Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis.

AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and -1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes.

Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin. METHODS: We searched for randomized trials comparing SGLT-2i to DPP-4i as add-on therapy to metformin in Type 2 diabetes.We pooled trials reporting outcomes between 12 and 26 weeks together while trials reporting results ≥52 weeks were pooled together. The primary outcomes were the change in haemoglobin A1c (A1c) at ≤26 and ≥52 weeks. Sensitivity analyses were performed according to the dose of SGLT-2i and according to baseline A1c for the primary outcomes. RESULTS: Seven trials met our inclusion criteria. There was a statistically significant reduction in A1c at ≥52 weeks favouring SGLT-2i compared to DPP-4i (MD [95% CI]=-0.11% [-0.20, -0.03]) but no significant difference at ≤26 weeks (MD [95% CI]=-0.05% [-0.16, 0.05]). SGLT-2i caused significantly more weight loss compared to DPP-4i at ≤26 weeks and ≥52 weeks (MD [95% CI]=-2.31kg [-2.66, -1.96] and -2.45kg [-2.83, -2.07], respectively). SGLT-2i treated patients had a significantly more genital infection compared to DPP-4i. On restricting the analysis according to the SGLT-2i FDA-approved dose, only higher doses at ≥52 weeks showed a statistically significant reduction in A1c compared to DPP-4i. On restricting the analysis according to baseline A1c, results favoured DPP-4i if baseline A1c was<8.5%, but favoured SGLT-2i if ≥8.5%. CONCLUSION: While both SGLT-2i and DPP-4i can reduce A1c, SGLT-2i causes a more robust A1c reduction and more weight loss but with more genital infections. Higher doses of SGLT-2i showed more efficacy when compared to DPP-4i; however, this data should be interpreted cautiously given the limited number of trials.

Comparative safety and tolerability of duloxetine vs. pregabalin vs. duloxetine plus gabapentin in patients with diabetic peripheral neuropathic pain.

OBJECTIVE: The safety and tolerability of three treatments for diabetic peripheral neuropathic pain (DPNP) were compared. METHODS: A 12-week, randomized, open-label study confirming the non-inferiority of duloxetine (N = 138) vs. pregabalin (N = 134) and the combination of duloxetine plus gabapentin (N = 135) as the primary outcome was previously published. Patients had an inadequate pain response to a stable dose of gabapentin (≥ 900 mg/day) for ≥ 5 weeks prior to study enrolment. Data from that study were assessed in this current analysis for a detailed report of safety and tolerability. RESULTS: Completion rates did not differ significantly between the groups. Discontinuation because of adverse events was significantly greater in the duloxetine (19.6%) vs. pregabalin group (10.4%; p = 0.04); no differences emerged between the duloxetine vs. duloxetine plus gabapentin (13.3%) groups (p = 0.19) or pregabalin vs. duloxetine plus gabapentin groups (p = 0.57). Adverse event rates varied: nausea, insomnia, hyperhidrosis and decreased appetite were reported significantly more often in patients treated with duloxetine vs. patients treated with pregabalin (each p ≤ 0.01); insomnia significantly more in patients treated with duloxetine vs. duloxetine plus gabapentin (p = 0.01); peripheral oedema significantly more in patients treated with pregabalin vs. duloxetine and duloxetine plus gabapentin (p ≤ 0.001 each) and nausea, hyperhidrosis, decreased appetite and vomiting significantly more in patients treated with duloxetine plus gabapentin vs. pregabalin (each p ≤ 0.05). At end-point, weight change differed significantly among treatment groups: patients in the pregabalin group on average gained weight (1.0 ± 0.04 kg); while, patients in the duloxetine and duloxetine plus gabapentin groups on average lost weight (-2.39 ± 0.04 and -1.06 ± 0.04 kg, respectively) (pregabalin vs. duloxetine, p ≤ 0.001; pregabalin vs. duloxetine plus gabapentin, p ≤ 0.001; duloxetine vs. duloxetine plus gabapentin, p = 0.01). CONCLUSION: Duloxetine, pregabalin and duloxetine plus gabapentin were generally safe and tolerable for the treatment of DPNP.

Patient-reported experience with Velosulin human insulin in continuous subcutaneous insulin infusion.

A multicenter, retrospective survey of 339 patients with insulin-dependent diabetes mellitus was done to evaluate patient experience with Velosulin Human insulin, a regular insulin in a phosphate buffer, used in continuous subcutaneous insulin infusion. Patients had used this insulin exclusively for 3 months preceding the survey. Responses were elicited through interviews conducted by physicians or nurses. Patients were queried as to the occurrence of specific complications associated with pump therapy that occurred while using Velosulin Human insulin, including hypoglycemia, diabetic ketoacidosis, unexplained hyperglycemia, tubing obstruction, and infection or abscess at the infusion site. Most patients reported that they did not experience any of these complications during the preceding 3 months. The most frequently cited complication was hyperglycemia unexplained by dosage, exercise, or dietary changes, reported by 110 (32%) patients. The second most frequently reported complication was tubing obstruction, reported by 99 (29%) patients. The reported frequencies of the other complications were: severe hypoglycemia, 45 (13%) patients; diabetic ketoacidosis, 28 (8%) patients; and infection or abscess at the infusion site, 26 (8%) patients. The low morbidity reported by the patients in this survey probably was due in large part to careful patient selection, a high level of motivation on the part of the patients, and experience and education on the part of the health care team, as well as to the use of buffered regular human insulin.

