Edited by Helaine E. Resnick, PhD, MPH

A review in this issue of Diabetes Care (p. 3124) provides a historic perspective of the hyperosmolar hyperglycemic state (HHS), a summary of the epidemiology and pathophysiology of this condition, and a synopsis of areas for future research. The new report covers more than a century of progress since 1886 when an “unusual diabetic coma” was first observed. It includes a description of a series of observations in the late 1950s that offered a firmer understanding that HHS resulted in osmotic diuresis, polyuria, and progressive water deficit that coincided with negative or trace ketonuria. Clinically, the elevations in glucose concentrations that are observed in HHS occur without significant ketosis and result from a number of factors including insulin deficiency and increases in counterregulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone. The hyperglycemia that is observed in HHS results from increased gluconeogenesis and accelerated glycogenolysis coupled with inadequate peripheral glucose uptake, mostly in muscle. It has been estimated that HHS occurs in <1% of all hospital admissions among people with diabetes. However, mortality has been reported to range from 10 to 20%, a level that is 10 times higher than the mortality rate among people with diabetic ketoacidosis (DKA). HHS is most common in older patients with type 2 diabetes. Within this group, those with a precipitating infection represent about 40–60% of all cases, with pneumonia being the most common infection. Importantly, as many as 20% of HHS cases do not have an existing diagnosis of diabetes, perhaps due to the high prevalence of undiagnosed diabetes in older adults. Although HHS is better understood now than in the past, the new report highlights a number of areas that would benefit from additional research. Suggested work includes an examination of why ketones are absent in HHS but a cardinal feature of DKA, prospective studies to understand the impact of inflammatory and oxidative stress markers on HHS outcomes, clinical initiatives that promote early detection and management of HHS in children, and clinical trials to evaluate anticoagulant therapy in HHS patients. — Helaine E. Resnick, PhD, MPH

Pasquel and Umpierrez. Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment. Diabetes Care 2014;37:3124–3131

This issue of Diabetes Care (p. 2926) features study results that support a new option for patients with type 2 diabetes who are poorly controlled on insulin and metformin. The new report focused on the contribution of the GLP-1 receptor agonist liraglutide to glucose control when it was used in combination with basal insulin and metformin. All patients in the study were taking metformin, and one group received once-daily insulin degludec + liraglutide (IDegLira) while the other received only insulin degludec (IDeg). The patients were followed for 26 weeks with a focus on the primary end point of change in A1C between baseline and study end. The results of the study suggested a meaningful role for liraglutide: In the IDegLira arm, A1C was reduced by 1.9% compared to only 0.9% in the IDeg arm. Further, the IDegLira group lost 2.7 kg during the study period while the IDeg arm had no weight change. Importantly, the incidence of hypoglycemia and other adverse events was similar in the two groups—findings that suggest similar safety profiles. Given that clinicians often hesitate to increase insulin dosing in patients who are poorly controlled because of issues such as hypoglycemia, adherence, and weight gain, the availability of another option for glucose lowering among patients who are not meeting glycemic control goals is sorely needed. The results of the new study suggest that IDegLira was superior in lowering glucose relative to IDeg alone, and the new combination treatment was associated with weight loss with no added risk of hypoglycemia. The once-daily treatment regimen is also appealing from the standpoint of patient adherence, a factor that is often of great concern to both clinicians and patients. — Helaine E. Resnick, PhD, MPH

Buse et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 2014;37:2926–2933

A new report in this issue of Diabetes Care (p. 2947) helps to clarify the role of a key inflammatory marker in both the development and progression of diabetic nephropathy. C-reactive protein (CRP) has been associated cross-sectionally with diabetic nephropathy, but these associations—along with results of poorly controlled longitudinal studies—have failed to cement a link between this inflammatory marker and renal dysfunction. Further, the distinction between CRP’s role in the development versus the progression of nephropathy in diabetes has yet to be established. The newly published data that shed light on these questions are from a Japanese diabetes registry in which more than 2,500 patients with type 2 diabetes were characterized at baseline with regard to both CRP levels and renal function. Baseline CRP was divided into quartiles, and the development of new cases of nephropathy (incidence) and the worsening of existing cases (progression) were identified over 1 year of follow-up. The data showed that quartile of baseline CRP was associated with incident microalbuminuria but not progression of albuminuria among patients with existing renal dysfunction at baseline. Among people with normal albumin at baseline, the risk of developing microalbuminuria was 1.31, 1.55, and 1.57 in the 2nd, 3rd, and 4th quartiles of baseline CRP, respectively, relative to those in the first quartile. These results were adjusted for a large number of potentially confounding characteristics including demographic factors as well as use of ACE, ARB, statins, and NSAIDs. The linear associations between CRP quartile and incident microalbuminuria were not observed in parallel analyses that focused on progression of existing nephropathy cases. These results suggest that CRP may be a useful tool for predicting the onset of nephropathy in patients with type 2 diabetes, but less useful in predicting progression of this condition once it is established. — Helaine E. Resnick, PhD, MPH

Hayashino et al. Serum high-sensitivity C-reactive protein levels are associated with high risk of development, not progression, of diabetic nephropathy among Japanese type 2 diabetic patients: a prospective cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT7]). Diabetes Care 2014;37:2947–2952

Research in this issue of Diabetes Care (p. 2989) provides evidence that being overweight or obese—even in the absence of traditional metabolic risk factors—is associated with substantially increased risk of developing diabetes. The new report used data from nearly 34,000 young nondiabetic men who were categorized according to the number of ATP-III risk factors at baseline. Among these men was a group with no risk factors, and they were defined as “metabolically healthy” (MH) based on normal levels of glucose, blood pressure, triglyceride, and HDL. Among these MH men, 4,207 were overweight and 631 were obese at the beginning of the study. The cohort was followed for more than 6 years during which new cases of diabetes were ascertained. Based on 734 new diabetes cases that were identified during the follow-up period, the data showed an expected relationship between baseline BMI and subsequent diabetes risk. In the cohort as a whole, each additional unit of increase in BMI was associated with a 10.6% increase in the risk of diabetes. However, the relationship between BMI and diabetes risk was present even among men who were MH at baseline: Diabetes incidence in this group was 1.15, 2.10, and 4.34 in the lean, overweight, and obese groups, respectively. The relationship between BMI and diabetes risk among the MH men persisted in multivariate models that controlled for a variety of risk factors. Relative to the lean MH group, those models showed that the risk of diabetes was 1.89 and 3.88 in the overweight and obese groups, respectively. These intriguing results do not support the idea that there is a “benign” obesity whose impact differs from long-held observations about the unfavorable impact of obesity on metabolic risk. — Helaine E. Resnick, PhD, MPH

Twig et al. Diabetes risk among overweight and obese metabolically healthy young adults. Diabetes Care 2014;37:2989–2995