Basal-bolus Insulin Research Articles

Cost Analysis of FreeStyle Libre®2 System in Type2 Diabetes Mellitus Population.

IntroductionFreeStyle Libre® 2 system is a sensor-based flash-monitoring system that measures interstitial fluid glucose. The study aimed to compare cost of FreeStyle Libre 2 system and self-monitoring of blood glucose (SMBG) in the type 2 diabetes mellitus (T2DM) population from the Spanish Health System perspective.MethodsOn the basis of data collected from a literature review, the cost of glucose monitoring was modelled for patients with T2DM on a basal-bolus insulin regimen. The cost estimate included annual consumption for glucose monitoring (strips, lancets and sensors) and severe hypoglycaemic events (SHE) management. A published rate of SHE (2.5 episodes/patient-year) was considered. A reduction of SHE (− 48.8%) associated with FreeStyle Libre 2 system, derived from the REPLACE trial, was applied. Hospital attendance for 20.5% of SHEs (with subsequent hospitalization in 16.0%) was applied. Consumption of strips and lancets was set at 6/day for SMBG (derived from national monitoring recommendations), and 0.2/day for FreeStyle Libre 2 system users, with 26 FreeStyle Libre 2 sensors/year. Unitary costs (€, year 2020 excluding VAT) were derived from literature (€0.28/strip; €0.09/lancet; €3.09/daily FM sensor; €3804/hospitalized SHE; €1794/hospital-attended non-admitted SHE; €389/community-attended SHE).ResultsCosts were €2700 and €2120/year/patient using SMBG or FreeStyle Libre 2 system, respectively. For 1000 patients with T2DM using basal-bolus insulin, 1220 SHEs/year (with 48 hospitalizations) could be prevented and FreeSytle Libre 2 system could generate cost savings of up to €580,953/year versus SMBG (− 21.5%).Conclusion FreeStyle Libre 2 system is a potential cost-saving strategy in patients with T2DM in Spain on a basal-bolus insulin regimen.

Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type2 diabetes undergoing intensive glycemic control.

Aims/IntroductionPainful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control.Materials and MethodsThis exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only.ResultsParticipants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain.ConclusionsThis study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.

Inpatient Glycaemic Control is Poor in Patients Receiving Insulin Therapy

Patients with diabetes mellitus (DM) are admitted to hospital more frequently than the general population and have longer inpatient stays. Tight inpatient glycaemic control improves outcome but is difficult to achieve, especially in those on insulin. We prospectively reviewed the capillary blood glucose (CBG) control of hospital inpatients receiving insulin to determine their level of control and to examine healthcare providers’ responses to dysglycaemia. Between March and June 2020, all patients on insulin admitted to Bantry General Hospital for more than 24 hrs were reviewed. CBG recordings were individually categorised as either hypoglycaemic (CBG < 4mmol/L), euglycaemic (CBG = 4–9.9mmol/L), mildly hyperglycaemic (CBG = 10-14mmol/L) or severely hyperglycaemic (CBG >14mmol/L). Each patient’s individual insulin dose was reviewed and compared with their concurrent CBG level and categorised as either appropriate or inappropriate. Other factors that were reviewed included whether a HbA1C was performed, whether a referral to the diabetic clinical nurse specialist was made and whether the patient was on glucocorticoid therapy.16 patients were enrolled, average age 77. 497 CBG checks were recorded over 108 patient days. Average length of stay was 6.6 days. All patients had type 2 DM. 10 patients were on basal insulin therapy, 4 were on basal-bolus insulin, 2 were on mixed insulin. CBG was checked sub-optimally (i.e. fewer than 4 times per day) on 35/108 patient days. 355/497 CBG checks were in the euglycaemic range; but only 3 patients were entirely euglycaemic throughout admission.17 hypoglycaemic events occurred in 5 patients. These events were spread unevenly with 1 patient having 10 hypoglycaemic events while the other 7 events were spread between the remaining 4 patients.125 severely hyperglycaemic events occurred in 13 patients. Again, these events were spread unevenly with over half (67/125) events occurring in only 3 patients. Of these 13 patients, 5 were on glucocorticoid therapy. All 5 patients that had hypoglycaemic events also had severely hyperglycaemic events. Of the hypoglycaemic events recorded, only 12/17 were treated appropriately (i.e. with 15-20g of fast-acting carbohydrate and a reduction in subsequent insulin dose). Of the hyperglycaemic events recorded, 77/125 were managed appropriately (i.e. with either a stat dose of bolus insulin being administered or an increase in subsequent insulin doses being made or both). 6 prescribing errors were recorded in total. HbA1c was checked in 5 patients. An inpatient referral was made by the medical team to the diabetes clinical nurse specialist for only 4 patients. Inpatient glycaemic control was suboptimal in the majority of patients. Dysglycaemia, especially hyperglycaemia, remains problematic. Insulin doses were not adjusted often enough or dramatically enough. Further doctor and nurse education is required in this area.

