Caroline K. Kramer

Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis

BACKGROUNDnCombination 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.nnnMETHODSnWe 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.nnnFINDINGSnOf 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).nnnINTERPRETATIONnGLP-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.nnnFUNDINGnNone.

Short-term intensive insulin therapy in type 2 diabetes mellitus: a systematic review and meta-analysis

BACKGROUNDnStudies 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.nnnMETHODSnWe 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.nnnFINDINGSnWe 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.nnnINTERPRETATIONnShort-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.nnnFUNDINGnNone.

Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes: The LIBRA Trial

OBJECTIVE Clinical studies evaluating the effects of medications on β-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of β-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve β-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT. RESEARCH DESIGN AND METHODS In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years duration and an A1C of 6.8 ± 0.8% (51 ± 8.7 mmol/mol) completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection, with serial assessment of β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test performed every 12 weeks. RESULTS The primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group (339.8 ± 27.8 vs. 229.3 ± 28.4, P = 0.008). Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group (6.2 ± 0.1% vs. 6.6 ± 0.1%, P = 0.055) (44 ± 1.1 vs. 49 ± 1.1 mmol/mol). At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤6.0% (42 mmol/mol) and glucose tolerance in the nondiabetic range. Despite this level of glycemic control, no difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups (P = 0.61). Two weeks after stopping treatment, however, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost (191.9 ± 24.7 vs. 238.1 ± 25.2, P = 0.20). CONCLUSIONS Liraglutide provides robust enhancement of β-cell function that is sustained over 48 weeks in early T2DM but lost upon cessation of therapy.

Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis

Objective To investigate the association of coronary artery calcium score with all cause mortality and cardiovascular events in people with type 2 diabetes. Design Systematic review and meta-analysis of observational studies. Data sources Studies were identified from Embase, PubMed, and abstracts from the 2011 and 2012 annual meetings of the American Diabetes Association, European Association for the Study of Diabetes, American College of Cardiology, and American Heart Association (2011). Eligibility criteria Prospective studies that evaluated baseline coronary artery calcium score in people with type 2 diabetes and subsequent all cause mortality or cardiovascular events (fatal and non-fatal). Data extraction Two independent reviewers extracted the data. The predictive value of the coronary artery calcium score was assessed by random effects model. Results Eight studies were included (n=6521; 802 events; mean follow-up 5.18 years). The relative risk for all cause mortality or cardiovascular events, or both comparing a total coronary artery calcium score of ≥10 with a score of <10 was 5.47 (95% confidence interval 2.59 to 11.53; I2=82.4%, P<0.001). The overall sensitivity of a total coronary artery calcium score of ≥10 for this composite outcome was 94% (95% confidence interval 89% to 96%), with a specificity of 34% (24% to 44%). The positive and negative likelihood ratios were 1.41 (95% confidence interval 1.20 to 1.66) and 0.18 (0.10 to 0.30), respectively. For people with a coronary artery calcium score of <10, the post-test probability of the composite outcome was about 1.8%, representing a 6.8-fold reduction from the pretest probability. Four studies evaluated cardiovascular events as the outcome (n=1805; 351 events). The relative risk for cardiovascular events comparing a total coronary artery calcium score of ≥10 with a score of <10 was 9.22 (2.73 to 31.07; I2=76.7%, P=0.005). The positive and negative likelihood ratios were 1.67 (1.30 to 2.17) and 0.11 (0.04 to 0.29), respectively. Conclusion In people with type 2 diabetes, a coronary artery calcium score of ≥10 predicts all cause mortality or cardiovascular events, or both, and cardiovascular events alone, with high sensitivity but low specificity. Clinically, the finding of a coronary artery calcium score of <10 may facilitate risk stratification by enabling the identification of people at low risk within this high risk population.

Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials

BACKGROUNDnClosed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance.nnnMETHODSnWe did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9-10 mmol/L or 3·9-8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854.nnnFINDINGSnWe identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02-16·16; p<0·0001), from a weighted mean of 58·21% for conventional pump therapy (I2=84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12-23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies (I2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies.nnnINTERPRETATIONnArtificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors.nnnFUNDINGnNone.

