A few diabetes papers of interest

i. Clinical Inertia in Type 2 Diabetes Management: Evidence From a Large, Real-World Data Set.

Despite clinical practice guidelines that recommend frequent monitoring of HbA1c (every 3 months) and aggressive escalation of antihyperglycemic therapies until glycemic targets are reached (1,2), the intensification of therapy in patients with uncontrolled type 2 diabetes (T2D) is often inappropriately delayed. The failure of clinicians to intensify therapy when clinically indicated has been termed “clinical inertia.” A recently published systematic review found that the median time to treatment intensification after an HbA1c measurement above target was longer than 1 year (range 0.3 to >7.2 years) (3). We have previously reported a rather high rate of clinical inertia in patients uncontrolled on metformin monotherapy (4). Treatment was not intensified early (within 6 months of metformin monotherapy failure) in 38%, 31%, and 28% of patients when poor glycemic control was defined as an HbA1c >7% (>53 mmol/mol), >7.5% (>58 mmol/mol), and >8% (>64 mmol/mol), respectively.

Using the electronic health record system at Cleveland Clinic (2005–2016), we identified a cohort of 7,389 patients with T2D who had an HbA1c value ≥7% (≥53 mmol/mol) (“index HbA1c”) despite having been on a stable regimen of two oral antihyperglycemic drugs (OADs) for at least 6 months prior to the index HbA1c. This HbA1c threshold would generally be expected to trigger treatment intensification based on current guidelines. Patient records were reviewed for the 6-month period following the index HbA1c, and changes in diabetes therapy were evaluated for evidence of “intensification” […] almost two-thirds of patients had no evidence of intensification in their antihyperglycemic therapy during the 6 months following the index HbA1c ≥7% (≥53 mmol/mol), suggestive of poor glycemic control. Most alarming was the finding that even among patients in the highest index HbA1c category (≥9% [≥75 mmol/mol]), therapy was not intensified in 44% of patients, and slightly more than half (53%) of those with an HbA1c between 8 and 8.9% (64 and 74 mmol/mol) did not have their therapy intensified.”

“Unfortunately, these real-world findings confirm a high prevalence of clinical inertia with regard to T2D management. The unavoidable conclusion from these data […] is that physicians are not responding quickly enough to evidence of poor glycemic control in a high percentage of patients, even in those with HbA1c levels far exceeding typical treatment targets.

ii. Gestational Diabetes Mellitus and Diet: A Systematic Review and Meta-analysis of Randomized Controlled Trials Examining the Impact of Modified Dietary Interventions on Maternal Glucose Control and Neonatal Birth Weight.

“Medical nutrition therapy is a mainstay of gestational diabetes mellitus (GDM) treatment. However, data are limited regarding the optimal diet for achieving euglycemia and improved perinatal outcomes. This study aims to investigate whether modified dietary interventions are associated with improved glycemia and/or improved birth weight outcomes in women with GDM when compared with control dietary interventions. […]

From 2,269 records screened, 18 randomized controlled trials involving 1,151 women were included. Pooled analysis demonstrated that for modified dietary interventions when compared with control subjects, there was a larger decrease in fasting and postprandial glucose (−4.07 mg/dL [95% CI −7.58, −0.57]; P = 0.02 and −7.78 mg/dL [95% CI −12.27, −3.29]; P = 0.0007, respectively) and a lower need for medication treatment (relative risk 0.65 [95% CI 0.47, 0.88]; P = 0.006). For neonatal outcomes, analysis of 16 randomized controlled trials including 841 participants showed that modified dietary interventions were associated with lower infant birth weight (−170.62 g [95% CI −333.64, −7.60]; P = 0.04) and less macrosomia (relative risk 0.49 [95% CI 0.27, 0.88]; P = 0.02). The quality of evidence for these outcomes was low to very low. Baseline differences between groups in postprandial glucose may have influenced glucose-related outcomes. […] we were unable to resolve queries regarding potential concerns for sources of bias because of lack of author response to our queries. We have addressed this by excluding these studies in the sensitivity analysis. […] after removal of the studies with the most substantial methodological concerns in the sensitivity analysis, differences in the change in fasting plasma glucose were no longer significant. Although differences in the change in postprandial glucose and birth weight persisted, they were attenuated.”

