Lars Hansen

Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapagliflozin to Metformin

OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin. RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA1c ≥8.0% and ≤12.0% (64–108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET. RESULTS Patients had a mean baseline HbA1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m2. At week 24, the adjusted mean change from the baseline HbA1c was –1.5% (–16.1 mmol/mol) with SAXA+DAPA+MET versus –0.9% (–9.6 mmol/mol) with SAXA+MET (difference −0.59% [–6.4 mmol/mol], P < 0.0001) and –1.2% (–13.1 mmol/mol) with DAPA+MET (difference −0.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in ≤1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia. CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone.

Clinical Benefit of a Gluten-Free Diet in Type 1 Diabetic Children With Screening-Detected Celiac Disease: A population-based screening study with 2 years’ follow-up

OBJECTIVE—This study was performed to 1) determine the prevalence of celiac disease in Danish children with type 1 diabetes and 2) estimate the clinical effects of a gluten-free diet (GFD) in patients with diabetes and celiac disease. RESEARCH DESIGN AND METHODS—In a region comprising 24% of the Danish population, all patients <16 years old with type 1 diabetes were identified and 269 (89%) were included in the study. The diagnosis of celiac disease was suspected in patients with endomysium and tissue transglutaminase antibodies in serum and confirmed by intestinal biopsy. Patients with celiac disease were followed for 2 years while consuming a GFD. RESULTS—In 28 of 33 patients with celiac antibodies, an intestinal biopsy showed villous atrophy. In 5 patients, celiac disease had been diagnosed previously, giving an overall prevalence of 12.3% (95% CI 8.6–16.9). Patients with celiac disease had a lower SD score (SDS) for height (P < 0.001) and weight (P = 0.002) than patients without celiac disease and were significantly younger at diabetes onset (P = 0.041). A GFD was obtained in 31 of 33 patients. After 2 years of follow-up, there was an increase in weight SDS (P = 0.006) and in children <14 years old an increase in height SDS (P = 0.036). An increase in hemoglobin (P = 0.002) and serum ferritin (P = 0.020) was found, whereas HbA1c remained unchanged (P = 0.311) during follow-up. CONCLUSIONS—This population-based study showed the highest reported prevalence of celiac disease in type 1 diabetes in Europe. Patients with celiac disease showed clinical improvements with a GFD. We recommend screening for celiac disease in all children with type 1 diabetes.

Non-replication of genome-wide based associations between common variants in INSIG2 and PFKP and obesity in studies of 18,014 Danes.

Background The INSIG2 rs7566605 and PFKP rs6602024 polymorphisms have been identified as obesity gene variants in genome-wide association (GWA) studies. However, replication has been contradictory for both variants. The aims of this study were to validate these obesity-associations through case-control studies and analyses of obesity-related quantitative traits. Moreover, since environmental and genetic factors may modulate the impact of a genetic variant, we wanted to perform such interaction analyses. We focused on physical activity as an environmental risk factor, and on the GWA identified obesity variants in FTO (rs9939609) and near MC4R (rs17782313) as genetic risk factors. Materials and Methods The four variants were genotyped in a combined study sample comprising a total of 18,014 subject ascertained from, the population-based Inter99 cohort (n = 6,514), the ADDITION screening cohort (n = 8,662), a population-based study sample (n = 680) and a type 2 diabetic patient group (n = 2,158) from Steno Diabetes Center. Results No association with overweight, obesity or obesity-related measures was shown for either the INSIG2 rs7566605 or the PFKP rs6602024 variants. However, an interaction between the INSIG2 rs7566605 variant and the level of self-reported physical activity (p Int = 0.004) was observed. A BMI difference of 0.53 (SE 0.42) kg/m2 was found when comparing physically passive homozygous C-allele carriers with physically passive G-allele carriers. No interactions between the two variants and FTO rs9939609 and MC4R rs17782313 were observed. Conclusions The INSIG2 rs7566605 and PFKP rs6602024 polymorphisms play no apparent role in the development of common forms of obesity in the Danish population. However, if replicated, the INSIG2 rs7566605 may influence the level of BMI in combination with the level of physical activity.

Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes

OBJECTIVE To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment. RESEARCH DESIGN AND METHODS Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0–11.5% [64–102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5–10.5% [58–91 mmol/mol]) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7–10.5% [53–91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol). RESULTS Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (−0.82 vs. −0.10% [−9 vs. −1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%). CONCLUSIONS Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy.

Postprandial Dynamics of Plasma Glucose, Insulin, and Glucagon in Patients with Type 2 Diabetes Treated with Saxagliptin Plus Dapagliflozin Add-On to Metformin Therapy

OBJECTIVE To analyze changes in plasma glucose, insulin, and glucagon in relation to glycemic response during treatment with dual add-on of saxagliptin (SAXA) plus dapagliflozin (DAPA) to metformin XR (MET) compared with SAXA add-on or DAPA add-on alone to MET in patients with type 2 diabetes mellitus (T2DM) poorly controlled with MET. METHODS Double-blind trial in adults with glycated hemoglobin (HbA1c) ≥8.0 to ≤12.0% randomized to SAXA 5 mg/day plus DAPA 10 mg/day (n = 179), or SAXA 5 mg/day and placebo (n = 176), or DAPA 10 mg/day and placebo (n = 179) added to background MET ≥1,500 mg/day. The mean change from baseline in the area under the curve from 0 to 180 minutes (AUC0-180 min) was calculated for glucose, insulin, and glucagon obtained during a liquid meal tolerance test (MTT). RESULTS Glucose AUC0-180 min was reduced more from baseline with SAXA + DAPA + MET (-12,940 mg/dL) compared with SAXA + MET (-6,309 mg/dL) and DAPA + MET (-11,247 mg/dL). Insulin AUC0-180 min significantly decreased with SAXA + DAPA + MET (-1,120 μU/mL) and DAPA + MET (-1,019 μU/mL) and increased with SAXA + MET (661 μU/mL). Glucagon AUC0-180 min only increased with DAPA + MET (2,346 pg/mL). The changes in glucose (P<.0001) and insulin (P = .0003) AUC0-180 min correlated with change in HbA1c, whereas the change in glucagon AUC0-180 min did not (P = .27). CONCLUSIONS When added to background MET, the combination of SAXA + DAPA provided additional reductions in glucose AUC0-180 min and HbA1c without the increase in insulin seen with SAXA and without the increase in glucagon seen with DAPA. Changes in insulin and glucose but not glucagon AUC0-180 min correlated with change in HbA1c.

Studies of metabolic phenotypic correlates of 15 obesity associated gene variants.

Aims Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms. Methods 15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes. Results Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15–1.20 for overweight, 1.10–1.25 for obesity, and 1.41–1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78–0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07–1.27, p = 7.8×10−4)). Conclusions Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI.

Randomized, Double-Blind Trial of Triple Therapy With Saxagliptin Add-on to Dapagliflozin Plus Metformin in Patients With Type 2 Diabetes

OBJECTIVE The objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to dapagliflozin plus metformin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients on stable metformin (≥1,500 mg/day) for ≥8 weeks with glycated hemoglobin (HbA1c) 8.0–11.5% (64–102 mmol/mol) at screening received open-label dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA1c 7–10.5% [53–91 mmol/mol]) were then randomized to receive placebo (n = 153) or saxagliptin 5 mg/day (n = 162) in addition to background dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA1c from baseline to week 24. RESULTS There was a significantly greater reduction in HbA1c at 24 weeks with saxagliptin add-on (–0.51% [–5.6 mmol/mol]) versus placebo (–0.16% [–1.7 mmol/mol]) add-on to dapagliflozin plus metformin (difference, –0.35% [95% CI –0.52% to –0.18%] and –3.8 [–5.7 to –2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia. CONCLUSIONS Triple therapy with the addition of saxagliptin to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with type 2 diabetes inadequately controlled with dapagliflozin plus metformin.

