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Genetic Polymorphisms in ADORA2A and CYP1A2 Influence Caffeine's Effect on Postprandial Glycaemia.
Banks, NF, Tomko, PM, Colquhoun, RJ, Muddle, TWD, Emerson, SR, Jenkins, NDM
Scientific reports. 2019;(1):10532
Abstract
The liver enzyme cytochrome P450 1A2 (CYP1A2) is responsible for 90% of caffeine metabolism, while caffeine exerts many of its effects via antagonist binding to adenosine A2a receptors (ADORA2A). This study aimed to examine whether functional single nucleotide polymorphisms (SNPs) in 1976T > C (ADORA2A; rs5751876) and -163C > A (CYP1A2; rs762551) influence the effect of caffeine on the postprandial glucose (GLU) response to a carbohydrate meal. We report that individuals with the 1976T > C CC, but not CT/TT genotypes display elevated GLU levels after consuming caffeine and carbohydrate (CHO + CAFF) versus carbohydrate only (CHO). The GLU area under the curve (AUC) was also greater during the CHO + CAFF condition compared to the CHO condition in CC, but not the CT/TT genotypes. The -163C > A AC/CC, but not AA, genotypes displayed greater GLU concentrations 60-min post meal during CHO + CAFF versus CHO. Our data suggest that caffeine-induced impairments in postprandial glycaemia are related to 1976T > C and -163C > A SNPs.
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Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second-line therapy after metformin monotherapy: Retrospective data for 10 256 individuals from the United Kingdom and Germany.
Khunti, K, Godec, TR, Medina, J, Garcia-Alvarez, L, Hiller, J, Gomes, MB, Cid-Ruzafa, J, Charbonnel, B, Fenici, P, Hammar, N, et al
Diabetes, obesity & metabolism. 2018;(2):389-399
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AIM: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies. MATERIALS AND METHODS This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance. RESULTS Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was -1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, -0.45% per unit increase in HbA1c; HbA1c ≥9%, -0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92-1.09%; P < .001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (≥70 years, 1.13%; <70 years, 1.02% [P < .001]). CONCLUSIONS Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions.
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Glycaemic outcomes of an Individualized treatMent aPproach for oldER vulnerable patIents: A randomized, controlled stUdy in type 2 diabetes Mellitus (IMPERIUM).
Heller, SR, Pratley, RE, Sinclair, A, Festa, A, Kiljański, J, Brusko, CS, Duan, R, Heine, RJ
Diabetes, obesity & metabolism. 2018;(1):148-156
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AIMS: To compare the glycaemic outcomes of 2 glucose-lowering treatment strategies in vulnerable (moderately ill and/or frail) patients aged ≥65 years with type 2 diabetes whose individual HbA1c targets were not met with diet/exercise and/or oral anti-hyperglycaemic medications (OAMs). METHODS The primary endpoint of this study was a composite of achieving/maintaining individualized HbA1c targets without "clinically significant" hypoglycaemia (severe hypoglycaemia or repeated hypoglycaemia causing interruption of patients' activities or blood glucose <54 mg/dL). Strategy-A comprised glucose-dependent therapies (n = 99) with a non-sulphonylurea OAM and a glucagon-like peptide-1 receptor agonist as the first injectable. Strategy-B comprised non-glucose-dependent therapies (n = 93) with sulphonylurea as the preferred OAM and insulin glargine as the first injectable. RESULTS There was no significant difference between Strategy-A and Strategy-B in percentages of patients achieving the primary endpoint (64.5% vs 54.9%; P = .190). Mean incidences (A vs B) of total (10.2% vs 53.8%), documented symptomatic (5.1% vs 36.6%), and asymptomatic (8.2% vs 32.3%) hypoglycaemia were lower for Strategy-A (P < .001 each). Proportions of patients achieving/maintaining HbA1c target (A, 63.3% vs B, 55.9%) were similar. CONCLUSION Similar proportions of older, vulnerable aged ≥65 years patients with type 2 diabetes achieved/maintained glycaemic treatment goals without clinically significant hypoglycaemia with Strategies A or B. However, Strategy-A resulted in lower risk of total, documented symptomatic, and asymptomatic hypoglycaemia. These results identify an approach of potential clinical benefit in this age group and will inform future clinical research in older patients with type 2 diabetes.
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Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.