Unfortunate Case of Hypoglycemia Induced Seizures Resulting in Anoxic Encephalopathy

Background: Severe hypoglycemia in patient with diabetes mellitus can manifest as seizures and coma, most commonly occurring after excessive insulin administration. Clinical Case: A 35-year-old woman with uncontrolled type 1 diabetes mellitus on basal-bolus insulin, complicated by gastroparesis, hypoglycemia unawareness, and frequent hypoglycemic episodes due to a tendency to give more than the recommended amount of insulin, who presented with seizures and diffuse brain edema as severe manifestations of profound hypoglycemia. Hemoglobin A1c was 7.3% but patient had wide variation in blood glucose (40- 300 mmol/L) on her glucometer. Patient had initially self-treated overnight hypoglycemic symptoms by drinking soda and then fell asleep without re-checking her blood sugar. She was then unresponsive in the morning. Patient’s husband reported that there was no glucagon at home since he used the last one and did not refill. On EMS arrival, patient had a blood glucose of 25, for which she received dextrose and glucagon with improvement of blood glucose but no change in mentation. En route to the hospital, patient developed tonic-clonic seizures and decerebrate posturing. She received Ativan and was intubated for airway protection. On exam, she had bilateral dilated sluggishly reactive pupils, eyes opened spontaneously but did not track, and limbs moved spontaneously but there was no purposeful movement. Initial CT head without contrast showed significant diffuse brain edema. Repeat MRI brain with and without contrast showed bilateral basal ganglia diffusion restriction with associated T2 and FLAIR hyperintense signal, suggestive of toxic-metabolic etiology including hypoglycemia. Video EEG showed findings consistent with anoxic encephalopathy. Patient received IV mannitol and IV dexamethasone for cerebral edema and Keppra for seizure prophylaxis, but was unable to be weaned from the ventilator and had to undergo tracheostomy and PEG tube placement, and was eventually discharged to inpatient rehabilitation. Conclusion: This case highlights the dangers of accidental overcorrection of high blood sugar with short-acting insulin and not appropriately treating hypoglycemia, which can lead to irreversible brain injury due to prolonged hypoglycemia. This unfortunate case highlights the importance of educating patients with diabetes mellitus on insulin how to appropriately manage low sugars to avoid such outcomes.

DKA in Diet-Controlled Patient With Type 2 Diabetes and ESRD Precipitated by Acute COVID-19

Type 2 diabetes mellitus (T2DM) is the main factor for the global rise in end stage renal disease (ESRD), accounting for about 45% of the dialysis patient population in United States. Although T2DM is a common cause for ESRD, it is uncommon for well controlled T2DM patients on dialysis to develop DKA. The COVID-19 pandemic has highlighted infections as a precipitating cause of diabetic ketoacidosis (DKA) and stresses the importance of optimal glycemic control. We report a case of a previously diet controlled patient with T2DM and ESRD admitted with DKA and acute COVID-19. 46-year-old male with diet controlled T2DM, HIV (human immunodeficiency virus) on HAART (highly active antiretroviral therapy), ESRD secondary to HIV associated nephropathy was admitted from an outpatient dialysis unit with vomiting, chills and body aches. He was on metformin monotherapy prior to dialysis initiation. Regular self-monitored blood glucoses ranged 80-130mg/dl with HbA1C of 6% one month prior. Lab tests on admit revealed serum glucose 499mg/dl, elevated anion gap 21mmol/L, potassium 3.5mmol/L (3.5–5.0), HbA1C: 14.7%, elevated beta-hydroxybutyrate 5.6mmol/L(normal:<=0.4), CD4 count 500 (489–1457/µL) with an undetectable HIV viral load however COVID-19 polymerase chain reaction was detectable. He was managed with cautious fluid resuscitation requiring a total of one-liter normal saline, higher potassium dialysate (3K+), and continuous insulin infusion with resolution of abdominal symptoms and DKA. No other infections or precipitating factors were found and acute COVID-19 infection was managed symptomatically. He was discharged on basal bolus insulin regimen on day seven of admit. Up to a third of patients with diabetes on dialysis do not require anti-hyperglycemic therapy, such as our case. Potential factors leading to reduced insulin requirements include reduced renal insulin clearance,reduced renal gluconeogenesis, protein-energy wasting, reduced body weight and accumulation of uremic toxins (guanidino compounds postulated to act as biguanide agents). Our case highlights that acute COVID-19 can precipitate DKA in previously well controlled T2DM patients on hemodialysis while being aware of the need for cautious fluid and potassium administration due to lack of osmotic diuresis in anuric dialysis patients. Close self-monitoring of blood glucose should be emphasized in patients withT2DM with ESRD, including diet controlled T2DM patients, in order to reduce hyperglycemic emergencies and inpatient admissions especially during COVID-19 pandemic.