Fetal Sex and Maternal Risk of Gestational Diabetes Mellitus: The Impact of Having a Boy

OBJECTIVE Retrospective analyses of perinatal databases have raised the intriguing possibility of an increased risk of gestational diabetes mellitus (GDM) in women carrying a male fetus, but it has been unclear if this was a spurious association. We thus sought to evaluate the relationship between fetal sex and maternal glucose metabolism in a well-characterized cohort of women reflecting the full spectrum of gestational glucose tolerance from normal to mildly abnormal to GDM. RESEARCH DESIGN AND METHODS A total of 1,074 pregnant women underwent metabolic characterization, including oral glucose tolerance test (OGTT), at mean 29.5 weeks gestation. The prevalence of GDM, its pathophysiologic determinants (β-cell function and insulin sensitivity/resistance), and its clinical risk factors were compared between women carrying a female fetus (n = 534) and those carrying a male fetus (n = 540). RESULTS Women carrying a male fetus had lower mean adjusted β-cell function (insulinogenic index divided by HOMA of insulin resistance: 9.4 vs. 10.5, P = 0.007) and higher mean adjusted blood glucose at 30 min (P = 0.025), 1 h (P = 0.004), and 2 h (P = 0.02) during the OGTT, as compared with those carrying a female fetus. Furthermore, women carrying a male fetus had higher odds of developing GDM (odds ratio 1.39 [95% CI 1.01–1.90]). Indeed, male fetus further increased the relative risk of GDM conferred by the classic risk factors of maternal age >35 years and nonwhite ethnicity by 47 and 51%, respectively. CONCLUSIONS Male fetus is associated with poorer β-cell function, higher postprandial glycemia, and an increased risk of GDM in the mother. Thus, fetal sex potentially may influence maternal glucose metabolism in pregnancy.

Each degree of glucose intolerance in pregnancy predicts distinct trajectories of β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum.

OBJECTIVE Glucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes mellitus (T2DM) that is proportional to the severity of antepartum dysglycemia (i.e., highest in women with gestational diabetes mellitus [GDM], followed by those with milder dysglycemia). However, the pathophysiologic changes driving this risk are not known. Thus, we evaluated the longitudinal changes in β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum after gestational dysglycemia. RESEARCH DESIGN AND METHODS A total of 337 women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT at 3 months, 1 year, and 3 years postpartum. The antepartum GCT/OGTT identified four gestational glucose tolerance groups: GDM (n = 105); gestational impaired glucose tolerance (GIGT; n = 60); abnormal GCT, followed by normal glucose tolerance (NGT) on the OGTT (abnormal GCT NGT; n = 96); and normal GCT with NGT (n = 76). RESULTS At each of 3 months, 1 year, and 3 years postpartum, the prevalence of glucose intolerance increased from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all P < 0.001), whereas β-cell function, assessed by the Insulin Secretion-Sensitivity Index-2 (ISSI-2), and insulin sensitivity (Matsuda index), progressively decreased across the groups (all P < 0.002). Each group predicted distinct trajectories of ISSI-2, Matsuda index, and fasting and 2-h glucose (all P < 0.001). Notably, GDM, GIGT, and abnormal GCT NGT predicted varying rates of declining β-cell function and insulin sensitivity, as well as rising glycemia, compared with normal GCT NGT. CONCLUSIONS Each degree of gestational glucose intolerance predicts distinct trajectories of β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum that drive their differential risk of future T2DM.

The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight From the LIBRA Trial

CONTEXTnIn patients with type 2 diabetes (T2DM), impaired suppression of postprandial glucagonemia is a metabolic defect that contributes to hyperglycemia. Treatment with a glucagon-like peptide-1 agonist can reduce hyperglucagonemia in the acute setting, but little is known about the durability of this effect with long-term treatment.nnnOBJECTIVEnThe purpose of this study was to evaluate the impact of chronic liraglutide therapy on glucagon regulation in early T2DM. Design/Setting/Participants/Intervention: In this double-blind, randomized, placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 years duration were randomized to either daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with serial assessment of the glucose, insulin, C-peptide, and glucagon responses to a 75-g oral glucose tolerance test every 12 weeks.nnnMAIN OUTCOME MEASURESnThe glucagon response was assessed with the incremental area under the glucagon curve (iAUCglucagon) from measurements at 0, 30, 60, 90, and 120 minutes on each oral glucose tolerance test.nnnRESULTSnAs expected, compared with placebo, liraglutide induced a robust enhancement of the postchallenge insulin and C-peptide response at each of the 12-, 24-, 36-, and 48-week time points, with a concomitant reduction in glycemic excursion. However, liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12 weeks and persisted over the 48-week treatment period. Indeed, baseline-adjusted iAUCglucagon was significantly higher in the liraglutide group compared with placebo at 12 weeks (170.2 ± 34.9 vs 65.4 ± 36.4 pg/mL · 2 hours, P = .04), 36 weeks (162.2 ± 27.9 vs 55.7 ± 30.4 pg/mL · 2 hours, P = .01), and 48 weeks (155.5 ± 26.5 vs 45.7 ± 27.0 pg/mL · 2 hours, P = .006).nnnCONCLUSIONnIn contrast to its acute glucagon-lowering effect, chronic treatment with liraglutide is associated with increased postchallenge hyperglucagonemia in patients with early T2DM.

