https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)60953-3.pdf

Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial

ContextPharmacotherapies that augment the incretin pathway have recently become available, but their role in the management of type 2 diabetes is not well defined.ObjectiveTo assess the efficacy and safety of incretin-based therapy in adults with type 2 diabetes based on randomized controlled trials published in peer-reviewed journals or as abstracts.Data SourcesWe searched MEDLINE (1966–May 20, 2007) and the Cochrane Central Register of Controlled Trials (second quarter, 2007) for English-language randomized controlled trials involving an incretin mimetic (glucagonlike peptide 1 [GLP-1] analogue) or enhancer (dipeptidyl peptidase 4 [DPP4] inhibitor). We also searched prescribing information, relevant Web sites, reference lists and citation sections of recovered articles, and abstracts presented at recent conferences.Study SelectionRandomized controlled trials were selected if they were at least 12 weeks in duration, compared incretin therapy with placebo or other diabetes medication, and reported hemoglobin A1c data in nonpregnant adults with type 2 diabetes.Data ExtractionTwo reviewers independently assessed trials for inclusion and extracted data. Differences were resolved by consensus. Meta-analyses were conducted for several efficacy and safety outcomes.ResultsOf 355 potentially relevant articles identified, 51 were retrieved for detailed evaluation and 29 met the inclusion criteria. Incretins lowered hemoglobin A1c compared with placebo (weighted mean difference, −0.97% [95% confidence interval {CI}, −1.13% to −0.81%] for GLP-1 analogues and −0.74% [95% CI, −0.85% to −0.62%] for DPP4 inhibitors) and were noninferior to other hypoglycemic agents. Glucagonlike peptide 1 analogues resulted in weight loss (1.4 kg and 4.8 kg vs placebo and insulin, respectively) while DPP4 inhibitors were weight neutral. Glucagonlike peptide 1 analogues had more gastrointestinal side effects (risk ratio, 2.9 [95% CI, 2.0-4.2] for nausea and 3.2 [95% CI, 2.5-4.4] for vomiting). Dipeptidyl peptidase 4 inhibitors had an increased risk of infection (risk ratio, 1.2 [95% CI, 1.0-1.4] for nasopharyngitis and 1.5 [95% CI, 1.0-2.2] for urinary tract infection) and headache (risk ratio, 1.4 [95% CI, 1.1-1.7]). All but 3 trials had a 30-week or shorter duration; thus, long-term efficacy and safety could not be evaluated.ConclusionsIncretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.

https://friedmanfellows.com/assets/pdfs/elibrary/37.%202007_Amori_JAMA_Incretin_Meta-Analysis.pdf

Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis.

Background Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age. Objectives To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies. Search strategy A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators. Selection criteria Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy. Data collection and analysis The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data. Main results Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies. Authors' conclusions There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

/pdf/risk-of-fatal-and-nonfatal-lactic-acidosis-with-metformin-4ujte07kg8.pdf

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus.

Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d'etre is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to beta-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.

/pdf/the-role-of-incretins-in-glucose-homeostasis-and-diabetes-epycrms6jb.pdf

The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

Aim: To compare the efficacy and safety of sitagliptin vs glipizide in patients with type 2 diabetes and inadequate glycaemic control [haemoglobin A1c (HbA1c) ≥ 65 and ≤10%] on metformin monotherapy

Methods:  After a metformin dose titration/stabilization period (≥1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg qd (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA1c changes from baseline at Week 52 using a per-protocol approach

Results:  From a mean baseline of 75%, HbA1c changes from baseline were −067% at Week 52 in both groups, confirming non-inferiority The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide) Fasting plasma glucose changes from baseline were −056 mmol/l (−100 mg/dl) and −042 mmol/l (−75 mg/dl) for sitagliptin and glipizide, respectively The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated patients compared with 50 events in sitagliptin-treated patients Sitagliptin led to weight loss (change from baseline =−15 kg) compared with weight gain (+11 kg) with glipizide [between-treatment difference (95% confidence interval) =−25 kg (−31, −20); p < 0001]

Conclusions:  In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c-lowering efficacy over 52 weeks in patients on ongoing metformin therapy Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1463-1326.2006.00704.x

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double‐blind, non‐inferiority trial

Objective: To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed.

Methods:  In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A1c (HbA1c) values of 6.5–10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day.