“This review highlights limitations of the current literature examining dietary interventions in GDM. Most studies are too small to demonstrate significant differences in our primary outcomes. Seven studies had fewer than 50 participants and only two had more than 100 participants (n = 125 and 150). The short duration of many dietary interventions and the late gestational age at which they were started (38) may also have limited their impact on glycemic and birth weight outcomes. Furthermore, we cannot conclude if the improvements in maternal glycemia and infant birth weight are due to reduced energy intake, improved nutrient quality, or specific changes in types of carbohydrate and/or protein. […] These data suggest that dietary interventions modified above and beyond usual dietary advice for GDM have the potential to offer better maternal glycemic control and infant birth weight outcomes. However, the quality of evidence was judged as low to very low due to the limitations in the design of included studies, the inconsistency between their results, and the imprecision in their effect estimates.”

iii. Lifetime Prevalence and Prognosis of Prediabetes Without Progression to Diabetes.

Impaired fasting glucose, also termed prediabetes, is increasingly prevalent and is associated with adverse cardiovascular risk (1). The cardiovascular risks attributed to prediabetes may be driven primarily by the conversion from prediabetes to overt diabetes (2). Given limited data on outcomes among nonconverters in the community, the extent to which some individuals with prediabetes never go on to develop diabetes and yet still experience adverse cardiovascular risk remains unclear. We therefore investigated the frequency of cardiovascular versus noncardiovascular deaths in people who developed early- and late-onset prediabetes without ever progressing to diabetes.”

“We used data from the Framingham Heart Study collected on the Offspring Cohort participants aged 18–77 years at the time of initial fasting plasma glucose (FPG) assessment (1983–1987) who had serial FPG testing over subsequent examinations with continuous surveillance for outcomes including cause-specific mortality (3). As applied in prior epidemiological investigations (4), we used a case-control design focusing on the cause-specific outcome of cardiovascular death to minimize the competing risk issues that would be encountered in time-to-event analyses. To focus on outcomes associated with a given chronic glycemic state maintained over the entire lifetime, we restricted our analyses to only those participants for whom data were available over the life course and until death. […] We excluded individuals with unknown age of onset of glycemic impairment (i.e., age ≥50 years with prediabetes or diabetes at enrollment). […] We analyzed cause-specific mortality, allowing for relating time-varying exposures with lifetime risk for an event (4). We related glycemic phenotypes to cardiovascular versus noncardiovascular cause of death using a case-control design, where cases were defined as individuals who died of cardiovascular disease (death from stroke, heart failure, or other vascular event) or coronary heart disease (CHD) and controls were those who died of other causes.”

“The mean age of participants at enrollment was 42 ± 7 years (43% women). The mean age at death was 73 ± 10 years. […] In our study, approximately half of the individuals presented with glycemic impairment in their lifetime, of whom two-thirds developed prediabetes but never diabetes. In our study, these individuals had lower cardiovascular-related mortality compared with those who later developed diabetes, even if the prediabetes onset was early in life. However, individuals with early-onset prediabetes, despite lifelong avoidance of overt diabetes, had greater propensity for death due to cardiovascular or coronary versus noncardiovascular disease compared with those who maintained lifelong normal glucose status. […] Prediabetes is a heterogeneous entity. Whereas some forms of prediabetes are precursors to diabetes, other types of prediabetes never progress to diabetes but still confer increased propensity for death from a cardiovascular cause.”

iv. Learning From Past Failures of Oral Insulin Trials.

Very recently one of the largest type 1 diabetes prevention trials using daily administration of oral insulin or placebo was completed. After 9 years of study enrollment and follow-up, the randomized controlled trial failed to delay the onset of clinical type 1 diabetes, which was the primary end point. The unfortunate outcome follows the previous large-scale trial, the Diabetes Prevention Trial–Type 1 (DPT-1), which again failed to delay diabetes onset with oral insulin or low-dose subcutaneous insulin injections in a randomized controlled trial with relatives at risk for type 1 diabetes. These sobering results raise the important question, “Where does the type 1 diabetes prevention field move next?” In this Perspective, we advocate for a paradigm shift in which smaller mechanistic trials are conducted to define immune mechanisms and potentially identify treatment responders. […] Mechanistic trials will allow for better trial design and patient selection based upon molecular markers prior to large randomized controlled trials, moving toward a personalized medicine approach for the prevention of type 1 diabetes.