Mathieu, C, Bode, BW, Franek, E, Philis-Tsimikas, A, Rose, L, Graungaard, T, Birk Østerskov, A, Russell-Jones, D
Diabetes, obesity & metabolism. 2018;(5):1148-1155
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AIMS: To compare the safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D). MATERIALS AND METHODS onset 1 was a randomized, multicentre, treat-to-target, phase III, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52-week study period. RESULTS Between August 2013 and June 2015, 381 participants were assigned to double-blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were -0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (-0.10% [95% confidence interval {CI} -0.19;-0.00]; P = .0424). Changes from baseline in 1-hour postprandial plasma glucose (PPG) increment (meal test; faster aspart -1.05 mmol/L; IAsp -0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference -0.91 mmol/L [95% CI -1.40;-0.43]; -16.48 mg/dL [95% CI -25.17;-7.80]; P = .0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments. CONCLUSIONS At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.
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Efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as monotherapy or add-on to metformin in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.
Wang, Z, Sun, J, Han, R, Fan, D, Dong, X, Luan, Z, Xiang, R, Zhao, M, Yang, J
Diabetes, obesity & metabolism. 2018;(1):113-120
Abstract
AIMS: To compare the efficacy and safety of dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) as monotherapy or add-on to metformin (Met) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS PubMed, Embase and ClinicalTrials.gov sites were systematically searched for randomized controlled trials to assess the efficacy and safety of DPP-4is and SGLT-2is in patients with T2DM. Risk ratio (RR) and weighted mean difference (WMD) were used to evaluate outcomes. RESULTS In the analysis of 25 randomized trials, which involved 14 619 patients, SGLT-2is were associated with a significantly stronger reduction in haemoglobin A1c (HbA1c) (WMD 0.13%, 95% credible interval [CI], 0.04%-0.22%, P = .005) and fasting plasma glucose (FPG) (WMD 0.80 mmol/L, 95% CI, 0.58-1.01 mmol/L, P < .00001) than were DPP-4is. However, no significant difference between the 2 drug categories was found in the risk of hypoglycaemic events (RR, 0.99; 95% CI, 0.78-1.26, P = .92). SGLT-2is plus Met was associated with a more significant decrease in FPG (WMD 0.71 mmol/L, 95% CI, 0.43-1.00 mmol/L, P < .00001) than was DPP-4is plus Met. However, no differences were found in the reduction of HbA1c (WMD 0.11%, 95% CI, -0.03%-0.25%, P = .12) or the risk of hypoglycaemic events (RR, 1.02; 95% CI, 0.80-1.31, P = .86). CONCLUSIONS This review revealed that, compared to DPP-4is, SGLT-2is significantly reduced HbA1c, FPG and body weight without increasing the risk of hypoglycaemia in diabetes treatment.
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Short and medium-term efficacy of sodium glucose co-transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized clinical trials.
Monami, M, Liistro, F, Scatena, A, Nreu, B, Mannucci, E
Diabetes, obesity & metabolism. 2018;(5):1213-1222
Abstract
AIMS: Sodium glucose co-transport-2 (SGLT-2) inhibitors reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of this meta-analysis was the systematic collection of available data from randomized trials, in order to establish the durability of the efficacy of SGLT-2 inhibitors on glycaemic control and body mass index. METHODS A meta-analysis was performed, including all trials with a duration of at least 12 weeks, comparing SGLT-2 inhibitors with non-SGLT-2 inhibitor agents in type 2 diabetes. The principal outcome was the effect of SGLT-2 inhibitors on hemoglobin A1c (HbA1c) at 12, 24, 52 and 104 weeks. Data on body mass index at the same time points were also collected. RESULTS Among 66 randomized trials, HbA1c reduction at 12, 24, 52 and 104 weeks was 0.63% (0.57; 0.68, 0.63% (0.57; 0.70), 0.66% (0.57; 0.74) and 0.60% (0.40; 0.81), respectively. SGLT-2 inhibitors showed a greater efficacy than dipeptidyl-peptidase-4 inhibitors (DPP-4i). Sulfonylureas appeared to be superior to SGLT-2 inhibitors at 12 weeks, but not at 24 and 52 weeks; SGLT-2 inhibitors produced a greater reduction in HbA1c than did sulfonylureas at 104 weeks. SGLT-2 inhibitor-induced weight loss in placebo-controlled trials appeared to increase progressively with the duration of treatment. CONCLUSIONS SGLT-2 inhibitors showed a good persistence of efficacy, at least up to 2 years, with a small but significant superiority over DPP-4i. Sulfonylureas are more effective in the very short term, but less effective in the longer term.
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Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.
Wysham, CH, Rosenstock, J, Vetter, ML, Dong, F, Öhman, P, Iqbal, N
Diabetes, obesity & metabolism. 2018;(1):165-172
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AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.
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Effect of exenatide QW or placebo, both added to titrated insulin glargine, in uncontrolled type 2 diabetes: The DURATION-7 randomized study.
