Cardiovascular safety of liraglutide for the treatment of type 2 diabetes.

INTRODUCTION: Liraglutide is a GLP-1 RA that is an option for treatment of T2DM. Typical of all new glucose-lowering agents, its CV safety profile is of great interest. Areas covered: This article outlines the efficacy of the GLP-1 RA liraglutide from RCTs, moving through the pivotal phase 3 LEAD trials, and subsequent meta-analyses to assess CV safety. This review describes evolution of regulatory requirements to obtain safety information through dedicated CVOTs. Expert opinion: Since the FDA mandated that CV outcomes for new diabetes therapies should be assessed via a dedicated CVOT, opinion of their utility in T2DM evolved from cynicism through to enthusiasm. In LEADER, liraglutide became the second modern glucose-lowering agent to demonstrate significant CV benefit. CVOTs are now providing important answers, highlighting the CV benefits of modern glucose-lowering agents, but also raising several questions, notably whether the effects seen with liraglutide and empagliflozin are class-effects or are unique to these molecules. Furthermore it is unknown if these results in patients with high CV risk are applicable to all patients with T2DM, and should be incorporated into new treatment guidelines. In our view it's prudent to suggest that CVOT findings cannot currently be extrapolated to the whole T2DM population.

Renal complications of diabetes.

INTRODUCTION: Diabetic nephropathy is a leading cause of chronic kidney disease (CKD) in the UK. These patients are at significantly increased risk of cardiovascular disease and of progression to end-stage renal disease. We review the epidemiology, pathogenesis and natural history of diabetic nephropathy and evaluate the therapeutic options available. SOURCES OF DATA: We searched Medline and PubMed for source articles relevant to diabetic nephropathy and CKD. AREAS OF AGREEMENT: Early multifactorial intervention including strict blood pressure control, the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin two-receptor blockers (A2RB's) and good metabolic control attenuates cardiovascular risk and slows the rate of progression of renal disease. AREAS OF CONTROVERSY: Current areas of uncertainty include the relative benefits of ACE inhibitors and A2RBs in combination, whether direct renin inhibitors are harmful in patients with diabetes and also the positioning of hypoglycaemic agents as renal function declines. GROWING POINTS: What are the appropriate metabolic and blood pressure targets for patients with diabetes? AREAS TIMELY FOR DEVELOPMENT: Therapeutic strategies as kidney function declines.

Daytime variability of postprandial glucose tolerance and pancreatic B-cell function using 12-h profiles in persons with Type 2 diabetes.

AIMS: To study the variation in daytime glucose tolerance and pancreatic B-cell function at different levels of glycated haemoglobin (HbA(1c)) in subjects with Type 2 diabetes (T2DM). METHODS: T2DM subjects (n = 49; 34 men) had 12-h daytime plasma glucose (PG), insulin (PI), total (PTp) and intact proinsulin (PIp) profiles determined in response to three identical test meals at 4-h intervals. Subjects were divided into three groups according to HbA(1c)--group 1: < 7.3% (n = 18); group 2: 7.3-8.0% (n = 17); group 3: > 8.0% (n = 14). Fasting and preprandial (prior to meals 2 and 3) concentrations, total area under the curve (AUC), AUC above fasting (dAUC) and maximum postprandial metabolic concentrations (C(max)) were compared between the three meals and across the groups. RESULTS: Subjects in group 1 had significantly higher fasting plasma glucose (FPG) compared with preprandial PG concentrations (7.1 +/- 0.2 vs. 5.9 +/- 0.3 vs. 5.4 +/- 0.2; P < 0.01). Subjects in groups 2 and 3 had significantly higher FPG compared with preprandial PG levels prior to meal 3. PG.dAUC was highest in response to meal 1 and lowest following meal 2 (P < 0.05). FPI concentrations were significantly lower compared with preprandial PI concentrations. Subjects in group 1 had significantly higher PI prior to meal 2 compared with meal 3. PI.dAUC was highest in response to meal 1. Subjects in group 1 had lowest PI.dAUC following meal 2. FTp and FIp concentrations were also significantly lower compared with preprandial concentrations. PTp.dAUC and PIp.dAUC was highest in response to meal 1. CONCLUSIONS: There appears to be a shift in diurnal variation in glucose homeostasis and pancreatic B-cell function. Subjects had decreased glucose tolerance in response to the first and third meal of the day irrespective of glycaemic control. The variability in glucose tolerance was reflected by both quantitative and qualitative dysfunction of the pancreatic B-cell.

Relative and absolute contributions of postprandial and fasting plasma glucose to daytime hyperglycaemia and HbA(1c) in subjects with Type 2 diabetes.