Determinants of reversibility of β-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes

Short-term intensive insulin therapy (IIT) can improve pancreatic β-cell function when administered early in the course of type 2 diabetes mellitus (T2DM). However, the degree of improvement in response to this therapy varies between patients. Thus, we sought to characterize the determinants of improvement in β-cell function in response to short-term IIT in early T2DM. Sixty-three patients with mean 3.0 ± 2.1 yr duration of T2DM and Hb A1c of 6.8 ± 0.8% underwent 4 wk of IIT consisting of basal insulin detemir and premeal insulin aspart, with oral glucose tolerance test administered at baseline and 1 day post-IIT. β-Cell function before and after IIT was assessed by Insulin Secretion Sensitivity Index-2 (ISSI-2). Reversibility of β-cell dysfunction was defined as percentage change in ISSI-2 of ≥25%. Overall, the study population experienced an increase in ISSI-2 from baseline to post-IIT (P = 0.01), with one-third of participants achieving ≥25% improvement in ISSI-2. Compared with their peers, those with increases in ISSI-2 of ≥25% had greater decrements in fasting glucose (P < 0.0001), Hb A1c (P = 0.001), ALT (P = 0.04), AST (P = 0.02), and HOMA-IR (P < 0.0001). On logistical regression analysis, baseline Hb A1c (OR = 2.83, 95% CI 1.16-6.88, P = 0.02) and change in HOMA-IR (OR = 0.008, 95%CI 0.0004-0.16, P = 0.001) emerged as independent predictors of reversibility of β-cell dysfunction. Indeed, reversibility of β-cell dysfunction was achieved in only those participants in whom IIT yielded an improvement in HOMA-IR. In conclusion, decline in HOMA-IR may be a key determinant of improvement of β-cell function in response to short-term IIT, suggesting a fundamental contribution of insulin resistance to the reversible component of β-cell dysfunction in early T2DM.

Glycemic Variability in Patients With Early Type 2 Diabetes: The Impact of Improvement in β-Cell Function

OBJECTIVE Increased glycemic variability has been reported to be associated with the risk of hypoglycemia and possibly diabetes complications and is believed to be due to β-cell dysfunction. However, it is not known whether improvement in β-cell function can reduce glycemic variability. Because short-term intensive insulin therapy (IIT) can improve β-cell function in early type 2 diabetes (T2DM), our objective was to determine whether the β-cell functional recovery induced by this therapy is associated with decreased glycemic variability. RESEARCH DESIGN AND METHODS Sixty-one patients with T2DM of 3.0 years mean duration underwent 4 weeks of IIT, which consisted of basal insulin detemir and premeal insulin aspart. Glucose variability was assessed in both the first and the last week by the coefficient of variation of capillary glucose on daily 6-point self-monitoring profiles. β-Cell function before and after IIT was assessed with the Insulin Secretion-Sensitivity Index-2 (ISSI-2). RESULTS Between the first and the last week on IIT, 55.7% of patients had a reduction in glucose variability. Change in glucose variability was negatively correlated with the change in β-cell function (ISSI-2) (r = −0.34, P = 0.008). On multiple linear regression analyses, percentage change in ISSI-2 emerged as the only factor independently associated with the change in glucose variability (standardized β = −0.42, P = 0.03). Moreover, patients with an increase in ISSI-2 ≥25% experienced a reduction in glucose variability compared with their peers who had almost no change (−0.041 ± 0.06 vs. −0.0002 ± 0.04, respectively; P = 0.006). CONCLUSIONS In early T2DM, glycemic variability is a modifiable parameter that can be reduced by improving β-cell function with short-term IIT.