Guja, C, Frías, JP, Somogyi, A, Jabbour, S, Wang, H, Hardy, E, Rosenstock, J
Diabetes, obesity & metabolism. 2018;(7):1602-1614
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AIMS: To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin. METHODS This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose. RESULTS Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events. CONCLUSIONS Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.
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Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial.
Pratley, RE, Eldor, R, Raji, A, Golm, G, Huyck, SB, Qiu, Y, Sunga, S, Johnson, J, Terra, SG, Mancuso, JP, et al
Diabetes, obesity & metabolism. 2018;(5):1111-1120
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AIM: To evaluate the efficacy and safety of ertugliflozin and sitagliptin co-administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin. METHODS In this study (Clinicaltrials.gov NCT02099110), patients with glycated haemoglobin (HbA1c) ≥7.5% and ≤11.0% (≥58 and ≤97 mmol/mol) with metformin ≥1500 mg/d (n = 1233) were randomized to ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100) or to co-administration of E5/S100 or E15/S100. The primary endpoint was change from baseline in HbA1c at Week 26. RESULTS At Week 26, least squares mean HbA1c reductions from baseline were greater with E5/S100 (-1.5%) and E15/S100 (-1.5%) than with individual agents (-1.0%, -1.1% and -1.1% for E5, E15 and S100, respectively; P < .001 for all comparisons). HbA1c <7.0% (<53 mmol/mol) was achieved by 26.4%, 31.9%, 32.8%, 52.3% and 49.2% of patients in the E5, E15, S100, E5/S100 and E15/S100 groups, respectively. Fasting plasma glucose reductions were significantly greater with E5/S100 and E15/S100 compared with individual agents. Body weight and systolic blood pressure (SBP) significantly decreased with E5/S100 and E15/S100 vs S100 alone. Glycaemic control, body weight and SBP effects of ertugliflozin were maintained to Week 52. Genital mycotic infections were more common among ertugliflozin-treated patients compared with those treated with S100. Incidences of symptomatic hypoglycaemia and adverse events related to hypovolaemia or urinary tract infection were similar among groups. CONCLUSIONS In patients with uncontrolled type 2 diabetes while using metformin, co-administration of ertugliflozin and sitagliptin provided more effective glycaemic control through 52 weeks compared with the individual agents.
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Safety and efficacy of once-weekly semaglutide vs additional oral antidiabetic drugs in Japanese people with inadequately controlled type 2 diabetes: A randomized trial.
Kaku, K, Yamada, Y, Watada, H, Abiko, A, Nishida, T, Zacho, J, Kiyosue, A
Diabetes, obesity & metabolism. 2018;(5):1202-1212
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AIM: To evaluate the safety and efficacy of once-weekly subcutaneous semaglutide as monotherapy or combined with an oral antidiabetic drug (OAD) vs an additional OAD added to background therapy in Japanese people with type 2 diabetes (T2D) inadequately controlled on diet/exercise or OAD monotherapy. METHODS In this phase III, open-label trial, adults with T2D were randomized 2:2:1 to semaglutide 0.5 mg or 1.0 mg, or one additional OAD (a dipeptidyl peptidase-4 inhibitor, biguanide, sulphonylurea, glinide, α-glucosidase inhibitor or thiazolidinedione) with a different mode of action from that of background therapy. The primary endpoint was number of adverse events (AEs) after 56 weeks. RESULTS Baseline characteristics were balanced between treatment arms (601 randomized). More AEs were reported in the semaglutide 0.5 mg (86.2%) and 1.0 mg (88.0%) groups than in the additional OAD group (71.7%). These were typically mild/moderate. Gastrointestinal AEs were most frequent with semaglutide, which diminished over time. The mean glycated haemoglobin (HbA1c) concentration (baseline 8.1%) was significantly reduced with semaglutide 0.5 mg and 1.0 mg vs additional OAD (1.7% and 2.0% vs 0.7%, respectively; estimated treatment difference [ETD] vs additional OAD -1.08% and -1.37%, both P < .0001). Body weight (baseline 71.5 kg) was reduced by 1.4 kg and 3.2 kg with semaglutide 0.5 mg and 1.0 mg, vs a 0.4-kg increase with additional OAD (ETD -1.84 kg and -3.59 kg; both P < .0001). For semaglutide-treated participants, >80% achieved an HbA1c concentration <7.0% (Japanese Diabetes Society target). CONCLUSIONS Semaglutide was well tolerated, with no new safety issues identified. Semaglutide treatment significantly reduced HbA1c and body weight vs additional OAD treatment in Japanese people with T2D.