Andrew Drexler

Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State

Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS) are potentially fatal hyperglycemic crises that occur as acute complications of uncontrolled diabetes mellitus. The authors provide a review of the current epidemiology, precipitating factors, pathogenesis, clinical presentation, evaluation, and treatment of DKA and HHS. The discovery of insulin in 1921 changed the life expectancy of patients with diabetes mellitus dramatically. Today, almost a century later, DKA and HHS remain significant causes of morbidity and mortality across different countries, ages, races, and socioeconomic groups and a significant economic burden for society.

Pilot Study Using Mobile Health to Coordinate the Diabetic Patient, Diabetologist, and Ophthalmologist

Background: In the United States, more than 25 million adults have diabetes, 40% of diabetics have diabetic retinopathy, and diabetes is the leading cause of blindness in people 20 to 74 years of age. Clinical trials have shown that strict control of blood glucose level and other risk factors delays diabetic retinopathy onset, progression, and vision loss. Methods: Patients with Type 1 or Type 2 diabetes mellitus, access to an Apple iPhone or iPad, and no psychological or medical condition that would interfere with the study participated in a nonrandomized clinical trial using SightBook™, a free mobile app that enables self-measurement of visual function and creates a password-protected web account for each patient. Results: Sixty patients enrolled in the clinical trial over a 6 month period. Twenty-six participants were men and 34 were women, with ages from 23 to 72 years (mean 45 ± 15) and diabetes duration of 1.5 to 50 years (mean 15.5 ± 11.5). Thirty-nine (65%) patients reported Type 1 diabetes and 21 (35%) patients reported Type 2 diabetes. Every patient established a personal web account on SightBook and invited participation of treating physicians; 51 (85%) patients completed the validated self-reported outcome assessments. Diabetologist examinations of 49 (82%) patients demonstrated systolic hypertension (≥140 mgHg) in 20% and hemoglobin A1c ≥ 7.0% in 56%. Ophthalmology examinations of 45 patients showed visual acuity in the worse-seeing eye of < 20/40 in 18% and diabetic retinopathy in 42% of patients. Conclusions: This clinical trial used a mobile health app to incorporate diabetic patient self-measurement of vision and coordinate the diabetic patient, diabetologist, and ophthalmologist for control of diabetes and diabetic retinopathy risk factors.

Fibrate use in diabetes: new concepts.

It has long been appreciated that diabetes is associated with a specific dyslipidemia characterized by elevated triglyceride, reduced high-density lipoprotein (HDL) cholesterol, and elevated levels of small, dense lowdensity lipoprotein (LDL), with these abnormalities in turn associated with insulin resistance, and with increased cardiovascular disease (CVD) risk both in type 2 and type 1 diabetes. The fibrates gemfibrozil and bezafibrate reduce CVD among diabetic people, but the evidence for CVD reduction with fenofibrate in the large Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial has been difficult to interpret, in part because of the greater use of statins among patients randomized to the placebo arm of the study. Although FIELD showed reductions in nonfatal myocardial infarction, total CVD, and revascularization, CVD mortality increased, a finding that raises concern in the general use of this agent among diabetic patients. Subset analysis showed greater benefit among the group with low HDL cholesterol, particularly when triglyceride levels were elevated at the same time. The trial also revealed evidence of reduction in albuminuria, and decreased macular edema and proliferative retinopathy, leading to a lessened requirement for laser photocoagulation; the two observations suggest an effect on microvascular disease, although there is evidence of reduction in the glomerular filtration rate, so the agent should be used cautiously. In this regard, the lipid substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was of great interest, comparing patients randomized to more and less intensive glycemic control, with both groups randomized to simvastatin versus simvastatin plus fenofibrate. Fenofibrate showed a trend to increasing HDL cholesterol, particularly during the initial year of the study, and led to a sustained reduction in triglyceride levels. Overall, there was no significant reduction in CVD, but the subset with triglyceride ‡204 mg ⁄dL and HDL cholesterol £34 mg ⁄dL did show a 29% lower CVD event rate. Furthermore, the progression of diabetic retinopathy was significantly reduced with both glycemic control (P = 0.003) and fenofibrate use (P = 0.006). Among those randomized to intensive glycemic control, 5.3% of those receiving a fenofibrate, but 7.1% of those receiving placebo, had progression, which was a non-significant trend; in the standard glycemic control arm, 7.6% of those receiving fenofibrate and 13.4% of those receiving placebo had progression, suggesting the benefit was seen with either of the two interventions, although not clearly demonstrating a beneficial effect of their interaction (Fig. 1). It is interesting to speculate as to whether the retinopathy effect is directly related to lipid-lowering or reflects participation of peroxisome proliferator-activated receptor-a in the process of retinal ischemia leading to vasoproliferation. Is it, then, appropriate to recommend fibrates for CVD prevention among persons with diabetes? The intervention may lead to benefits in the subset of people with the typical diabetic dyslipidemia pattern. Should we, in addition, consider fibrates to accompany our efforts to control glycemia in the prevention of microvascular disease? This may be a reasonable recommendation for persons with or at risk of developing retinopathy, particularly when the risk of hypoglycemia limits the ability to attain excellent glycemic control. Triglyceride levels were an independent risk factor for retinopathy among type 1 diabetic patients Intensive glycemic control Non-intensive glycemic control Fenofibrate Placebo 0% 5% 10% 15%