“Before a disease can be prevented, it must be predicted. The ability to assess risk for developing type 1 diabetes (T1D) has been well documented over the last two decades (1). Using genetic markers, human leukocyte antigen (HLA) DQ and DR typing (2), islet autoantibodies (1), and assessments of glucose tolerance (intravenous or oral glucose tolerance tests) has led to accurate prediction models for T1D development (3). Prospective birth cohort studies Diabetes Autoimmunity Study in the Young (DAISY) in Colorado (4), Type 1 Diabetes Prediction and Prevention (DIPP) study in Finland (5), and BABYDIAB studies in Germany have followed genetically at-risk children for the development of islet autoimmunity and T1D disease onset (6). These studies have been instrumental in understanding the natural history of T1D and making T1D a predictable disease with the measurement of antibodies in the peripheral blood directed against insulin and proteins within β-cells […]. Having two or more islet autoantibodies confers an ∼85% risk of developing T1D within 15 years and nearly 100% over time (7). […] T1D can be predicted by measuring islet autoantibodies, and thousands of individuals including young children are being identified through screening efforts, necessitating the need for treatments to delay and prevent disease onset.”

“Antigen-specific immunotherapies hold the promise of potentially inducing tolerance by inhibiting effector T cells and inducing regulatory T cells, which can act locally at tissue-specific sites of inflammation (12). Additionally, side effects are minimal with these therapies. As such, insulin and GAD have both been used as antigen-based approaches in T1D (13). Oral insulin has been evaluated in two large randomized double-blinded placebo-controlled trials over the last two decades. First in the Diabetes Prevention Trial–Type 1 (DPT-1) and then in the TrialNet clinical trials network […] The DPT-1 enrolled relatives at increased risk for T1D having islet autoantibodies […] After 6 years of treatment, there was no delay in T1D onset. […] The TrialNet study screened, enrolled, and followed 560 at-risk relatives over 9 years from 2007 to 2016, and results have been recently published (16). Unfortunately, this trial failed to meet the primary end point of delaying or preventing diabetes onset.”

“Many factors influence the potency and efficacy of antigen-specific therapy such as dose, frequency of dosing, route of administration, and, importantly, timing in the disease process. […] Over the last two decades, most T1D clinical trial designs have randomized participants 1:1 or 2:1, drug to placebo, in a double-blind two-arm design, especially those intervention trials in new-onset T1D (18). Primary end points have been delay in T1D onset for prevention trials or stimulated C-peptide area under the curve at 12 months with new-onset trials. These designs have served the field well and provided reliable human data for efficacy. However, there are limitations including the speed at which these trials can be completed, the number of interventions evaluated, dose optimization, and evaluation of mechanistic hypotheses. Alternative clinical trial designs, such as adaptive trial designs using Bayesian statistics, can overcome some of these issues. Adaptive designs use accumulating data from the trial to modify certain aspects of the study, such as enrollment and treatment group assignments. This “learn as we go” approach relies on biomarkers to drive decisions on planned trial modifications. […] One of the significant limitations for adaptive trial designs in the T1D field, at the present time, is the lack of validated biomarkers for short-term readouts to inform trial adaptations. However, large-scale collaborative efforts are ongoing to define biomarkers of T1D-specific immune dysfunction and β-cell stress and death (9,22).”

T1D prevention has proven much more difficult than originally thought, challenging the paradigm that T1D is a single disease. T1D is indeed a heterogeneous disease in terms of age of diagnosis, islet autoantibody profiles, and the rate of loss of residual β-cell function after clinical onset. Children have a much more rapid loss of residual insulin production (measured as C-peptide area under the curve following a mixed-meal tolerance test) after diagnosis than older adolescents and adults (23,24), indicating that childhood and adult-onset T1D are not identical. Further evidence for subtypes of T1D come from studies of human pancreata of T1D organ donors in which children (0–14 years of age) within 1 year of diagnosis had many more inflamed islets compared with older adolescents and adults aged 15–39 years old (25). Additionally, a younger age of T1D onset (<7 years) has been associated with higher numbers of CD20+ B cells within islets and fewer insulin-containing islets compared with an age of onset ≥13 years associated with fewer CD20+ islet infiltrating cells and more insulin-containing islets (26,27). This suggests a much more aggressive autoimmune process in younger children and distinct endotypes (a subtype of a condition defined by a distinct pathophysiologic mechanism), which has recently been proposed for T1D (27).”