The Peruvian Experience: New-Onset Diabetes Presenting With Diabetic Ketoacidosis in Patients With COVID19 Infections

Introduction: Data has emerged about patients with T2DM may experience DKA and HHS if infected with SARS-CoV-2. There is limited data about new-onset diabetes in patients with COVID-19. We describe a case series of three Peruvian patients with new onset diabetes presenting with DKA who remained insulin dependent several months after infection resolution. Case 1: A 59-year-old man with no significant past medical history and normal glucose presented with fever and dyspnea for five days. He was hospitalized with hypoxemic respiratory failure and tested positive forCOVID19. Hypoxemia improved with supportive care, but on day three, he became lethargic, tachycardic, and tachypneic with 95% oxygen saturation on room air. Biochemistry revealed an anion gap metabolic acidosis with pH 7.3, bicarbonate 10 mmol/L (22–28), β-hydroxybutyrate 5.4 mmol/L (<0.5), and glucose 679 mg/dL. He was treated with continuous insulin infusion. After DKA resolved, he was transitioned to basal-bolus insulin and remained insulin-dependent during outpatient follow-up. Case 2: A 49-year-old man in good health prior to admission, was transferred to our hospital for acute respiratory failure and positive testing for SARS-CoV-2. Two days later he became confused, tachycardic, and tachypneic with 90% oxygen saturation. DKA was diagnosed based on a pH 7.1, bicarbonate 8 mmol/L, β-hydroxybutyrate 5 mmol/L and glucose 625 mg/dL. He was transferred to the ICU for continuous insulin infusion. After resolution of his DKA, subcutaneous insulin was started. Preadmission hemoglobin A1c was 4.5%. He remained on insulin post hospital discharge. Case 3: A 33-year-old man with normal glucose prior to admission was transferred to our hospital from an outpatient office with a two-day history of dyspnea and altered sensorium. He was tachycardic and tachypneic with 96% oxygen saturation on 3L nasal cannula. He tested positive for SARS-CoV-2. DKA was diagnosed with glucose 690 mg/dL, bicarbonate 4 mmol/L, serum β-hydroxybutyrate 5.8 mmol/L and pH 6.6. He was resuscitated with intravenous fluids and an insulin infusion was started. DKA resolved after 5 days and he was discharged home on subcutaneous insulin. He remained insulin-dependent on follow-up. Conclusion: New-onset diabetes with DKA due to SARS-CoV-2 is increasingly recognized, and beta-cell dysfunction can be permanent, resulting in insulin-dependent diabetes. Accordingly, our patients remained insulin-dependent several months post discharge.

Prolonged Honeymoon Period in a Thai Patient With Adult-Onset Type 1 Diabetes Mellitus - Metabolic Flexibility in Autoimmune Diabetes?

