Anti-PD-L1 therapy and the onset of diabetes mellitus with positive pancreatic autoantibodies.

An 84-year-old woman with metastatic squamous cell carcinoma of the nasopharynx and no history of diabetes was started on the antiprogrammed cell death ligand-1 (anti-PD-L1) antibody durvalumab. Four months later, she presented in diabetic ketoacidosis with glucose 488 mg/dL, anion gap 16, positive serum ketones and A1C9.1%. Antiglutamic acid decarboxylase 65 (GAD) antibody was 13 U/mL (normal, <0.5 U/mL), c-peptide 0.4 ng/dL (normal, 1.1-4.3 ng/mL) and glucose 142 mg/dL. A man with metastatic papillary urothelial carcinoma was treated with the PD-L1 inhibitor atezolizumab. He had no history of diabetes. Nine weeks after initiation, he developed fatigue and polyuria with blood glucose 336 mg/dL, c-peptide 0.6 ng/mL, A1C8.2% and GAD antibodies 28.4 U/mL (normal, <1 U/mL). Due to the diagnosis of autoimmune diabetes, both patients were treated with insulin. Autoimmune diabetes is a rare immune-related adverse effect of PD-L1 inhibitors. We present the first two cases with documented positive pancreatic autoantibodies.

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.

Assessing the Performance of a Noninvasive Glucose Monitor in People with Type 2 Diabetes with Different Demographic Profiles.

BACKGROUND: Noninvasive glucose-monitoring devices represent an exciting frontier in diabetes research. GlucoTrack® is a noninvasive device that indirectly measures glucose fluctuation in the earlobe tissue. However, GlucoTrack measurements may be susceptible to effects of quasi-stable factors that may be affected by demographic profiles. The current study, thus, examined device performances in people with type 2 diabetes with different demographic profiles, focusing on age, gender, body mass, and whether the earlobe is pierced. MATERIALS AND METHODS: Clinical trials were conducted on 172 type 2 adult diabetic subjects. Device performance was clinically evaluated using the Clarke error grid (CEG) analysis and statistically assessed using absolute relative difference (ARD). RESULTS: CEG analysis revealed that 97.6% of glucose readings were within the clinically acceptable CEG A + B zones. Mean and median ARD were 22.3% and 18.8%, respectively. Likelihood ratio and parametric bootstrap tests revealed that there were no significant differences in ARD values across age, gender, body mass, and whether the earlobe was pierced, indicating that the accuracy of GlucoTrack remains consistent across the tested demographic profiles. CONCLUSIONS: Our results suggest that GlucoTrack performance does not depend on demographic profiles of its users and it is thus suitable for various people with type 2 diabetes.

Pilot study using mobile health to coordinate the diabetic patient, diabetologist, and ophthalmologist.

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. 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. 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. 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.

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.

Who needs an artificial pancreas? (？).

The development of a closed-loop "artificial pancreas" would be a welcome advance for both endocrinologists and diabetic patients struggling to attain near normal glycemic control. While great strides in automatically controlling blood sugar in the fasting, sedentary state have been made through complex mathematical modeling, management of blood sugar excursions due to food and exercise have been more problematic. An artificial pancreas is not feasible at this time because of limitations inherent in the currently available technology.

What role will 'gliptins' play in glycemic control?

The gliptins, a new class of oral drugs for type 2 diabietes mellitus, lower blood glucose levels by a novel mechanism: ie, by inhibiting the enzyme dipeptidyl peptidase 4, thereby increasing the circulating levelsof incretins (gut hormones that can boost insulin levels). This article reviews the current evidence on the effectiveness of gliptins and suggests several ways in which these agents could be used in diabetes treatment.

Evaluating the cardiovascular effects of the thiazolidinediones and their place in the management of type 2 diabetes in relation to the metabolic syndrome.

