Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.

BACKGROUND: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. OBJECTIVES: The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). STUDY DESIGN: ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Blood pressure and fasting lipid changes after 24 weeks' treatment with vildagliptin: a pooled analysis in >2,000 previously drug-naïve patients with type 2 diabetes mellitus.

INTRODUCTION: We have previously shown modest weight loss with vildagliptin treatment. Since body weight balance is associated with changes in blood pressure (BP) and fasting lipids, we have assessed these parameters following vildagliptin treatment. METHODS: Data were pooled from all double-blind, randomized, controlled, vildagliptin mono-therapy trials on previously drug-naïve patients with type 2 diabetes mellitus who received vildagliptin 50 mg once daily (qd) or twice daily (bid; n=2,108) and wherein BP and fasting lipid data were obtained. RESULTS: Data from patients receiving vildagliptin 50 mg qd or bid showed reductions from baseline to week 24 in systolic BP (from 132.5±0.32 to 129.8±0.34 mmHg; P<0.0001), diastolic BP (from 81.2±0.18 to 79.6±0.19 mmHg; P<0.0001), fasting triglycerides (from 2.00±0.02 to 1.80±0.02 mmol/L; P<0.0001), very low density lipoprotein cholesterol (from 0.90±0.01 to 0.83±0.01 mmol/L; P<0.0001), and low density lipoprotein cholesterol (from 3.17±0.02 to 3.04±0.02 mmol/L; P<0.0001), whereas high density lipoprotein cholesterol increased (from 1.19±0.01 to 1.22±0.01 mmol/L; P<0.001). Weight decreased by 0.48±0.08 kg (P<0.001). CONCLUSION: This large pooled analysis demonstrated that vildagliptin shows a significant reduction in BP and a favorable fasting lipid profile that are associated with modest weight loss.

Experience with DPP-4 inhibitors in the management of patients with type 2 diabetes fasting during Ramadan.

A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting.

Experience with vildagliptin in patients ≥75 years with type 2 diabetes and moderate or severe renal impairment.

INTRODUCTION: Patients with type 2 diabetes (T2DM) are at increased risk for renal impairment (RI) and, in addition, there is an age-related decline in renal function. At the same time, T2DM treatment is more complex and treatment options are more limited in elderly patients as well as patients with RI, with the patient population ≥75 years with moderate or severe RI posing unique challenges, in particular, the high risk and more severe consequences of hypoglycemia. It was, therefore, of interest to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor vildagliptin in patients with T2DM ≥75 years who also have moderate or severe RI. METHODS: In this sub-analysis of data derived from a previously described randomized, double-blind, parallel-group, 24-week study, 105 patients (50 randomized to vildagliptin 50 mg qd and 55 to placebo) ≥75 years (mean age ~78 years) with T2DM and moderate or severe RI (mean baseline estimated glomerular filtration rate ~35 ml/min/1.73 m(2)) were included. RESULTS: The adjusted mean change in glycated hemoglobin (HbA1c) with vildagliptin was -1.0% from a baseline of 7.8% (between-group difference -0.8%; p < 0.001). This improvement in glycemic control was not associated with an increased risk of hypoglycemia; the rate of confirmed hypoglycemia was 0.49 events per patient-year with vildagliptin and 0.96 events per patient-year with placebo (not significant). Weight remained stable with vildagliptin treatment. Adverse events (AEs) (58.0% vs. 72.7%), serious AEs (14.0% vs. 16.4%), discontinuations due to AEs (4.0% vs. 9.1%) and deaths (0% vs. 5.5%) were reported at a comparable or lower frequency in patients receiving vildagliptin versus patients receiving placebo. CONCLUSION: In this uniquely fragile elderly population ≥75 years with T2DM and moderate or severe RI, vildagliptin was well tolerated and efficacious, with no increase in the rate of hypoglycemia compared to placebo despite the marked improvement in glycemic control.

Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes.

CONTEXT: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes. OBJECTIVE: The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D). PATIENTS AND METHODS: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter. MAIN OUTCOME MEASURE: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165-195 of the test) was measured. RESULTS: During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curve(glucagon) 2.4±0.2 vs. 2.6±0.2 nmol/liter×minutes, P=0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5±1.0 pmol/liter with vildagliptin vs. 1.7±0.8 pmol/liter with placebo, P=NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was -3.4±1.0 mmol/mol (-0.32±0.09%; P=0.002)] from baseline of 57.9 mmol/mol (7.5%). CONCLUSIONS: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D.

Effects of vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled type 2 diabetes patients.

BACKGROUND: Bone metabolism is a dynamic process that is influenced by food ingestion. Endogenous incretins have been shown to be important regulators of bone turnover. The aim of the present study was to assess whether a dipeptidylpeptidase (DPP)-4 inhibitor affects markers of bone resorption and calcium homeostasis. METHODS: The present study was a single-center, double blind, randomized clinical trail. Fifty-nine drug-naïve patients with type 2 diabetes (T2D) were randomized to either 1 year treatment with the DPP-4 inhibitor vildagliptin (100 mg, once daily; n = 29) or placebo (n = 30). Patients received a standardized breakfast after measurement of serum concentrations of cross-linked C-terminal telopeptide (s-CTx), a bone resorption marker influenced by food intake, before and after 50 weeks treatment. RESULTS: Vildagliptin did not change postprandial s-CTx concentrations compared with pretreatment levels (between-group ratio 1.15 ± 0.17; P = 0.320). Fasting serum alkaline phosphatase, calcium, and phosphate were also unaffected y 1 year treatment with vildagliptin. CONCLUSIONS: Treatment with vildagliptin for 1 year was not associated with changes in markers of bone resorption and calcium homeostasis in drug-naïve patients with T2D and mild hyperglycemia.

Incretin therapies in the management of elderly patients with type 2 diabetes mellitus.

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes.

BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. MATERIALS AND METHODS: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). RESULTS: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 ± 4.9 and 34.6 ± 4.0%, P = 0.80). CONCLUSIONS: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP-4 inhibition may have caused these effects.

The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion.

BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test. METHODS: There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA. RESULTS: Glibenclamide provoked hypoglycemia (

Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year.

OBJECTIVE: To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related beta-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a 12-week core study, placebo (n = 51) or vildagliptin (n = 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated. RESULTS: In subjects completing 52 weeks with participation in all meal tests (n = 57), HbA(1c) (A1C) decreased in the vildagliptin/metformin group (VM group, n = 31) but increased in the placebo/metformin group (PM group, n = 26; between-group difference -1.0 +/- 0.2%; P < 0.001; baseline of all subjects combined 7.7 +/- 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference -0.9 +/- 0.3 mmol/l, P = 0.016; baseline 9.8 +/- 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0- to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference +0.011 +/- 0.03 pmol/l 30 min/mmol/l, P = 0.018; baseline 0.036 +/- 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference +27 +/- 4 ml x min(-1) x m(-2), P = 0.036; baseline 246 +/- 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference +3.2 +/- 1.0, P = 0.040; baseline 9.1 +/- 0.5). The change in adaptation index correlated to the change in A1C (r = -0.39, P = 0.004). CONCLUSIONS: This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves beta-cell function along with improved postmeal insulin sensitivity.

Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes.

OBJECTIVE: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment. RESEARCH DESIGN AND METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52. RESULTS: In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001). CONCLUSIONS: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.

Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes.

The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.