Can we go Beyond Surrogates

Two years ago, data presented at the annual American Diabetes Association (ADA) meeting in New Orleans showed a marked decrease in deaths, especially those due to cardiovascular disease, with the use of empagliflozin. Two major questions have been asked: (i) was the result a fluke; and (ii) was it a class effect, or was it specific to the agent used? The hope that both questions would be answered by a second study has been answered: the conclusions of EMPA-REG were not an anomaly and it is a class effect, not one caused by a specific drug. Importantly, do these studies require us to alter our algorithms for the treatment of type 2 diabetes? The CANagliflozin cardioVascular Assessment Study (CANVAS) was designed similarly to EMPA-REG, enrolling individuals who either had known cardiac disease or were at high risk for cardiac disease. In fact, CANVAS involved two stages, CANVAS and CANVAS R, which can be analyzed together. There were 10 142 patients in the combined trial followed for a mean of 3.6 years. The average age was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had known cardiovascular disease. In EMPA-REG, 7020 patients were followed for 3.1 years, 28.5% were women, and all had established cardiovascular disease. The primary endpoint of both studies was the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. In both studies, the components of the composite endpoint were studied along with other endpoints, including hospitalization for heart failure, all-cause mortality, and progression of renal disease. The primary endpoint was identically positive for superiority with hazard ratio of 0.86 for empagliflozin versus placebo and for canagliflozin versus placebo. Some differences were observed: both death from cardiovascular disease and all-cause mortality occurred significantly less frequently with empagliflozin in EMPA-REG, but the 13% lower total and cardiovascular mortality seen with canagliflozin in CANVAS was not statistically significant. Both studies showed a lower likelihood of hospitalization for heart failure with the intervention, even in patients without known heart failure at baseline, suggesting either that that diagnosis is often missed or that de novo heart failure may be prevented by these agents. Perhaps the strongest answer to the initial two questions comes from the CVD-REAL Study. Rather than being a randomized controlled clinical trial, that study analyzed medical claims, primary care or hospital records, and national registries from the US, Norway, Denmark, Sweden, Germany, and the UK, including 309 056 patients started on a sodium-glucose cotransporter 2 (SGLT2) inhibitor or on other glucose-lowering drugs using a propensity score matching algorithm. Canagliflozin was used by 53% of those receiving SGLT2 inhibitors, dapagliflozin was used by 42% and empagliflozin was used by 5%; those using these agents had hazard ratios for hospitalization for heart failure and for mortality of 0.61 and 0.49, respectively, with no differences either by country or by drug. The interesting hypothesis that this and the two controlled trials show the harm of alternative treatments of diabetes rather than the benefit of SGLT2 inhibitors has not been confirmed by subset analyses of drug use in the control groups. There are several potentially important differences between the studies. Strokes increased with empagliflozin in EMPA-REG (not statistically significant). There was a significantly increased likelihood of lower extremity amputation in CANVAS, although these events may not have been fully studied in EMPA-REG. Finally, the benefit of SGLT2 inhibitor therapy were seen within 3 months in EMPA-REG, while not appearing as rapidly in CANVAS. Furthermore, in neither study was there a reduction in non-fatal myocardial infarction. These considerations suggest that the benefit of SGLT2 inhibitors is not due to improvement in the underlying atherosclerotic process. It is likely that all SGLT2 inhibitors will receive an indication for secondary prevention of heart failure; whether the agents should be used in primary prevention is a much more difficult question, because it would require a very large study of patients without heart disease. The introduction of HbA1c measurements in the late 1970s radically and significantly improved our treatment of diabetes. However, our treatment of diabetes is ultimately not to lower HbA1c, but to prevent the complications of diabetes. Values of HbA1c are only a surrogate measure of diabetes. Currently, there is little agreement on the treatment algorithm for diabetes after metformin therapy. One may now argue that an SGLT2 inhibitor should be the preferred second-line therapy.