AIMS: To determine the relative and absolute contributions of postprandial glucose (PPG) and fasting or preprandial plasma glucose (FPG) to daytime hyperglycaemia and HbA(1c) respectively, in persons with type 2 diabetes (T2DM). METHODS: Subjects (n = 52; 37 men) had 12hr plasma glucose (PG) profiles determined in response to three serial identical test meals. PPG exposure was calculated for each meal. Excess hyperglycaemia was calculated above a PG concentration of 5.5 mmol/l. Fasting hyperglycaemia was the difference between excess hyperglycaemia and PPG exposure. Subjects were divided into three groups according to HbA(1c)-(Gp1:<7.3%;Gp2:7.3%-8.0%;Gp3:>8.0%) and the relative contribution of PPG exposure and fasting hyperglycaemia to excess hyperglycaemia calculated for each meal. The absolute contribution of PPG and fasting hyperglycaemia to excess HbA(1c) (mean HbA(1c)-5.1%) was also calculated. RESULTS: The relative contributions of PPG exposure to excess hyperglycaemia for the three groups were: 58.3%, 54.3% and 35.4% (P = 0.483-Group 1 vs. Group 2; P = 0.002-Group 2 vs. Group 3) for meal 1; 69.8%, 54.7% and 23.7% (P = 0.163-Group 1 vs. Group 2; P = 0.005-Group 2 vs. Group 3) for meal 2; 85.8%, 70.2% and 48.6% (P = 0.153-Group 1 vs. Group 2; P = 0.046-Group 2 vs. Group 3) for meal 3. Absolute contributions of PPG to excess HbA(1c) in the three groups were 1.4%, 1.6% and 1.3% (P = NS). CONCLUSION: The relative contribution of postprandial glucose to excess hyperglycaemia decreases as glycaemic control deteriorates, being dominant with HbA(1c)

Use of cystatin C-based estimations of glomerular filtration rate in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The Modification of Diet in Renal Disease (MDRD) equation has recognised limitations when using estimated GFR in persons at risk of chronic kidney disease. Equations based on cystatin C provide an alternative method. We compared performance of the MDRD equation with a selection of cystatin C-based formulae for estimation of GFR in normoalbuminuric patients with type 2 diabetes. METHODS: Estimated GFR was calculated using the MDRD equation and the cystatin C formulae proposed by several investigator teams. Isotopic GFR was measured using plasma clearance of (51)Cr-EDTA. RESULTS: We studied 106 participants, of whom 83 (78%) were men with the following characteristics, mean (SD): age 61 (9) years, HbA(1c) 7.10 (1.27)%, creatinine 89.0 (12.7) micromol/l, cystatin C 0.859 (0.234) mg/l and isotopic GFR 104.5 (20.1) ml min(-1) 1.73 m(-2). MDRD estimated GFR was 77.4 (13.6) ml min(-1) 1.73 m(-2) (p < 0.05 for difference from isotopic GFR). Cystatin C-based calculations of estimated GFR were: Perkins 124.5 (31.8), Rule 90.0 (30.0), Stevens (age) 96.0 (30.4) and Stevens (creatinine) 85.6 (19.0) ml min(-1) 1.73 m(-2) (p < 0.05 for difference with isotopic GFR). For Arnal's, MacIsaac's and Tan's formulae cystatin-C estimated GFR were 101.7 (34.8), 102.1 (27.0) and 101.6 (27.8) ml min(-1) 1.73 m(-2), respectively (p = NS for difference with isotopic GFR). Cystatin C-based formulae were less biased and, with the exception of Perkins' formula, more accurate to within 10% of isotopic GFR than MDRD. CONCLUSIONS/INTERPRETATION: Performance of cystatin C equations was superior to MDRD in normoalbuminuric patients with type 2 diabetes. These results support further evaluation of cystatin C for estimation of GFR in persons at risk of chronic kidney disease.

Performance of the revised '175' Modification of Diet in Renal Disease equation in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Estimation of GFR (eGFR) is recommended for the assessment of kidney function in all patients with diabetes. We studied performance of the traditional '186' Modification of Diet in Renal Disease (MDRD) equation, and the 2005 revised '175' MDRD equation in patients with type 2 diabetes. METHODS: Two hundred and ninety-three mainly normoalbuminuric (267/293) patients were recruited. Patients were classified as having mild renal impairment (group 1, GFR <90 ml min(-1) 1.73 m(-2)) or normal renal function (group 2, GFR >or=90 ml min(-1) 1.73 m(-2)). eGFR was calculated by the traditional 186 MDRD equation using traditional creatinine values and the revised 175 MDRD equation using isotope dilution mass spectrometry-standardised creatinine values. Isotopic GFR was measured by the four-sample plasma clearance of (51)Cr-EDTA. RESULTS: For patients in group 1, mean +/- SD isotopic (51)Cr-EDTA GFR (iGFR) was 83.8 +/- 4.3 ml min(-1) 1.73 m(-2), and eGFR was 73.2 +/- 11.9 and 75.8 +/- 13.7 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -10.6 with the 186 MDRD and -7.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. In group 2, iGFR was 119.4 +/- 20.2 ml min(-1) 1.73 m(-2), and eGFR was 92.3 +/- 18.6 and 97.5 +/- 21.6 ml min(-1) 1.73 m(-2) using the 186 and 175 MDRD equations, respectively. Method bias was -27.1 with the 186 MDRD equation and -21.9 ml min(-1) 1.73 m(-2) (p < 0.05) with the 175 MDRD equation. CONCLUSIONS/INTERPRETATION: In patients newly diagnosed with type 2 diabetes, the revised 175 MDRD equation was less biased than the traditional 186 MDRD equation. Despite a continued tendency to underestimate isotopically measured GFR, use of standardised creatinine values is a positive step towards improved estimation of GFR.