Summary Background Combination treatment with a glucagon-like peptide-1 (GLP-1) agonist and basal insulin has been proposed as a treatment strategy for type 2 diabetes that could provide robust ...glucose-lowering capability with low risk of hypoglycaemia or weight gain. We thus did a systematic review and meta-analysis of randomised controlled trials to assess the effect of this combination treatment on glycaemic control, hypoglycaemia, and weight gain in patients with type 2 diabetes. Methods We systematically searched PubMed, Embase, Cochrane, Web of Knowledge, FDA.gov , and ClinicalTrials.gov for randomised controlled trials (published between Jan 1, 1950, and July 29, 2014; no language restrictions) comparing GLP-1 agonist and basal insulin combination treatment to other anti-diabetic treatments. Our main endpoints were glycaemic control, hypoglycaemia, and change in weight. We assessed pooled data by use of a random-effects model. Findings Of 2905 identified studies, 15 were eligible and were included in our analysis (N=4348 participants). Compared with other anti-diabetic treatments, GLP-1 agonist and basal insulin combination treatment yielded an improved mean reduction in glycated haemoglobin (HbA1c ) of −0·44% (95% CI −0·60 to −0·29), an improved likelihood of achieving the target HbA1c of 7·0% or lower (relative risk RR 1·92; 95% CI 1·43 to 2·56), no increased relative risk of hypoglycaemia (0·99; 0·76 to 1·29), and a mean reduction in weight of −3·22 kg (−4·90 to −1·54). Furthermore, compared with basal-bolus insulin regimens, the combination treatment yielded a mean reduction in HbA1c of −0·1% (−0·17 to −0·02), with lower relative risk of hypoglycaemia (0·67, 0·56 to 0·80), and reduction in mean weight (−5·66 kg; −9·8 to −1·51). Interpretation GLP-1 agonist and basal insulin combination treatment can enable achievement of the ideal trifecta in diabetic treatment: robust glycaemic control with no increased hypoglycaemia or weight gain. This combination is thus a potential therapeutic strategy that could improve the management of patients with type 2 diabetes. Funding None.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral glucose-lowering agents indicated for the treatment of type 2 diabetes. In the CANagliflozin cardioVascular Assessment Study (CANVAS) ...Program, the SGLT2 inhibitor canagliflozin was associated with an increased risk for lower-limb amputation (LLA) (including minor and major amputation) versus placebo (hazard ratio HR 1.97 95% CI 1.41, 2.75) in patients with type 2 diabetes and high cardiovascular risk. In the EMPA-REG OUTCOME trial in patients with type 2 diabetes and established cardiovascular disease, the proportion of patients with LLA was similar between those treated with empagliflozin and placebo. Here, Inzucchi et al report further analyses of LLA in the EMPA-REG OUTCOME trial.
Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus. Long‐acting insulin analogs provide ...relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro. These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes. In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer‐acting insulin analogs. In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower. While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies.
Studies have shown that, when implemented early in the course of type 2 diabetes mellitus, treatment with intensive insulin therapy for 2-3 weeks can induce a glycaemic remission, wherein patients ...are able to maintain normoglycaemia without any anti-diabetic medication. We thus did a systematic review and meta-analysis of interventional studies to assess the effect of short-term intensive insulin therapy on the pathophysiological defects underlying type 2 diabetes mellitus (pancreatic β-cell dysfunction and insulin resistance) and identify clinical predictors of remission.
We identified studies published between 1950 and Nov 19, 2012, which assessed the effect of intensive insulin therapy on β-cell function or insulin resistance, or both, or assessed long-term drug-free glycaemic remission in adults aged 18 years or older with newly diagnosed type 2 diabetes mellitus. We calculated pooled estimates by random-effects model. This study is registered with International Prospective Register of Systematic Reviews, number CRD42012002829.