“Safe and specific therapies capable of being used in children are needed for T1D prevention. The vast majority of drug development involves small biotechnology companies, specialty pharmaceutical firms, and large pharmaceutical companies, more so than traditional academia. A large amount of preclinical and clinical research (phase 1, 2, and 3 studies) are needed to advance a drug candidate through the development pipeline to achieve U.S. Food and Drug Administration (FDA) approval for a given disease. A recent analysis of over 4,000 drugs from 835 companies in development during 2003–2011 revealed that only 10.4% of drugs that enter clinical development at phase 1 (safety studies) advance to FDA approval (32). However, the success rate increases 50% for the lead indication of a drug, i.e., a drug specifically developed for one given disease (32). Reasons for this include strong scientific rationale and early efficacy signals such as correlating pharmacokinetic (drug levels) to pharmacodynamic (drug target effects) tests for the lead indication. Lead indications also tend to have smaller, better-defined “homogenous” patient populations than nonlead indications for the same drug. This would imply that the T1D field needs more companies developing drugs specifically for T1D, not type 2 diabetes or other autoimmune diseases with later testing to broaden a drug’s indication. […] In a similar but separate analysis, selection biomarkers were found to substantially increase the success rate of drug approvals across all phases of drug development. Using a selection biomarker as part of study inclusion criteria increased drug approval threefold from 8.4% to 25.9% when used in phase 1 trials, 28% to 46% when transitioning from a phase 2 to phase 3 efficacy trial, and 55% to 76% for a phase 3 trial to likelihood of approval (33). These striking data support the concept that enrichment of patient enrollment at the molecular level is a more successful strategy than heterogeneous enrollment in clinical intervention trials. […] Taken together, new drugs designed specifically for children at risk for T1D and a biomarker selecting patients for a treatment response may increase the likelihood for a successful prevention trial; however, experimental confirmation in clinical trials is needed.”

v. Metabolic Karma — The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture.

“Cardiovascular (CV) disease remains the major cause of mortality and is associated with significant morbidity in both type 1 and type 2 diabetes (14). Despite major improvements in the management of traditional risk factors, including hypertension, dyslipidemia, and glycemic control prevention, retardation and reversal of atherosclerosis, as manifested clinically by myocardial infarction, stroke, and peripheral vascular disease, remain a major unmet need in the population with diabetes. For example, in the Steno-2 study and in its most recent report of the follow-up phase, at least a decade after cessation of the active treatment phase, there remained a high risk of death, primarily from CV disease despite aggressive control of the traditional risk factors, in this originally microalbuminuric population with type 2 diabetes (5,6). In a meta-analysis of major CV trials where aggressive glucose lowering was instituted […] the beneficial effect of intensive glycemic control on CV disease was modest, at best (7). […] recent trials with two sodium–glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin (11,12), and two long-acting glucagon-like peptide 1 agonists, liraglutide and semaglutide (13,14), have reported CV benefits that have led in some of these trials to a decrease in CV and all-cause mortality. However, even with these recent positive CV outcomes, CV disease remains the major burden in the population with diabetes (15).”

“This unmet need of residual CV disease in the population with diabetes remains unexplained but may occur as a result of a range of nontraditional risk factors, including low-grade inflammation and enhanced thrombogenicity as a result of the diabetic milieu (16). Furthermore, a range of injurious pathways as a result of chronic hyperglycemia previously studied in vitro in endothelial cells (17) or in models of microvascular complications may also be relevant and are a focus of this review […] [One] major factor that is likely to promote atherosclerosis in the diabetes setting is increased oxidative stress. There is not only increased generation of ROS from diverse sources but also reduced antioxidant defense in diabetes (40). […] vascular ROS accumulation is closely linked to atherosclerosis and vascular inflammation provide the impetus to consider specific antioxidant strategies as a novel therapeutic approach to decrease CV disease, particularly in the setting of diabetes.”

“One of the most important findings from numerous trials performed in subjects with type 1 and type 2 diabetes has been the identification that previous episodes of hyperglycemia can have a long-standing impact on the subsequent development of CV disease. This phenomenon known as “metabolic memory” or the “legacy effect” has been reported in numerous trials […] The underlying explanation at a molecular and/or cellular level for this phenomenon remains to be determined. Our group, as well as others, has postulated that epigenetic mechanisms may participate in conferring metabolic memory (5153). In in vitro studies initially performed in aortic endothelial cells, transient incubation of these cells in high glucose followed by subsequent return of these cells to a normoglycemic environment was associated with increased gene expression of the p65 subunit of NF-κB, NF-κB activation, and expression of NF-κB–dependent proteins, including MCP-1 and VCAM-1 (54).