Results:  Patients (N = 91) with a mean baseline HbA1c value of 7.7% (range: 6.2–10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA1c was −0.6% (−0.8, −0.4) in the sitagliptin group compared with −0.2% (−0.4, 0.1) in the placebo group [between-group difference (95% CI) = −0.4% (−0.7, −0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA1c of −0.7% (−0.9, −0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups.

Conclusions:  In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Summary
Objectives: To evaluate the 2-year safety and efficacy of adding sitagliptin or glipizide to ongoing metformin in patients with type 2 diabetes.

Methods:  Patients who were on a stable dose of metformin (≥ 1500 mg/day) for at least 8 weeks were randomised in a double-blind manner to receive either sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (up-titrated up to 20 mg/day based upon prespecified glycaemic criteria) (N = 584). The efficacy analysis assessed the change in HbA1c from baseline using the per-protocol (PP) population.

Results:  For the PP cohort, mean baseline HbA1c was 7.3% in both groups. After 2 years, the least squares (LS) mean change in HbA1c from baseline [95% confidence interval (CI)] was −0.54% (−0.64, −0.45) with sitagliptin (n = 248) and −0.51% (−0.60, −0.42) with glipizide (n = 256). The rise in HbA1c from week 24 to week 104 [i.e. coefficient of durability (COD)] was smaller with sitagliptin [COD (95% CI) 0.16%/year (0.10, 0.21)] compared with glipizide [0.26%/year (0.21, 0.31)]. The proportion of patients with an HbA1c< 7% was 63% and 59% with sitagliptin and glipizide, respectively. The beta-cell responsiveness to a meal challenge was maintained with sitagliptin and decreased with glipizide. The proportion of patients who reported hypoglycaemia was 5% with sitagliptin and 34% with glipizide [difference in proportions (95% CI) = −29% (−33, −25)]. Relative to baseline, sitagliptin was associated with weight loss (−1.6 kg) compared with weight gain (+0.7 kg) with glipizide.

Conclusion:  In patients with type 2 diabetes, adding sitagliptin to metformin monotherapy improved glycaemic control over 2 years, similar to the glucose-lowering efficacy observed with adding glipizide, but with greater durability and generally better maintenance of beta-cell function. Sitagliptin was generally well tolerated with a lower risk of hypoglycaemia and weight loss compared with weight gain observed with glipizide.

Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study.

Objective:In clinical trials, the degree of glucose lowering with sitagliptin has been correlated with the magnitude of dipeptidyl peptidase-4 (DPP-4) inhibition over 24 h. Previous studies evaluating sitagliptin doses ranging from 25 to 200 mg/day demonstrated that the daily dose of 100 mg provided maximal glucose-lowering efficacy for this compound in patients with type 2 diabetes. However, sitagliptin 200 mg once daily provided numerically greater percent plasma DPP-4 inhibition compared with 100 mg once daily. The purpose of this study was to evaluate whether sitagliptin 200 mg once daily provides greater improvement in glycemic efficacy as assessed by weighted mean glucose (WMG) over 24 h relative to sitagliptin 100 mg once daily and to relate the percent DPP-4 inhibition achieved with these doses to any between-treatment differences in glycemic efficacy.Methods:In a double-blind crossover study, patients with type 2 diabetes (fasting plasma glucose [FPG] 130–250 mg/dL) were randomized to one...

Sitagliptin 100 mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement.

Objective: In clinical trials, the degree of glucose lowering with sitagliptin has been correlated with the magnitude of dipeptidyl peptidase-4 (DPP-4) inhibition over 24 h. Previous studies evaluating sitagliptin doses ranging from 25 to 200 mg/day demonstrated that the daily dose of 100 mg provided maximal glucose-lowering efficacy for this compound in patients with type 2 diabetes. However, sitagliptin 200 mg once daily provided numerically greater percent plasma DPP-4 inhibition compared with 100 mg once daily. The purpose of this study was to evaluate whether sitagliptin 200 mg once daily provides greater improvement in glycemic efficacy as assessed by weighted mean glucose (WMG) over 24 h relative to sitagliptin 100 mg once daily and to relate the percent DPP-4 inhibition achieved with these doses to any between-treatment differences in glycemic efficacy.

D. Sheng

Papers

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double‐blind, non‐inferiority trial

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study.

Sitagliptin 100 mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement.

Original article Sitagliptin 100mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement