Dose distribution and up-titration patterns of metformin monotherapy in patients with type 2 diabetes.

AIMS: To assess the dose distribution among users of metformin monotherapy as well as the patterns of up-titration following initiation of therapy in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This was a retrospective cohort study of adults with T2DM in the United Kingdom (UK). Metformin dose distribution was assessed at 0, 6 and 12 months in people initiating metformin monotherapy (new users) and cross-sectionally in people with ongoing metformin monotherapy (prevalent users). Patterns and predictors of up-titration were also analysed in new users. Dose distributions and treatment patterns were assessed descriptively; predictors of up-titration were determined using multivariable logistic regressions. RESULTS: Totals of 6174 new users and 8733 prevalent users were included. New users initiated metformin at >0 mg to ≤500 mg (25%), >500 mg to ≤1000 mg (47%), >1000 mg to ≤1500 mg (17%) or >1500 mg to ≤2000 mg (12%) daily. This distribution did not vary over time. Prevalent users of metformin received doses of >0 mg to ≤500 mg (14%), >500 mg to ≤1000 mg (40%), >1000 mg to ≤1500 mg (15%), >1500 mg to ≤2000 mg (29%) or >2000 mg (1%) daily. Among new users of metformin, 6.7% and 10.8% had been up-titrated at 6 and 12 months, respectively, despite the majority having glycated haemoglobin >53 mmol/mol. Predictors of up-titration included younger age and higher HbA1c. CONCLUSIONS: A majority of T2DM patients taking metformin received a dose ≤1000 mg/day. Up-titration of metformin is infrequent in the first year postinitiation.

Double-blind, randomized clinical trial assessing the efficacy and safety of early initiation of sitagliptin during metformin uptitration in the treatment of patients with type 2 diabetes: The CompoSIT-M study.

AIMS: To characterize the glycaemic efficacy and safety of initiation of the dipeptidyl peptidase-4 inhibitor sitagliptin during metformin dose escalation in people with type 2 diabetes (T2D) not at glycated haemoglobin (HbA1c) goal on a sub-maximal dose of metformin. MATERIALS AND METHODS: Study participants with HbA1c ≥58 mmol/mol and ≤97 mmol/mol (≥7.5% and ≤11.0%) while on 1000 mg/d metformin were randomized to sitagliptin 100 mg once daily or placebo. All were to uptitrate metformin to 2000 mg/d. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is superior to placebo when initiated during uptitration of metformin in reducing HbA1c at week 20. [ClinicalTrials.gov Identifier: NCT02791490, EudraCT: 2015-004224-59] RESULTS: A total of 458 participants (mean HbA1c 71.1 mmol/mol [8.7%], T2D duration 6.3 years) were treated. After 20 weeks, the least squares (LS) mean changes from baseline in HbA1c were -12.1 mmol/mol (-14.0, -10.1) (-1.10% [-1.28, -0.93]) and -7.6 mmol/mol (-9.6, -5.6) (-0.69% [-0.88, -0.51]) with sitagliptin and placebo, respectively; the between-group difference in LS mean changes from baseline HbA1c was -4.5 mmol/mol (-6.5, -2.5) (-0.41% [-0.59, -0.23]); P < 0.001. The likelihood of having HbA1c <53 mmol/mol (<7.0%) at week 20 was higher in the sitagliptin group than in the placebo group in the overall population (relative risk 1.7, P = 0.002) and in those with a baseline HbA1c ≥69 mmol/mol (≥8.5%) (relative risk 2.4, P = 0.026). There were no notable differences between groups with regard to adverse events overall, hypoglycaemia events, changes in body weight or other safety variables. CONCLUSION: In participants not at HbA1c goal on a sub-maximal dose of metformin, addition of sitagliptin at the time of metformin dose uptitration improved glycaemic response and HbA1c goal attainment, with similar safety and tolerability, compared to metformin uptitration alone.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active-controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c ≤11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa-Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, -0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naïve at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Single-dose euglycaemic clamp studies demonstrating pharmacokinetic and pharmacodynamic similarity between MK-1293 insulin glargine and originator insulin glargine (Lantus) in subjects with type 1 diabetes and healthy subjects.