Is there a U‐shaped curve of A1c versus mortality?

In a report 2 years ago based on the UK General Practice Research Database, Currie et al. obtained information on 27 965 diabetic people receiving oral agents in combination and on 20 005 diabetic people who initially received oral agents and subsequently received insulin. Over a 5-year follow-up period, the lowest mortality was for those with a mean A1c of 7.5%. Either higher or, worrisomely, lower A1c levels were associated with lower survival. This was particularly true in the insulin-treated group, for whom mortality nearly doubled at either A1c 10.5% or A1c 6.0% compared with A1c 7.5%. Two recently published epidemiologic studies of diabetic patients with renal insufficiency show similar patterns. Shurraw et al. identified 23 296 diabetic patients with a glomerular filtration rate (GFR) lower than 60 mL ⁄min per 1.73 m, finding worse survival among those with A1c either >8% or <6.5%, although progression to end-stage renal disease (ESRD) only worsened at A1c >9%. In the second study performed on 54 757 diabetic patients receiving maintenance hemodialysis, Ricks et al. found that at A1c ‡10%, 3-year mortality was 19% greater than at A1c 7%–7.9%; however, mortality increased even more (by 35%) at A1c £5%. What is the biological implication of a ‘‘U-shaped curve’’? Efforts to understand the relationship between obesity and illness have been stymied by such relationships, although the divergence between smokers and non-smokers in relationships between body mass index (BMI) and mortality (with smokers showing higher mortality at lower BMI, and non-smokers exhibiting higher mortality at high BMI) has led to the hypothesis that the effects of lower weight are an effect of ill health. Some studies excluding cigarette and alcohol users and those with diagnosed illnesses still suggest higher mortality at both lower and higher body weight levels. Similar reports of U-shaped curves exist for blood pressure, alcohol use, fasting insulin, and the duration of sleep. The question for A1c is then whether the U-shaped curves suggest that type 2 diabetic patients are optimal at a moderately elevated level of A1c, with a causal relationship between low (i.e. normal for non-diabetic people) A1c and adverse outcome, or whether this apparent effect is due to confounding factors that lead to both lower A1c and worse outcome. Conceptually, it is difficult to understand how normal glucose levels for non-diabetic people would (directly) lead to adverse outcome among those with diabetes. However, it is important to realize that the relationship between glycemia and outcome may be less consistent as more advanced disease develops. Thus, in the study of Shurraw et al. the relationship between A1c and likelihood of progression to ESRD was significant only for a GFR >40 mL ⁄min per 1.73 m and was progressively stronger at higher baseline GFR levels. Similarly, in the Veteran’s Administration Diabetes Trial there appeared to be benefit of intensive glycemic control in those diabetic patients with baseline coronary calcium scores below, but not above, 100. It may be that certain advanced levels of diabetic complications do not benefit from improved glycemia, with intensive control only leading to a greater likelihood of harm from hypoglycemia. The notion that improved glycemia mediates adverse outcome then inherently conflates a biochemical measure of glycemic control with the measures taken to achieve lower glycemia. New approaches to improving glycemia may well allow benefit without adverse effects. Furthermore, although the relationship between A1c and glycemia is significant, in the study of Ricks et al. just over one-third of the variance in glucose was explained by the A1c level, and low glucose was much weaker in its association with mortality than was low A1c. It may be that A1c is not sufficiently precise to truly measure overall glycemic exposure. This may particularly be the case with renal insufficiency or with anemia, among the situations in which A1c can be particularly misleading, but it is important to realize that approximately 20% of diabetic people have A1c levels differing by >1% from that which would be predicted from their mean glucose. Do the ‘‘U-shaped curve’’ phenomena then imply that normalization of glycemia for type 2 diabetes is misguided? The jury is still out, but it seems that we doi: 10.1111/j.1753-0407.2012.00199.x Journal of Diabetes 4 (2012) 107–108

