Stanley Schwartz

STATEMENT BY AN AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/ AMERICAN COLLEGE OF ENDOCRINOLOGY CONSENSUS PANEL ON TYPE 2 DIABETES MELLITUS: AN ALGORITHM FOR GLYCEMIC CONTROL

This report presents an algorithm to assist primary care physicians, endocrinologists, and others in the management of adult, nonpregnant patients with type 2 diabetes mellitus. In order to minimize the risk of diabetes-related complications, the goal of therapy is to achieve a hemoglobin A1c (A1C) of 6.5% or less, with recognition of the need for individualization to minimize the risks of hypoglycemia. We provide therapeutic pathways stratified on the basis of current levels of A1C, whether the patient is receiving treatment or is drug naïve. We consider monotherapy, dual therapy, and triple therapy, including 8 major classes of medications (biguanides, dipeptidyl-peptidase-4 inhibitors, incretin mimetics, thiazolidinediones, alpha-glucosidase inhibitors, sulfonylureas, meglitinides, and bile acid sequestrants) and insulin therapy (basal, premixed, and multiple daily injections), with or without orally administered medications. We prioritize choices of medications according to safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and cost of medications. We recommend only combinations of medications approved by the US Food and Drug Administration that provide complementary mechanisms of action. It is essential to monitor therapy with A1C and self-monitoring of blood glucose and to adjust or advance therapy frequently (every 2 to 3 months) if the appropriate goal for each patient has not been achieved. We provide a flow-chart and table summarizing the major considerations. This algorithm represents a consensus of 14 highly experienced clinicians, clinical researchers, practitioners, and academicians and is based on the American Association of Clinical Endocrinologists/American College of Endocrinology Diabetes Guidelines and the recent medical literature.

Is incretin-based therapy ready for the care of hospitalized patients with type 2 diabetes?: The time has come for GLP-1 receptor agonists!

Significant data suggest that overt hyperglycemia, either observed with or without a prior diagnosis of diabetes, contributes to an increase in mortality and morbidity in hospitalized patients. In this regard, goal-directed insulin therapy has remained as the standard of care for achieving and maintaining glycemic control in hospitalized patients with critical and noncritical illness. As such, protocols to assist in the management of hyperglycemia in the inpatient setting have become commonplace in hospital settings. Clearly, insulin is a known entity, has been in clinical use for almost a century, and is effective. However, there are limitations to its use. Based on the observed mechanisms of action and efficacy, there has been a great interest in using incretin-based therapy with glucagon-like peptide-1 (GLP-1) receptor agonists instead of, or complementary to, an insulin-based approach to improve glycemic control in hospitalized, severely ill diabetic patients. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In this point narrative as presented below, Drs. Schwartz and DeFronzo provide an opinion that now is the time to consider GLP-1 receptor agonists as a logical consideration for inpatient glycemic control. It is important to note the recommendations they propose under “incretin-based approach” with these agents represent their opinion for use and, as they point out, well-designed prospective studies comparing these agents with insulin will be required to establish their efficacy and safety. In the counterpoint narrative following Drs. Schwartz and DeFronzo’s contribution, Drs. Umpierrez and Korytkowski provide a defense of insulin in the inpatient setting as the unquestioned gold standard for glycemic management in hospitalized settings. —William T. Cefalu Editor in Chief, Diabetes Care

Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults.

Despite the notion that there is a degree of commonality to the biological etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D), the lack of overlap in the genetic factors underpinning each of them suggests very distinct mechanisms. A disorder considered to be at the “intersection” of these two diseases is “latent autoimmune diabetes in adults” (LADA). Interestingly, genetic signals from both T1D and T2D are also seen in LADA, including the key HLA and transcription factor 7-like 2 (TCF7L2) loci, but the magnitudes of these effects are more complex than just pointing to LADA as being a simple admixture of T1D and T2D. We review the current status of the understanding of the genetics of LADA and place it in the context of what is known about the genetics of its better-studied “cousins,” T1D and T2D, especially with respect to the myriad of discoveries made over the last decade through genome-wide association studies.

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

BackgroundIn adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as ‘latent autoimmune diabetes in adults’ (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes.MethodsWe tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls.ResultsOverall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted.ConclusionLADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes.

Abstract The position statement on the management of hyperglycemia in patients with type 2 diabetes mellitus issued in 2012 by the American Diabetes Association and the European Association for the Study of Diabetes contains significant improvements over the 2009 version, including an emphasis on patient-centered care, enhanced strategies for lifestyle modification, a focus on comprehensive cardiovascular risk reduction, and increased pharmacotherapy choices. As diabetes management evolves over time, further improvements may be made in future consensus statements, including a focus on prevention and early treatment and improved glycemic control in all patients, including those with comorbidities. These goals will be achievable by waning use of therapies known to cause hypoglycemia and weight gain and the increased use of therapies that do not carry these risks.