We identified 1645 studies of which seven fulfilled inclusion criteria (n=839 participants). Five studies were non-randomised. A pooled analysis of the seven studies showed a post-intensive insulin therapy increase in Homeostasis Model Assessment of β-cell function as compared with baseline (1·13, 95% CI 1·02 to 1·25) and a decrease in Homeostasis Model Assessment of Insulin Resistance (-0·57, -0·84 to -0·29). In the four studies that assessed glycaemic remission (n=559 participants), the proportion of participants in drug-free remission was about 66·2% (292 of 441 patients) after 3 months of follow-up, about 58·9% (222 of 377 patients) after 6 months, about 46·3% (229 of 495 patients) after 12 months, and about 42·1% (53 of 126 patients) after 24 months. Patients who achieved remission had higher body-mass index than those who did not achieve remission (1·06 kg/m(2), 95% CI 0·55 to 1·58) and lower fasting plasma glucose (-0·59 mmol/L, 95% CI -1·11 to -0·07) at baseline.
Short-term intensive insulin therapy can improve the underlying pathophysiology in early type 2 diabetes mellitus, and thus might provide a treatment strategy for modifying the natural history of diabetes.
None.
In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established ...cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio HR 0.62 95% CI 0.49, 0.77). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin.
Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed.
Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA
. In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.
In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.
To evaluate the safety and efficacy of empagliflozin 10- and 25-mg doses plus a unique lower dose (2.5 mg) as adjunct to intensified insulin in patients with type 1 diabetes (T1D).
The EASE ...(Empagliflozin as Adjunctive to inSulin thErapy) program (
= 1,707) included two double-blind, placebo-controlled phase 3 trials: EASE-2 with empagliflozin 10 mg (
= 243), 25 mg (
= 244), and placebo (
= 243), 52-week treatment; and EASE-3 with empagliflozin 2.5 mg (
= 241), 10 mg (
= 248), 25 mg (
= 245), and placebo (
= 241), 26-week treatment. Together they evaluated empagliflozin 10 mg and 25 mg, doses currently approved in treatment of type 2 diabetes, and additionally 2.5 mg on 26-week change in glycated hemoglobin (primary end point) and weight, glucose time-in-range (>70 to ≤180 mg/dL), insulin dose, blood pressure, and hypoglycemia.
The observed largest mean placebo-subtracted glycated hemoglobin reductions were -0.28% (95% CI -0.42, -0.15) for 2.5 mg, -0.54% (-0.65, -0.42) for 10 mg, and -0.53% (-0.65, -0.42) for 25 mg (all
< 0.0001). Empagliflozin 2.5/10/25 mg doses, respectively, reduced mean weight by -1.8/-3.0/-3.4 kg (all
< 0.0001); increased glucose time-in-range by +1.0/+2.9/+3.1 h/day (
< 0.0001 for 10 and 25 mg); lowered total daily insulin dose by -6.4/-13.3/-12.7% (all
< 0.0001); and decreased systolic blood pressure by -2.1/-3.9/-3.7 mmHg (all
< 0.05). Genital infections occurred more frequently on empagliflozin. Adjudicated diabetic ketoacidosis occurred more with empagliflozin 10 mg (4.3%) and 25 mg (3.3%) but was comparable between empagliflozin 2.5 mg (0.8%) and placebo (1.2%). Severe hypoglycemia was rare and frequency was similar between empagliflozin and placebo.
Empagliflozin improved glycemic control and weight in T1D without increasing hypoglycemia. Ketoacidosis rate was comparable between empagliflozin 2.5 mg and placebo but increased with 10 mg and 25 mg. Ketone monitoring for early ketoacidosis detection and intervention and lower empagliflozin doses may help to reduce this risk.