AIMS: MK-1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and the USA (US-Lantus). MATERIALS AND METHODS: Both studies were single-dose, randomized, double-blind, single-centre, crossover studies with ≥7 days between dosing periods. A 2-treatment, 4-period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK-1293 to EU-Lantus for 30 hours after dosing. A 3-period crossover study in healthy subjects (N = 109) compared the PK and PD of MK-1293, EU-Lantus and US-Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK-1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC-MS/MS-based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform. RESULTS: In both studies, pre-specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC0-24 and Cmax of M1) and PD (GIR-AUC0-24 , GIR-AUC0-12 , GIR-AUC12-24 , and GIRmax ) primary endpoints. All treatments were well tolerated. CONCLUSION: Based on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174).

Calcineurin signaling regulates human islet {beta}-cell survival.

The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic ß-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant ß-cell failure. We sought to determine the effect of calcineurin inhibition on ß-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue ß-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human ß-cell apoptosis was significantly increased. Although we detected no human ß-cell replication, tacrolimus significantly decreased rodent ß-cell replication. Ex-4 nearly normalized both human ß-cell survival and rodent ß-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in ß-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurin-sensitive manner. Ex-4 restored Irs2 expression in tacrolimus-treated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human ß-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.

The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice.

Heterozygous mutations in the gene encoding the pancreatic homeodomain transcription factor pancreatic duodenal homeobox 1 (PDX1) are associated with maturity onset diabetes of the young, type 4 (MODY4) and type 2 diabetes. Pdx1 governs the early embryonic development of the pancreas and the later differentiation of the insulin-producing islet beta cells of the endocrine compartment. We derived a Pdx1 hypomorphic allele that reveals a role for Pdx1 in the specification of endocrine progenitors. Mice homozygous for this allele displayed a selective reduction in endocrine lineages associated with decreased numbers of endocrine progenitors and a marked reduction in levels of mRNA encoding the proendocrine transcription factor neurogenin 3 (Ngn3). During development, Pdx1 occupies an evolutionarily conserved enhancer region of Ngn3 and interacts with the transcription factor one cut homeobox 1 (Hnf6) to activate this enhancer. Furthermore, mRNA levels of all 4 members of the transcription factor network that regulates Ngn3 expression, SRY-box containing gene 9 (Sox9), Hnf6, Hnf1b, and forkhead box A2 (Foxa2), were decreased in homozygous mice. Pdx1 also occupied regulatory sequences in Foxa2 and Hnf1b. Thus, Pdx1 contributes to specification of endocrine progenitors both by regulating expression of Ngn3 directly and by participating in a cross-regulatory transcription factor network during early pancreas development. These results provide insights that may be applicable to beta cell replacement strategies involving the guided differentiation of ES cells or other progenitor cell types into the beta cell lineage, and they suggest a molecular mechanism whereby human PDX1 mutations cause diabetes.

Exendin-4 normalizes islet vascularity in intrauterine growth restricted rats: potential role of VEGF.

Intrauterine growth restriction (IUGR) induced by uterine artery ligation in pregnant rats leads to low birth weight and early insulin secretory defects followed by the development of insulin resistance, decline in beta-cell mass, and diabetes in adulthood. Neonatal administration of Exendin-4 (Ex-4) prevents the deterioration of beta-cell mass and the onset of adult-onset diabetes. Our aim was to determine whether this effect occurs through preservation of islet vascularization. In 2 wk-old IUGR rats, endothelial-specific lectin staining revealed a 40% reduction in islet vascular density (p = 0.027), which was normalized by neonatal Ex-4. VEGF-A protein expression was reduced in IUGR islets compared with controls at postnatal d 1 (P). Neonatal Ex-4 normalized islet VEGF protein expression at P7. Neither IUGR nor Ex-4 administration to IUGR rats affected relative VEGF splice isoform RNA levels. Together, the reduced vascularity in IUGR islets before the deterioration of beta-cell mass, and the enhancement of VEGF expression and normalization of islet vascularity by neonatal Ex-4, suggest islet vascularity as an early determinant of beta-cell mass and as a potential therapeutic target for diabetes prevention.

Transplant-associated hyperglycemia.

As patient survival after solid organ transplantation continues to improve, comorbidites associated with chronic hyperglycemia will assume increasing importance in limiting outcomes and quality of life. New-onset diabetes mellitus commonly occurs in the posttransplant setting and is associated with multiple complications including graft loss, cardiovascular disease, infection, and death. Furthermore, recent studies have begun to highlight the very high posttransplant prevalence and the significant cardiovascular implications of the prediabetic states of impaired fasting glucose and impaired glucose tolerance, indicating that the overall burden of transplantation-associated hyperglycemia is far greater than previously appreciated. Shared and distinct pathogenic factors and clinical repercussions exist among the organ-specific transplant scenarios. Diabetogenic immunosuppressive agents are common to all organ transplant settings, whereas glucose regulation is also strained by the restoration of failed hepatic and renal function. The atherogenic properties of hyperglycemia are particularly significant in the kidney transplant population, which has a marked predisposition to cardiovascular disease, whereas accelerated cardiac allograft vasculopathy and liver fibrosis have been associated with hyperglycemia in the heart and liver transplant settings, respectively. Aggressive screening will effectively detect transplant-associated hyperglycemia, whereas risk factor modification, lifestyle intervention and, where appropriate, drug therapy, may decrease its impact. Topics of future investigation should include the use of emerging diabetes therapies and avenues for the prevention and reversal of transplant-associated hyperglycemia.