Alterations of plasma opioid activity in human diabetics.

Plasma opioid levels were determined in 9 obese non-diabetic subjects, their 8 age matched controls, and in 29 diabetic patients; 10 maintained on diet alone, 6 on an oral hypoglycemic agent (chlorpropamide) and 13 treated with insulin. Five age matched controls for the diabetic groups were also studied for comparison. beta-endorphin and met-enkephalin levels were measured by radioimmunoassay. Enkephalin-like activity was measured by a receptor assay. Among the study groups, diabetic patients receiving insulin showed a 64% elevation of plasma beta-endorphins and diabetic patients on chlorpropamide showed a 121% increase in enkephalin-like activity. There were no statistically significant differences in the plasma met-enkephalin values in the treatment groups though levels were decreased (p less than 0.05) in diabetics vs non-diabetics. The pathophysiological importance of these alterations remains to be elucidated.

Hyperparathyroid crisis and acute necrotizing pancreatitis presenting as diabetic ketoacidosis.

The case history of a patient who presented with diabetic ketoacidosis and was subsequently found to have hyperparathyroid crisis complicated by acute necrotizing pancreatitis and phosphate depletion syndrome is reviewed. The interaction of these diseases and their treatment is discussed. The simultaneous presentation of hyperparathyroid crisis and acute necrotizing pancreatitis is rare, and no instance of survival has been reported previously.

Pancreatic alpha cell response to alanine during and after normal and diabetic pregnancies.

Pancreatic alpha cell response to oral alanine was assessed in the third trimester of pregnancy and in the puerperium in 16 insulin-dependent diabetic and 7 normal pegnant women. Insulin response was also measured in the nondiabetic subjects. The nondiabetic subjects had higher basal glucagon and insulin levels as well as a greater response to oral alanine stimulation at 34 weeks' gestation than at 6 weeks post partum. In addition, basal levels of both hormones remained low at a time remote from pregnancy (9 months post partum), indicating both hyperinsulinemia and hyperglucagonemia in the postabsorptive state in normal human pregnancy. The secretory response of glucagon and insulin or oral alanine was blunted at 6 weeks post partum in the nondiabetic subjects. This suggests that the late puerperium may not be an appropriate "nonpregnant control period" for metabolic studies. During pregnancy, basal and stimulated glucagon levels were not significantly different in diabetic and normal women. Despite higher concentrations of blood glucose in diabetic women, basal and stimulated glucagon secretion was equivalent in the 2 groups. No pegnancy-induced increment in glucagon secretion was evident in insulin-treated diabetic subjects. Thus hyperglucagonemia does not contribute to the increased requirements for insulin during pregnancy in these women.

Serotoninergic activation and inhibition: effects on carbohydrate tolerance and plasma insulin and glucagon.

Glucose and arginine infusion tests were performed on 12 healthy volunteers (8 males, 4 females) before and after serotoninergic activation [oral administration of L-5-hydroxytryptophan (5-HTP-) for 6 days] and serotoninergic inhibition (oral treatment with D,L-p-chloropenylalanine for 6 days). 5-HTP treatment markedly increased urinary 5-hydroxyindoleacetic acid excretion, increased the mild hyperglycemic effect of arginine infusion, and lowered the glucose disposal rate constant. The adverse effect of serotoninergic activation on glucose tolerance is not sufficiently explained by the observed changes in insulin and glucagon secretion during the fasting state and after intravenous glucose and arginine infusions. Serotoninergic inhibition did not affect the carbohydrate tolerance of normal individuals. The results of this work supports the idea that excessive indoleamine production is probably the main cause for carbohydrate intolerance in carcinoid tumors.

Lack of glucagon response to hypoglycemia in diabetic autonomic neuropathy.

Glucagon response to insulin hypoglycemia was tested in diabetics with autonomic neuropathy (N=9), diabetics without neuropathy (N=8), and normals (N=9). With similar levels of hypoglycemia, growth hormone and plasma cortisol increased in all groups. The glucagon response in normals (121+/-19 vs. 308+/-30 pg./ml., mean+/-S.E.M. of baseline vs. hypoglycemia peak) was significantly less in nonneuropathic diabetics than in normals (128+/-13 vs. 209+/-30) and absent in neuropathic diabetes (128+/-23 vs. 115+/-20). Arginine stimulation produced a glucagon response in the neuropathic diabetics (106+/-16 vs. 523+/-103). The data indicate that the capacity to release glucagon during hypoglycemia is lost in diabetic neuropathy while glucagon responsiveness to arginine is retained. Neuropathy in diabetes may contribute to metabolic instability.