalance, particularly in patients younger than 49 years; surgery resulted in sodium imbalance in 38% of young patients operated on for tumours < 22 mm and in 76% of young patients, operated on for tumours ≥ 22 mm. Overall, tumour size increased with patients' age, and tumour size was less predictive for sodium disturbances in elderly patients. Median time in hospital was 5 days for patients without sodium imbalance, 6 days for patients with hypernatraemia and 11 days for patients with hyponatraemia. CONCLUSIONS: Following pituitary surgery, patients with large tumours, in particular those of young age, are at higher risk for losing control of their plasma sodium level. Increased ADH secretion (hyponatraemia), but not transient diabetes insipidus was associated with a prolonged hospital stay. Postoperative follow-up of patients with sellar tumours should include careful monitoring of plasma sodium levels within the first two postoperative weeks and clear patients' instructions.

Are biochemical markers of neuroendocrine tumors coreleased with insulin following local calcium stimulation in patients with insulinomas?

OBJECTIVES: The objective was to test whether chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas. METHODS: We determined CgA, NSE, PP, insulin, C-peptide, and proinsulin in blood samples obtained during the ASVS test in 19 patients with insulinomas. Levels following calcium injection into the arteries supplying the tumor were compared with levels following calcium stimulation of arteries supplying healthy pancreatic tissue. RESULTS: After calcium injection into the artery supplying the insulinoma, a significant 8-fold increase in insulin (range, 2.3-117; P < 0.001), a 3.8-fold increase in C-peptide (1.7-32.4; P < 0.001), and a 1.9-fold increase in proinsulin (0.7-5.3, P < 0.001) were detectable whereas NSE and CgA did not increase. No significant increases in insulin, C-peptide, proinsulin, CgA, and NSE concentrations were found after calcium injection into control arteries. Pancreatic polypeptide increased 1.5-fold (0.8-4.5; P = 0.017) after calcium injection into the tumor artery and 2.4-fold (0.8-7.9; P = 0.016) after injection into the control artery. CONCLUSIONS: Insulin, C-peptide, and proinsulin are released by insulinoma cells in response to arterial calcium stimulation, whereas CgA and NSE are not released. Also from our study it seems that PP may be released by healthy islet cells after calcium stimulation.

A family with diabetes and heart failure.

The case of a middle-aged woman with early-onset diabetes mellitus, hypertrophic cardiomyopathy, premature sensorineural hearing loss and neuropsychiatric symptoms is described. The patient's family history revealed the classical pattern of maternally inherited diabetes and deafness (MIDD) and isolation of mitochondrial DNA from peripheral blood leucocytes showed an A3243G transition in the gene encoding for the tRNA(Leu(UUR)). Thus, the suspected diagnosis of a mitochondrial disorder was confirmed. Cardiac involvement turned out to be the dominating clinical feature in the patient. She died of cardiogenic shock and multiple organ failure within 1 year of diagnosis. Three out of nine affected family members had hypertrophic cardiomyopathy.

Effects of thyroxine replacement on serum creatinine and cystatin C in patients with primary and central hypothyroidism.

BACKGROUND: Serum cystatin C (CysC) is a marker for kidney function, possibly superior to serum creatinine (Cr). Cr is increased and CysC decreased in primary hypothyroidism; these changes are reversed upon thyroxine (T4) replacement therapy. This (pilot) study was performed to see whether these opposing changes of CysC and Cr could be confirmed in patients with central hypothyroidism. METHODS: Prospective case series of consecutively referred patients with primary and central hypothyroidism. CysC and Cr were determined at the time of diagnosis and following T4 replacement therapy. RESULTS: 32 patients with newly diagnosed hypothyroidism were included. In 16 patients with primary hypothyroidism, mean fT4 was 4.4 +/- 2.5 pmol/l (normal range 12 to 22) at diagnosis and increased to 20.1 +/- 5.2 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.79 +/- 0.27 mg/l (normal range 0.63 to 1.33) to 1.03 +/- 0.42 mg/l (p = 0.007) whereas Cr declined from 104 +/- 21 micromol/l to 90 +/- 19 micromol/l (p <0.001). In 16 patients with central hypothyroidism, mean fT4 was 6.5 +/- 1.6 pmol/l at diagnosis and increased to 15.7 +/- 3.3 pmol/l (p <0.001) following T4 replacement. CysC increased from 0.74 +/- 0.27 mg/l to 0.83 +/- 0.30 mg/l (p = 0.01) whereas Cr was not elevated at baseline (83 +/- 11 micromol/l) and did not decrease following treatment (84 +/- 10 micromol/l). CONCLUSIONS: CysC was low at diagnosis of hypothyroidism and significantly increased following T4 replacement in patients with primary as well as central hypothyroidism. T4 replacement decreased Cr levels in patients with primary hypothyroidism whereas Cr remained unchanged in;patients with central hypothyroidism. CysC may not accurately reflect kidney function in patients with primary and central thyroid dysfunction.

Insulin sensitivity in type 2 diabetes is closely associated with LDL particle size.

PRINCIPLES: Small dense LDLs have been found to be associated with type 2 diabetes (T2DM). This association has been observed in the context of decreased HDL cholesterol and increased triglycerides. METHODS: In the present study the relationship between LDL particle size and insulin sensitivity was assessed in 46 patients with T2DM (mean age 60 (11) years, HbA1c 7.6 (0.8) %). 75 g oral glucose tolerance testing was performed and composite insulin sensitivity index was calculated by the method of Matsuda and de Fronzo (ISI(comp)). Additional parameters included BMI, waist circumference, blood pressure, HDL cholesterol, triglycerides and LDL cholesterol. LDL particle size was measured by gradient gel electrophoresis. RESULTS: Log ISI(comp) correlated most strongly with LDL particle size (R = 0.61), less closely with HDL cholesterol (R = 0.48) and plasma triglycerides (R = -0.45) and not at all with LDL cholesterol (R = 0.001), as supported by multiple regression analyses where log ISI(com) was associated with LDL particle size (p = 0.004) and HDL cholesterol (p = 0.027) but not with triglycerides and LDL cholesterol. CONCLUSION: Log ISI(comp) estimated by a formula using endogenous insulin levels is very closely associated with LDL particle size in patients with T2DM. Our data suggest that smaller LDL particle size reflects the impact of insulin resistance on lipoprotein metabolism more strictly than do the traditional lipid parameters.