New-onset diabetes mellitus in the kidney recipient: diagnosis and management strategies.

Advancing care has markedly improved survival after kidney transplantation, leaving patients susceptible to the effects of chronic transplant-associated morbidities. New-onset diabetes mellitus (NODM) is common in kidney recipients, threatening health and longevity by predisposing to microvascular and cardiovascular disease and by reducing graft survival. A strong rationale therefore exists for the aggressive treatment of NODM in kidney recipients to limit these complications. Screening for diabetes should be systematic and should span the pre- and posttransplantation periods. Once NODM is diagnosed in the kidney transplant patient, a comprehensive plan of therapy should be used to achieve treatment targets. As in the general population, treatment includes lifestyle modification and drug therapy as needed, but transplant-specific factors add complexity to the care of kidney recipients. Among these, minimizing immunosuppression-related toxicity without compromising graft outcomes is of paramount importance. Preexisting allograft functional impairment and the potential for significant interactions with immunosuppressive agents mandate that the expanding armamentarium of hypoglycemic agents be used with care. A team-oriented treatment approach that capitalizes on the collective expertise of transplant physicians, diabetologists, nurse-educators, and dieticians will optimize both glycemic control and the overall health of hyperglycemic kidney recipients.

Transplant-associated hyperglycemia: a new look at an old problem.

New-onset diabetes has long been recognized as a common complication of kidney transplantation, promoting cardiovascular disease, death, and graft failure. Studies in recent years have begun to highlight the very high posttransplantation prevalence of the prediabetic states of impaired fasting glucose and impaired glucose tolerance and the significant repercussions of these states on cardiovascular health. Therefore, the overall burden of transplant-associated hyperglycemia (TAH), which encompasses new-onset diabetes and the prediabetic states, is far greater than previously appreciated. The kidney transplant population is predisposed to insulin resistance and to additional insults of hypertension and hyperlipidemia that, together with hyperglycemia, compose the metabolic syndrome and promote atherosclerosis. When recipients with an underlying, frequently nonmodifiable predisposition to glucose dysregulation encounter transplant-specific, often modifiable, diabetogenic exposures, TAH manifests. Aggressive screening will effectively detect TAH, whereas risk factor modification, lifestyle intervention, and, when appropriate, drug therapy may decrease its impact. Topics of future investigation should include the use of emerging diabetes therapies and avenues for the prevention and reversal of TAH.

Validation of steady-state insulin sensitivity indices in chronic kidney disease.

OBJECTIVE: Insulin resistance may contribute to cardiovascular disease and the progression of renal insufficiency in patients with chronic kidney disease (CKD). However, feasible methods for estimating insulin sensitivity in large-population CKD studies have not been validated. The purpose of this study was to attempt to validate several commonly used steady-state insulin sensitivity (SI-SS) indices in a CKD population. RESEARCH DESIGN AND METHODS: Twenty-seven subjects with estimated glomerular filtration rate (eGFR) ranging from 70 to <10 ml/min per 1.73 m2 (median eGFR = 48) underwent a frequently sampled intravenous glucose tolerance test (FSIVGTT) on a single occasion. Correlations were obtained between the minimal model-derived insulin sensitivity parameter from the FSIVGTT (SI-FSIVGTT) and seven SI-SS indices derived from fasting insulin and glucose data obtained just before the FSIVGTT. RESULTS: Each of the seven steady-state indices was significantly correlated with SI-FSIVGTT. For indices obtained using the mean of four fasting insulin and glucose values over 15 min, Pearson correlation coefficients (|r|) ranged from 0.51 to 0.87 (P < 0.01 for each). For indices using single fasting insulin and glucose values, |r| ranged from 0.51 to 0.72 (P < 0.01 for each). By both the four and one time point approaches, 1/I(0) had the highest correlation with SI-FSIVGTT. The correlation with SI-FSIVGTT did not change significantly according to eGFR level for any of the SI-SS indices. CONCLUSIONS: SI-SS indices are valid surrogates for SI-FSIVGTT in the CKD population. Their use will expand the range of testable hypotheses in CKD cohort studies.