Insulin treatment of Type 2 diabetes: a clinical perspective

Some copies of this issue of the Journal of Diabetes are being distributed in China with a reprint describing the findings of a consensus conference organized by NovoNordisk on how best to use the combination of 30% insulin aspart (rapid-acting) and 70% protamine-based (intermediate-acting) insulin (BIAsp 30). The article offers guidance in approaches to intensifying treatment with this form of insulin, but does not compare BIAsp 30 with other insulin treatment regimens, particularly for people with Type 2 diabetes, a most interesting and important topic. It is not widely appreciated that the UK Prospective Diabetes Study (UKPDS) presented evidence that Type 2 diabetic people receiving either of the sulfonylureas (SU) used for initial treatment had progressively increasing need for addition of insulin over time, with nearly 10% needing this treatment after 1 year, and a linear increase to approximately half requiring this by 6 years. Insulin alone was inferior to combined treatment with insulin + SU in maintaining glycemic control. Although one may argue that in the current era of the availability of multiple oral agents the use of insulin is less necessary, comparison of maximal dose metformin and pioglitazone plus titrated SU treatment versus metformin plus BIAsp 30 showed that although either approach could successfully maintain excellent glycemic control, the former led to both a greater increase in weight and an increasing frequency of hypoglycemia. Therefore, insulin plus oral agents may be a preferable approach to thiazolidinedione ⁄ SU ⁄metformin combinations for many Type 2 diabetic people. Multiple approaches have been shown to be effective with insulin treatment. The rapid-acting insulin analogs lispro, aspart, and glulisine lead to more physiologic replication of the normal postprandial insulin secretory pattern, with a reduction in postprandial glycemia. The use of such analogs in combination with a protamine-containing intermediate-acting insulins led to the development of BIAsp 30 and to the similar Eli Lilly product, namely protamine-lispro 75% ⁄ lispro 25% (BI-lispro 25), both of which have the advantage over both intermediate-acting insulin alone and combinations of regular human insulin plus intermediate-acting insulin of better reducing postprandial glycemia while maintaining benefit in overnight glucose-lowering. Furthermore, these preparations have greater simplicity of administration, with the potential for a reduced number of injections. However, one problem with all such protaminecontaining insulin preparations is their pronounced peak effect, often occurring at an undesirable time after evening administration, so that although effective in improving glycemia, many studies suggest that they do so at the expense of a greater likelihood of nocturnal hypoglycemia than seen with the ‘peakless’ insulin analogs detemir and glargine. (It should be noted that not all authors have reported this finding.) Furthermore, intermediate-acting insulin given alone may not be quite as effective as insulin glargine in lowering A1c. Detemir appears to have less variability in overnight glucose-lowering action than seen either with protamine–intermediate-acting insulin or with insulin glargine, with studies comparing it with intermediateacting insulin showing lesser degrees of weight gain. The question should then be asked, which is better: basal insulins, such as protamine-containing preparations, glargine, or detemir; bolus insulins, particularly the rapid-acting analogs lispro, aspart, and glulisine; or the combination insulin preparations BIAsp 30 and BI-lispro 25? This question was addressed by the Treating to Target in Type 2 Diabetes (4-T) study. A total of 708 Type 2 diabetic people were randomized to BIAsp 30, to aspart three times daily before meals, or to insulin detemir once or twice daily. At 1 year, the detemir group had a lesser improvement in A1c but less weight gain, less hypoglycemia, and a lower total daily insulin dose. After 3 years, when all patients were moved to a multiple daily insulin (MDI) approach, hypoglycemia rates remained significantly lower in those started on insulin detemir and, in addition, these patients continued to exhibit less weight gain even though the glycemic improvement was now similar across all groups. Furthermore, cardiovascular mortality was significantly lower in the group started on basal insulin initially and significantly more serious adverse events occurred in those people initially randomized to BIAsp 30. This context should be used in interpreting the consensus statement of Unnikrishnan et al. regarding intensification of insulin therapy with BIAsp 30. The authors appropriately suggest that this preparation, dosed up to three-times daily, may allow improved glycemic control over basal insulin preparations and Journal of Diabetes 2 (2010) 65–66

Treatment: Concepts and new developments

In 2014, diabetes affected 27% of people in the US with Medicare, the federal health insurance program for people ≥65 years or older as well as for certain younger people with disabilities. Comprising just 15% of total beneficiaries, but 34% of those with diabetes, were individuals having six or more conditions who, as a group, were responsible for 50% of total Medicare spending and for 75% of Medicare hospital readmissions. A recent report from the Centers for Medicare and Medicaid Services put total Medicare spending in 2014 at US

New approaches to wound healing for diabetes 促进糖尿病患者伤口愈合的新方法: Commentary

323.9 billion, the amount spent on the most expensive drugs US

New approaches to wound healing for diabetes 促进糖尿病患者伤口愈合的新方法

55.1 billion, and spending on insulin glargine (Lantus; Sanofi, Paris, France) at US

New approaches to wound healing for diabetes.