Evidence-Based Practice Use of Incretin-Based Therapy in the Natural History of Diabetes

Abstract The incretin class of anti-hyperglycemic agents, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-inhibitors, is an important addition to the therapeutic armamentarium for the management of appropriate patients with type 2 diabetes mellitus as an adjunct to diet and exercise and/or with the agents metformin, sulfonylureas, thiazolidinediones, or any combination thereof. More recently, US Food and Drug Administration (FDA)-approved indications for incretins were expanded to include use with basal insulin. This review article takes an evidence-based practice approach in discussing the importance of aggressive treatment for diabetes, the principles of incretin physiology and pathophysiology, use of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, and patient types and contexts where incretin therapy has been found beneficial, from metabolic syndrome to overt diabetes.

Obviating much of the need for insulin therapy in type 2 diabetes mellitus: A re-assessment of insulin therapy's safety profile.

ABSTRACT Current processes of care for diabetes mellitus (DM) were shaped during the era when insulin therapy was considered inexorable to the management of advanced stage type 2 (T2DM), though this no longer appears to be categorically true. There are also dashed hopes that insulin therapy can prevent or stall diabetes. While exogenous insulin remains a life-sparing tool for fully insulin-dependent DM, insulin therapy-induced hyperinsulinemia now appears to contribute to serious safety issues beyond hypoglycemia and weight gain. Iatrogenic and compensatory hyperinsulinemia are metabolic disruptors of β-cells, liver, muscle, kidney, brain, heart and vasculature, inflammation, and lipid homeostasis, among other systems. This may compromise β-cells, exacerbate insulin resistance (IR), and increase risk of cardiovascular (CV) disease. Striking associations between exogenous insulin and risks of CV events, cancer, and all-cause mortality in clinical trial and real-world cohorts caution that insulin may pose more harm than previously evidenced. At our disposal are numerous alternate tools that, alone or in combination, efficaciously manage hyperglycemia and glucolipotoxicity, and do so without inducing hypoglycemia, weight gain, or hyperinsulinemia. Moreover, these new tools support true precision therapy, as modern day drug classes can be aligned with the various mediating pathways of hyperglycemia at work in any given patient. Some also appear to promote β-cell survival, with intriguing data being presented for newer agents, such as incretins. As such, we encourage preferential use of non-insulin antidiabetic agents to injected insulin for the management of non-insulin-dependent patients with T2DM, including in advanced stage T2DM. The goal of this article is to augment existing literature to 1) correct misconceptions on the rationale and necessity for insulin therapy in T2DM, 2) discuss emerging negative safety data with insulin therapy, and, 3) offer a practical means to reduce reliance on insulin through delayed initiation, minimized dose, and, drug switching to safer agents, and, potentially, reframes processes of care.

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Abstract Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D. Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D. Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension. Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.

Weight reduction in diabetes.

Obesity and diabetes incidence and prevalence are rampant in our Westernized civilization; they are both increasing and carry with them many medical complications. There is clear evidence that aggressive treatment of these conditions, in particular preventing weight gain and ideally facilitating weight reduction in patients can minimize and reduce these complications. We review data supporting these observations, and review options and recommendations to support the practitioners in helping their patients achieve these goals safely.

Revisiting weight reduction and management in the diabetic patient: Novel therapies provide new strategies

Abstract Weight gain has been so synonymous with diabetes care that overweight/obesity is considered an intractable aspect of diabetes and its management. A healthy body mass index (BMI) is paramount, however, in preserving the cardiometabolic profile, slowing the course of the disease and extending the life expectancy of patients. It is also key to fostering a healthy and productive society at large. Two trends in care press us to challenge our assumptions about weight control in this population by reconsidering traditional approaches to the management of diabetes. First, new anti-diabetes drug classes have emerged that are more “weight-friendly” than previously available treatments and “gentler” on the faltering β cell. Second, novel anti-obesity agents are proving efficacious in patients with diabetes. This paper presents the composite of newer and older anti-obesity and anti-diabetic drugs. It makes recommendations for anti-diabetic regimens and processes of care that engender weight loss, or neutralize or minimize weight gain, while getting many patients to their glycated hemoglobin (HbA1c) goal. Anti-obesity agents that can be safely and effectively incorporated into these regimens for the patient needing supplemental support are reviewed in detail