Maximizing endogenous ß-cell regeneration.

PURPOSE OF REVIEW: Inadequate insulin-producing pancreatic ß-cell mass is a key feature of both type 1 and type 2 diabetes. Efforts to regenerate ß-cell mass from pancreatic precursors may thus ameliorate absolute or relative insulin deficiency, thereby improving glucose homeostasis. A clear understanding of the processes that govern the generation of new ß-cells in the mature pancreas will be fundamental to success in this effort. This review discusses the current state of knowledge regarding ß-cell regeneration and emphasizes recent studies of significance. RECENT FINDINGS: Recent reports demonstrate regenerative potential in the adult human pancreas. Further, they build on the strong existing evidence that proliferation of preexisting ß-cells is the predominant source of new ß-cells in adulthood by dissecting the cell cycle machinery components and critical signaling pathways required for ß-cell proliferation. Finally, ß-cell trophic peptides have demonstrated preclinical potential as pharmacologic regenerative agents and may form the basis for clinical interventions in the future. SUMMARY: Efforts to augment ß-cell regeneration by enhancing ß-cell viability and proliferation may lead to novel therapeutic approaches for type 1 and type 2 diabetes. An intimate understanding of the molecular mechanisms underlying the regulation of ß-cell proliferation and survival will be fundamental to the optimization of endogenous ß-cell regeneration.

Identification of transcriptional targets during pancreatic growth after partial pancreatectomy and exendin-4 treatment.

After partial pancreatectomy (Ppx), substantial regeneration of the endocrine and exocrine pancreatic compartments has been shown in adult rodents. Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist that augments endocrine beta-cell mass by stimulating neogenesis, proliferation, and cell survival. After Ppx, treatment with Ex-4 ameliorates hyperglycemia by stimulating beta-cell mass recovery. We utilized a cDNA microarray approach to identify genes differentially regulated during pancreatic regeneration after Ppx and/or Ex-4 administration. The pancreatic remnant after Ppx showed a large number of differentially regulated genes. In contrast, Ex-4 treatment resulted in a smaller number of differentially regulated genes. Of note, a common subset of genes regulated by Ex-4 and after Ppx was identified, including three members of the mitogenic Reg gene family, Reg2, -3gamma, and -3beta, as well as fragilis, a gene that maintains pluripotency during germ cell specification, and Serpin b1a, a member of an intracellular protease inhibitor family involved in cell survival. These observations were confirmed by real-time PCR. We determined that Reg3beta protein is also induced in the acinar pancreas after Ppx, suggesting a novel role for this factor in pancreatic growth or response to injury. Finally, comparison of transcription factor-binding sites present in the proximal promoters of these genes identified potential common transcription factors that may regulate these genes. Chromatin immunoprecipitation analyses confirmed Reg3gamma as a novel transcriptional target of Foxa2 (HNF3beta). Our data suggest molecular pathways that may regulate pancreatic growth and offer a unique set of candidate genes to target in the development of therapies aimed at improving pancreatic growth and function.

Role of glucagon-like peptide-1 in the pathogenesis and treatment of diabetes mellitus.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from enteroendocrine L cells in response to ingested nutrients. The first recognized and most important action of GLP-1 is the potentiation of glucose-stimulated insulin secretion in beta-cells, mediated by activation of its seven transmembrane domain G-protein-coupled receptor. In addition to its insulinotropic actions, GLP-1 exerts islet-trophic effects by stimulating replication and differentiation and by decreasing apoptosis of beta-cells. The GLP-1 receptor is expressed in a variety of other tissues important for carbohydrate metabolism, including pancreatic alpha-cells, hypothalamus and brainstem, and proximal intestinal tract. GLP-1 also appears to exert important actions in liver, muscle and fat. Thus, GLP-1 suppresses glucagon secretion, promotes satiety, delays gastric emptying and stimulates peripheral glucose uptake. The impaired GLP-1 secretion observed in type 2 diabetes suggests that GLP-1 plays a role in the pathogenesis of this disorder. Thus, because of its multiple actions, GLP-1 is an attractive therapeutic target for the treatment of type 2 diabetes, and major interest has resulted in the development of a variety of GLP-1 receptor agonists for this purpose. Ongoing clinical trials have shown promising results and the first analogs of GLP-1 are expected to be available in the near future.