3.7 billion, making it the most expensive single therapeutic agent for this population. Insulin treatment, then, is a particularly important and expensive component of diabetes treatment, and as new approaches become available it is relevant to review some of the patterns and developments in this area. Although the percentage of people in the US with diabetes using insulin decreased from 40% in 1997 to 33% in 2011, with the increase in diabetes prevalence the number using insulin increased from 3.4 to 5.8 million over the same period. Certainly, insulin is effective. In a pooled analysis of glargine titration studies of 2312 persons, the likelihood of attaining HbA1c 7.0% was 75% with baseline <8.0%, 60% with baseline >8.0 to <9.0%, and 38% with baseline HbA1c >9.0%, a pattern similar to that seen with most glucose-lowering treatments. Exploring the use of insulin glargine with metformin and with sulfonylureas in ameta-analysis of 15 randomized controlled trials, HbA1c decreased on average from 8.8% to 7.2% and fasting glucose from 10.9 to 6.6 mmol/L (from 196 to 119 mg/dL) over 24 weeks, although this was associated with hypoglycaemia (at annual rates on a stable insulin dosage of 4.1 and 1.4 episodes per person per year of glucose <3.9 and <3.1 mmol/L [<70 and <56 mg/dL], respectively) and weight gain (from 86.4 to 88.5 kg). These issues are also seen in “real-world” studies of type 2 diabetic patients starting insulin, with annual hypoglycemia rates around 30% with basal insulin alone and around 40% with basal-bolus and with premixed insulin, and 4-year weight gain of approximately 1 kg with basal insulin alone and 3–4 kg with basal-bolus and premixed regimens. Weight gain is particularly seen with higher baseline HbA1c levels and at higher insulin doses, and basal-bolus and premixed regimens track with a greater likelihood of >5 kg weight gain. Approaches to minimize weight gain include insulin administration with metformin and with glucagon-like peptide-1 receptor agonists (GLP-1RA), although the latter approach is not necessarily associatedwith a lessening of hypoglycaemia. It is crucial to realize that the issues of cost, complexity of administration, and the need for multiple injections, as well as older age and social isolation, may explain the unwillingness of many patients with diabetes to follow recommendations for insulin treatment, with medication possession ratios, proxy measures of adherence, ranging from 43% to 70% in various studies. Long-acting insulin analogs have been positioned as offering comparable glycemic control to isophane (neutral protamine Hagedorn [NPH]) insulin with reduced risks of symptomatic, overall, and nocturnal hypoglycemia with both insulins glargine and detemir, and a suggestion of modestly less weight gain with the latter, although it has been pointed out that evidence that these preparations are associated with fewer episodes of severe hypoglycemia has not been put forward. Two newer basal insulin preparations are insulin degludec (Tresiba; NovoNordisk, Bagsværd, Denmark) and a U300 preparation of insulin glargine (Toujeo; Sanofi). In some studies, insulin degludec is associated with lower fasting glucose than U100 insulin glargine and insulin detemir, although a differential effect on HbA1c has not been demonstrated. However, a meta-analysis has shown a significant 36% reduction in nocturnal hypoglycemia in type 2 diabetes with basal insulin alone, and comparable effects in type 1 and type 2 diabetic patients treated with basal-bolus regimens. Hypoglycemia rates were reduced by 25%–35% with insulin degludec compared with insulin glargine in diabetic people aged ≥65 years, as well as in those patients requiring >60 units insulin daily, although with a trend to greater weight gain. Similarly, U300 insulin glargine is associated with reduced rates of nocturnal hypoglycemia compared with U100 insulin glargine. A concern with these studies, as well as with the original studies comparing insulin glargine with NPH and those comparing insulin detemir with NPH, is that all studies of hypoglycemia were manufacturer sponsored and used doi: 10.1111/1753-0407.12381 Journal of Diabetes 8 (2016), 297–299