In further defining a potential epigenetic mechanism that could explain the glucose-induced upregulation of genes implicated in vascular inflammation, a specific histone methylation mark was identified in the promoter region of the p65 gene (54). This histone 3 lysine 4 monomethylation (H3K4m1) occurred as a result of mobilization of the histone methyl transferase, Set7. Furthermore, knockdown of Set7 attenuated glucose-induced p65 upregulation and prevented the persistent upregulation of this gene despite these endothelial cells returning to a normoglycemic milieu (55). These findings, confirmed in animal models exposed to transient hyperglycemia (54), provide the rationale to consider Set7 as an appropriate target for end-organ protective therapies in diabetes. Although specific Set7 inhibitors are currently unavailable for clinical development, the current interest in drugs that block various enzymes, such as Set7, that influence histone methylation in diseases, such as cancer (56), could lead to agents that warrant testing in diabetes. Studies addressing other sites of histone methylation as well as other epigenetic pathways including DNA methylation and acetylation have been reported or are currently in progress (55,57,58), particularly in the context of diabetes complications. […] As in vitro and preclinical studies increase our knowledge and understanding of the pathogenesis of diabetes complications, it is likely that we will identify new molecular targets leading to better treatments to reduce the burden of macrovascular disease. Nevertheless, these new treatments will need to be considered in the context of improved management of traditional risk factors.”

vi. Perceived risk of diabetes seriously underestimates actual diabetes risk: The KORA FF4 study.

“According to the International Diabetes Federation (IDF), almost half of the people with diabetes worldwide are unaware of having the disease, and even in high-income countries, about one in three diabetes cases is not diagnosed [1,2]. In the USA, 28% of diabetes cases are undiagnosed [3]. In DEGS1, a recent population-based German survey, 22% of persons with HbA1c ≥ 6.5% were unaware of their disease [4]. Persons with undiagnosed diabetes mellitus (UDM) have a more than twofold risk of mortality compared to persons with normal glucose tolerance (NGT) [5,6]; many of them also have undiagnosed diabetes complications like retinopathy and chronic kidney disease [7,8]. […] early detection of diabetes and prediabetes is beneficial for patients, but may be delayed by patients´ being overly optimistic about their own health. Therefore, it is important to address how persons with UDM or prediabetes perceive their diabetes risk.”

“The proportion of persons who perceived their risk of having UDM at the time of the interview as “negligible”, “very low” or “low” was 87.1% (95% CI: 85.0–89.0) in NGT [normal glucose tolerance individuals], 83.9% (81.2–86.4) in prediabetes, and 74.2% (64.5–82.0) in UDM […]. The proportion of persons who perceived themselves at risk of developing diabetes in the following years ranged from 14.6% (95% CI: 12.6–16.8) in NGT to 20.6% (17.9–23.6) in prediabetes to 28.7% (20.5–38.6) in UDM […] In univariate regression models, perceiving oneself at risk of developing diabetes was associated with younger age, female sex, higher school education, obesity, self-rated poor general health, and parental diabetes […] the proportion of better educated younger persons (age ≤ 60 years) with prediabetes, who perceived themselves at risk of developing diabetes was 35%, whereas this figure was only 13% in less well educated older persons (age > 60 years).”

The present study shows that three out of four persons with UDM [undiagnosed diabetes mellitus] believed that the probability of having undetected diabetes was low or very low. In persons with prediabetes, more than 70% believed that they were not at risk of developing diabetes in the next years. People with prediabetes were more inclined to perceive themselves at risk of diabetes if their self-rated general health was poor, their mother or father had diabetes, they were obese, they were female, their educational level was high, and if they were younger. […] People with undiagnosed diabetes or prediabetes considerably underestimate their probability of having or developing diabetes. […] perceived diabetes risk was lower in men, lower educated and older persons. […] Our results showed that people with low and intermediate education strongly underestimate their risk of diabetes and may qualify as target groups for detection of UDM and prediabetes.”

“The present results were in line with results from the Dutch Hoorn Study [18,19]. Adriaanse et al. reported that among persons with UDM, only 28.3% perceived their likeliness of having diabetes to be at least 10% [18], and among persons with high risk of diabetes (predicted from a symptom risk questionnaire), the median perceived likeliness of having diabetes was 10.8% [19]. Again, perceived risk did not fully reflect the actual risk profiles. For BMI, there was barely any association with perceived risk of diabetes in the Dutch study [19].”

July 2, 2018 - Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Immunology, Medicine, Molecular biology, Pharmacology, Studies

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