BACKGROUND: The aim of this work was to review evidence on the contribution of the metabolic syndrome to diabetes and atherosclerosis, to evaluate the effects of the thiazolidinediones (TZDs) on cardiovascular risk, and to assess the clinical use of TZDs and their associated risks and benefits. METHODS: Participants were a multidisciplinary panel of experts in endocrinology, cardiology, and nephrology. Available studies on hyperglycemia, hyperinsulinemia, beta-cell function, dyslipidemia, obesity, hypertension, inflammation, endothelial dysfunction, and vascular reactivity were reviewed through presentations by the experts. Assessments were made regarding the associations between characteristics of the metabolic syndrome, type 2 diabetes, and cardiovascular disease, along with the place of TZDs in therapy and management of related adverse clinical events. A panel was convened in November 2002 to develop conclusions based on scientific evidence presented during the meeting. Summary statements were evaluated based on strength and clinical relevance of the data and approved by all panel members. RESULTS AND CONCLUSIONS: Many characteristics of the metabolic syndrome are present before diabetes develops that greatly contribute to the cardiovascular disease burden associated with the progression of diabetes, such as atherosclerosis and coronary artery disease. Insulin resistance is a fundamental component of the metabolic syndrome, and interventions to improve insulin sensitivity are associated with positive cardiovascular effects. From current experimental and clinical data, TZDs appear to reduce risk factors for future cardiovascular events in patients with type 2 diabetes. Study data up to 2 years have demonstrated that TZDs effectively maintain glycemic control in patients with type 2 diabetes, which is attributed to their insulin-sensitizing effects and preservation of beta-cell function. Potential adverse events of TZDs include weight gain and edema, which are generally manageable. Aside from improving insulin sensitivity, TZDs improve lipid profiles, favorably alter deposition of adipose tissue to the periphery rather than visceral areas, decrease markers of inflammation and endothelial dysfunction, and restore vascular reactivity. These pleiotropic effects have the potential to improve cardiovascular outcomes in patients with type 2 diabetes. Trials are underway to confirm this potentially beneficial addition to proven therapies for hypertension, dyslipidemia, and atherosclerosis.

Lessons learned from landmark trials of type 2 diabetes mellitus and potential applications to clinical practice.

Landmark studies have demonstrated that diabetes is a significant risk factor for cardiovascular disease and mortality. Strong relationships exist between insulin resistance/hyperglycemia and mortality, microvascular complications, and cardiovascular complications. Lipid abnormalities frequently associated with type 2 diabetes and insulin resistance include low high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride levels. Lowering low-density lipoprotein cholesterol levels has been shown to improve the prognosis of patients with diabetes, and increasing HDL-C levels will significantly reduce the incidence of major coronary events. Higher levels of insulin sensitivity are associated with thinner intimal-medial thickness of the carotid artery, which indicates less atherosclerosis. Thiazolidinediones increase insulin sensitivity, decrease intimal-medial thickness, and appear to have inhibitory effects on the progression of atherosclerotic lesions. It is hoped that by preventing the onset of diabetes in high-risk individuals--and improving insulin sensitivity with lifestyle changes or pharmacologic treatment--the profound complications of type 2 diabetes will be prevented or delayed, as well.

Constructing an algorithm for managing type 2 diabetes. Focus on role of the thiazolidinediones.

With the understanding of type 2 diabetes mellitus constantly evolving, and with the introduction of many new agents during the past few years, it is often difficult to keep up to date with the management of type 2 diabetes. This article reviews the pathophysiology of type 2 diabetes, oral pharmacologic treatment, and proposed diabetes treatment algorithms, which aim to guide clinicians in the use of thiazolidinediones (TZDs) earlier in the course of diabetes. This is important because studies indicate that sulfonylureas, biguanides, and insulin do not protect the beta cell and cannot provide sustainable glycemic control. The basis for TZD use earlier in diabetes is 2-fold: to preserve beta-cell function while maintaining appropriate glycemic control for a longer duration than is usually attained through monotherapy with a secretagogue or biguanide, and to prevent or reverse the insulin resistance phenomenon of reduced insulin utilization that appears even prior to the clinical diagnosis of diabetes. Notably, decreasing insulin resistance also may reduce the incidence of adverse atherosclerotic consequences.

Update on diabetes diagnosis and management.

BACKGROUND: The American Diabetes Association has established recommendations for the testing of undiagnosed people. Once diagnosed, those with diabetes must strive to maintain a level of glucose control that results in a metabolism that approaches that of people without diabetes. The dentist also can provide risk-reduction strategies for people prone to develop diabetes, and refer patients with signs and symptoms suggestive of diabetes to physicians. METHODS: The authors describe criteria for establishing a diagnosis of diabetes and for identifying people at high risk of developing the disease. A combination of approaches in the medical management of type 1 and type 2 diabetes mellitus is presented, along with target outcomes. RESULTS: Patients with diabetes maintain a glycosylated hemoglobin value of no higher than 7 percent. New therapeutic research includes early clinical trials of islet cell transplantation and therapeutic cloning from human stem cells, which may provide an alternate source of insulin-producing islet cells and, thus, may offer a potential cure for diabetes. CONCLUSIONS: Rigorous metabolic control of diabetes can be achieved through a combination of therapeutic modalities and the establishment and maintenance of target outcomes. The dentist can implement preventive strategies and refer patients with signs and symptoms suggestive of diabetes to physicians. CLINICAL IMPLICATIONS: The dentist and physician must work together as a team to achieve rigorous metabolic control of diabetes in their patients.