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In a randomized, controlled trial, liraglutide (a glucagon-like peptide 1 receptor agonist) or placebo was added to usual care in patients with type 2 diabetes. In secondary analyses, rates of development and progression of diabetic kidney disease were lower with liraglutide.

Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. AbbVie.

Patients with type 2 diabetes at high cardiovascular risk received either once-weekly semaglutide, a glucagon-like peptide 1 analogue, or placebo. The rate of a first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke was significantly lower with semaglutide. Cardiovascular disease is the leading cause of death and complications in patients with type 2 diabetes. 1 Recently, trials evaluating a sodium–glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes in patients with type 2 diabetes who were at high risk for cardiovascular events. 2 , 3 Semaglutide, a GLP-1 analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration), 4 is currently in development but not yet approved for the treatment of type 2 diabetes. Regulatory guidance specifies the need to establish the cardiovascular safety of new therapies for type . . .

Aims/hypothesis The aim of this work was to study the potential long-term impact of a 7.8 years intensified, multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria in terms of gained years of life and years free from incident cardiovascular disease. Methods The original intervention (mean treatment duration 7.8 years) involved 160 patients with type 2 diabetes and microalbuminuria who were randomly assigned (using sealed envelopes) to receive either conventional therapy or intensified, multifactorial treatment including both behavioural and pharmacological approaches. After 7.8 years the study continued as an observational follow-up with all patients receiving treatment as for the original intensive-therapy group. The primary endpoint of this follow-up 21.2 years after intervention start was difference in median survival time between the original treatment groups with and without incident cardiovascular disease. Non-fatal endpoints and causes of death were adjudicated by an external endpoint committee blinded for treatment allocation. Results Thirty-eight intensive-therapy patients vs 55 conventional-therapy patients died during follow-up (HR 0.55 [95% CI 0.36, 0.83], p  = 0.005). The patients in the intensive-therapy group survived for a median of 7.9 years longer than the conventional-therapy group patients. Median time before first cardiovascular event after randomisation was 8.1 years longer in the intensive-therapy group ( p  = 0.001). The hazard for all microvascular complications was decreased in the intensive-therapy group in the range 0.52 to 0.67, except for peripheral neuropathy (HR 1.12). Conclusions/interpretation At 21.2 years of follow-up of 7.8 years of intensified, multifactorial, target-driven treatment of type 2 diabetes with microalbuminuria, we demonstrate a median of 7.9 years of gain of life. The increase in lifespan is matched by time free from incident cardiovascular disease. Trial registration: ClinicalTrials.gov registration no. NCT00320008. Funding: The study was funded by an unrestricted grant from Novo Nordisk A/S.

Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy. Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. Eli Lilly and Company.

In a double-blind trial, patients with type 1 diabetes and early-to-moderate diabetic kidney disease were randomly assigned to receive allopurinol, which may slow the decline in the glomerular filtration rate, or placebo. There were no clinically meaningful benefits of serum urate reduction on kidney outcomes with allopurinol therapy.

Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA 1c concentrations (>7·5%), and cardiovascular disease (or ≥2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A 1c [HbA 1c] of <6·0%) or standard (7·0–7·9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291·7 μmol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1·00, 95% CI 0·88–1·14; p=1·00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0·96, 0·89–1·02; p=0·19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0·95, 95% CI 0·85–1·07, p=0·42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0·95, 0·89–1·01, p=0·12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Six secondary measures at study end favoured intensive therapy (p<0·05). Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.

Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.

As compared with standard glucose control in patients with type 2 diabetes, intensive glucose control in the ADVANCE trial reduced the risk of nephropathy but not the risk of macrovascular events. There was no significant difference between the two groups in overall mortality. These findings, along with those of the ACCORD trial, raise complex questions about the role of intensive glucose control in type 2 diabetes. As compared with standard glucose control in patients with type 2 diabetes, intensive glucose control reduced the risk of nephropathy but not the risk of macrovascular events. There was no significant difference between the two groups in overall mortality. The prevalence of diabetes is increasing worldwide, and most people with diabetes will die or be disabled as a consequence of vascular complications. 1 , 2 Prospective studies have shown continuous associations of blood glucose and glycated hemoglobin levels with the risks of major vascular events. 3 , 4 However, previous randomized trials evaluating the effects of glycemic control in patients with diabetes have provided inconsistent evidence of effects on vascular disease. 5 – 11 Nevertheless, current guidelines recommend a target glycated hemoglobin level of 7.0% or less for most patients with diabetes. 12 – 14 The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release . . .

Propolis is a natural product with many biological properties including hypoglycemic activity and modulating lipid profile. The present study was designed to evaluate the effect of Iranian propolis extract on glucose metabolism, Lipid profile, Insulin resistance, renal and liver function as well as inflammatory biomarkers in patients with type 2 diabetes mellitus (T2DM). A double-blind, placebo-controlled clinical trial was conducted. The duration of the study lasted 90 days. Patients with T2DM were recruited and randomly divided into an Iranian propolis group (1000 mg/day) (n = 50) and a placebo group (n = 44). There was a significant decrease in the serum levels of glycosylated hemoglobin (HbA1c), 2-hour post prandial (2hpp), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), High sensitive C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α). However, there was a notable elevation in the serum HDL-C in the propolis group compared with the placebo group. In addition, a notable reduction in serum liver transaminase (ALT and AST) and blood urea nitrogen (BUN) concentrations in the propolis group was observed. Iranian propolis has beneficial effects on reducing post prandial blood glucose, serum insulin, insulin resistance, and inflammatory cytokines. It is also a useful treatment for preventing the liver and renal dysfunction, as well as, elevating HDL-C concentrations in patients with T2DM.