Lack of association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity and related metabolic phenotypes in a Danish large-scale study: case-control studies and analyses of quantitative traits

BackgroundSeveral studies in multiple ethnicities have reported linkage to type 2 diabetes on chromosome 1q21-25. Both PKLR encoding the liver pyruvate kinase and NOS1AP encoding the nitric oxide synthase 1 (neuronal) adaptor protein (CAPON) are positioned within this chromosomal region and are thus positional candidates for the observed linkage peak. The C-allele of PKLR rs3020781 and the T-allele of NOS1AP rs7538490 are reported to strongly associate with type 2 diabetes in various European-descent populations comprising a total of 2,198 individuals with a combined odds ratio (OR) of 1.33 [1.16–1.54] and 1.53 [1.28–1.81], respectively. Our aim was to validate these findings by investigating the impact of the two variants on type 2 diabetes and related quantitative metabolic phenotypes in a large study sample of Danes. Further, we intended to expand the analyses by examining the effect of the variants in relation to overweight and obesity.MethodsPKLR rs3020781 and NOS1AP rs7538490 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising a total of 16,801 and 16,913 individuals, respectively. The participants were ascertained from four different study groups; the population-based Inter99 cohort (nPKLR= 5,962, nNOS1AP= 6,008), a type 2 diabetic patient group (nPKLR= 1,873, nNOS1AP= 1,874) from Steno Diabetes Center, a population-based study sample (nPKLR= 599, nNOS1AP= 596) from Steno Diabetes Center and the ADDITION Denmark screening study cohort (nPKLR= 8,367, nNOS1AP= 8,435).ResultsIn case-control studies we evaluated the potential association between rs3020781 and rs7538490 and type 2 diabetes and obesity. No significant associations were observed for type 2 diabetes (rs3020781: pAF = 0.49, OR = 1.02 [0.96–1.10]; rs7538490: pAF = 0.84, OR = 0.99 [0.93–1.06]). Neither did we show association with overweight or obesity. Additionally, the PKLR and the NOS1AP genotypes were demonstrated not to have a major influence on diabetes-related quantitative metabolic phenotypes.ConclusionWe failed to provide evidence of an association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes.

Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes

We previously reported that dapagliflozin versus placebo as add‐on to saxagliptin plus metformin resulted in greater reductions in glycated haemoglobin (A1C), fasting plasma glucose (FPG) and body weight (BW) after 24 weeks of treatment in patients with type 2 diabetes (T2D). Here we report results after 52 weeks of treatment. Patients stabilized on open‐label metformin and saxagliptin 5 mg/day for 8‐16 weeks were randomized to placebo or dapagliflozin 10 mg/day plus open‐label saxagliptin plus metformin for 52 weeks. Changes from baseline to week 52 were greater with dapagliflozin versus placebo in A1C (−0.74% vs. 0.07%), FPG (−27 vs. 10 mg/dL) and BW (−2.1 vs. −0.4 kg). More patients achieved A1C <7% with dapagliflozin (29.4%) versus placebo (12.6%). Adverse events were similar with dapagliflozin (66%) and placebo (71%), and hypoglycaemia was rare (≤2%). Genital infections occurred more often with dapagliflozin (6%) than with placebo (1%); frequency of urinary tract infections was similar between the two groups (9% vs. 10%). Triple therapy with dapagliflozin add‐on to saxagliptin plus metformin is a durable, effective and well‐tolerated intervention for the treatment of T2D.

One-year efficacy and safety of saxagliptin add-on in patients receiving dapagliflozin and metformin

Greater reductions in glycated haemoglobin (HbA1c) with saxagliptin, a dipeptidyl peptidase‐4 inhibitor, versus placebo add‐on in patients with type 2 diabetes who had inadequate glycaemic control with dapagliflozin 10 mg/d plus metformin were demonstrated after 24 weeks of treatment. Results over 52 weeks of treatment were assessed in this analysis.