Abstract The increased prevalence of type 2 diabetes mellitus is primarily being driven by the increasing global rates of overweight/obesity. Given the magnitude of this epidemic, we can expect these ...metabolic abnormalities to play an increasing role in the development of cardiovascular disease. In a pathophysiologic sense, type 2 diabetes is a multiorgan, multifactorial condition, characterized by β-cell dysfunction, insulin resistance in peripheral tissues and the liver, defective incretin activity, and elevated levels of free fatty acids and proinflammatory mediators. Despite the considerable burden of disease associated with type 2 diabetes, most patients are not at, or are unable to achieve, recommended glycemic control guideline targets. In part, this is because of the relentlessly progressive nature of the disease, but it may also be attributable to the current diabetes treatment paradigm, which is characterized by ineffective lifestyle interventions, followed by monotherapy and frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia. Thus, it is most appropriate to rethink the current treatment paradigm for type 2 diabetes in the context of a more aggressive initial therapy; specifically with early initiation of combination therapy. Our current understanding of the complex pathophysiology of the disease and the progressive deterioration in glycemic control over time supports the philosophy of earlier intervention with a more comprehensive initial therapy. Thus, while control of hyperglycemia remains the paramount goal, focusing on the underlying pathophysiology of type 2 diabetes is increasingly becoming the therapeutic strategy, with the aim of potentially providing disease modification. Although this is a logical approach, it remains to be demonstrated that early combination therapy will result in disease modification in a clinical setting. Not surprisingly, the incretin-based therapies have gained a great deal of attention in the context of being a component of initial combination therapy, given their potential beneficial effects on β-cell function with lowered risk of weight gain and hypoglycemia.
Clinical studies evaluating the cardiovascular safety/impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors demonstrated a reduction in major adverse cardiovascular events driven primarily by ...a reduced cardiovascular mortality in individuals with type 2 diabetes and previous cardiovascular disease. These somewhat unexpected results are coupled with SGLT-2 inhibitors' known acute effect of improvement in glycemia, reduction in blood pressure, and weight loss. In this review, we summarize the mechanism of action of SGLT-2 inhibitors, the metabolic effects of this class of medication, and the remarkable results of cardiovascular safety trials. In addition, we discuss adverse effects associated with these medications and the current recommendations for the use of these agents in the management of diabetes.
The discovery of insulin in 1921 and the progress achieved in the ensuing century highlight the promise and challenge of biochemically modifying the molecule to achieve optimization of its delivery ...and therapeutic efficacy. Normal endogenous insulin secretion consists of a highly orchestrated physiologic loop wherein multiple metabolic signals trigger the pancreatic β cells to secrete the precise amount of insulin into the portal system required to maintain euglycemia. Accordingly, in the treatment of diabetes, attempting to replicate this complex physiology with exogenous insulin therapy given subcutaneously presents a clinical challenge. In this context, recombinant DNA-based technology has enabled the development of insulin analogs that have been specifically designed to confer advantageous pharmacodynamic features that can better mimic endogenous insulin secretion. In this review, we discuss the development of the most widely available insulin preparations and provide evidence-based insight into their use in clinical practice.
To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes.
A 52-week, ...double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin.
HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences ETDs: 1.8 mg liraglutide -0.20% 95% CI -0.32; -0.07; 1.2 mg liraglutide -0.15% 95% CI -0.27; -0.03; 0.6 mg liraglutide -0.09% 95% CI -0.21; 0.03). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 95% CI 0.88; 0.96; 1.2 mg liraglutide 0.95 95% CI 0.91; 0.99; 0.6 mg liraglutide 1.00 95% CI 0.96; 1.04). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg 95% CI -5.7; -4.2; 1.2 mg liraglutide -3.6 kg 95% CI -4.3; -2.8; 0.6 mg liraglutide -2.2 kg 95% CI -2.9; -1.5). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 95% CI 1.07; 1.59; 1.2 mg liraglutide 1.27 95% CI 1.03; 1.55; 0.6 mg liraglutide 1.17 95% CI 0.97; 1.43), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 95% CI 1.13; 4.34).
Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.
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