Abstract Background: ‘Honeymoon’ period among people with type 1 diabetes mellitus (T1DM) refers to the period of time (mostly less than 1 year) which beta-cell is still able to produce insulin to maintain good glycemic control shortly following the development of diabetes. This phenomenon remained incompletely understood but previous studies showed that absence of diabetic ketoacidosis (DKA) at initial presentation, short duration of symptoms, older age at presentation, and strenuous exercise could be potential factors. Herein, we report a 24-year old Thai patient with T1DM who has been in sustained complete remission for more than 5 years while he is maintaining low carbohydrate intake and regular exercise. Clinical Case: A 24-year-old male presented with a 6-month history of polyuria, polydipsia and weight loss of 15 kilograms (baseline BMI at 27.8 kg/m2). His initial laboratory data showed plasma glucose 398 mg/dL and A1C 9.3%. No ketonemia was found. He was diagnosed with stage 3 of Type 1 DM based on clinical presentation and positive pancreatic auto-antibodies (anti-GAD and anti-IA2). Euthyroid Hashimoto’s thyroiditis was also diagnosed based on his enlarged thyroid gland and positive thyroid auto-antibodies. He was started on basal-bolus insulin regimen for only 2 month and then A1C reversed to 5.9% within 2 months. Insulin was gradually withdrawn and completely stopped. Mixed meal stimulation test (MMST) was firstly evaluated at the second year of his diagnosis. The result revealed stimulated C-peptide at 5.5 ng/dL. Next-generation sequencing panel for monogenic diabetes revealed negative results. The patient maintains healthy lifestyle habit with low carbohydrate intake and regular exercise 5–6 times per week. His body weight was maintained at 60–63 kilograms during the past 4 years. His A1C was maintained between 5.0 to 6.0% without any anti-diabetic medication for more than 5 years. Repeated MMST in every 6–12 months still revealed preserved beta-cell functions and normal stimulated plasma glucose. Interestingly, repeated pancreatic auto-antibodies at 3 years after diagnosis showed negative anti-GAD and anti-IA2, but positive anti-ZnT8. The patient was advised to maintain his bodyweight and healthy behavior together with closely regular OPD follow-up. Conclusion: Restored beta-cell function with completely insulin withdrawal in new-onset T1DM has been reported in very few cases which have some common factors as in our patient (low carbohydrate intake with regular exercise). Delaying autoimmune activity by reducing metabolic load in newly diagnosed T1DM might play a role in maintaining a honeymoon period and could lead to an innovative therapeutic option in new-onset T1DM.

Phosphoinositide 3-Kinase Inhibitor-Induced Hyperglycemia

Background: Phosphoinositide 3-kinase inhibitors (PI3Ki) are a new class of medications used to treat HR positive, HER2 negative, PIK3CA mutated advanced or metastatic breast cancer. Inhibition of PI3K, a key enzyme in the insulin signaling pathway, leads to disruption of glucose metabolism and frequently hyperglycemia. Here we present a case of difficult to treat PI3Ki-induced hyperglycemia from alpelisib. Case: 78 yo woman with metastatic breast cancer and NASH cirrhosis was referred for new hyperglycemia after starting alpelisib. Baseline HbA1c was 6%. She was initially started on metformin and glipizide without any blood glucose (BG) improvement. After 6 days, alpelisib was held with BG recovery. Alpelisib was restarted 1 month later, again resulting in hyperglycemia. Dapagliflozin treatment quickly improved BG to <200 mg/dL, but she developed candida intertrigo so it was discontinued and insulin was started. She also began a ketogenic diet. After 2 weeks of insulin titration, she had stable BG <200 on 47u of insulin a day.Within days, she was admitted with encephalopathy and a UTI which improved with antibiotics and lactulose. Alpelisib, initially held, was restarted on day 2 resulting in worsening hyperglycemia. Inpatient BG ranges on alpelisib were: fasting 191–358, pre-lunch 260–383, pre-dinner 308–404, and bedtime 330–355, despite a rapid increase of basal-bolus insulin and initiation of metformin, pioglitazone, and a ketogenic diet. Total daily insulin needs went from 18u, to 124u by day 5 of alpelisib. Imaging revealed new bone and hepatic metastases. With difficult to control hyperglycemia and cancer progression, alpelisib was discontinued with rapid improvement of hyperglycemia. Discussion: Hyperglycemia is a common adverse and on target effect of PI3Ki use. PI3K inhibition leads to acute hyperglycemia within hours. The pancreas responds by increasing insulin release. Transient hyperglycemia can occur in all patients, but may become persistent with underlying insulin resistance, as seen in our patient. T2DM (with HbA1c >6.5%) and all T1DM patients were excluded in alpelisib trials yet diabetes is not a formal contraindication. Providers should be vigilant for this complication in patients with diabetes and prediabetes. It has been suggested that exogenous insulin and medications that increase endogenous insulin secretion may be counterproductive because they overcome PI3Ki-induced insulin signaling disruption and compromise anti-tumor effectiveness of PI3Ki. Thus, the preferred and most effective treatment may be an SGLT2i as was the case in our patient. Insulin sensitizers and a ketogenic diet can potentially also be effective. Increasing insulin may have limited efficacy as seen with our patient. Future studies are needed to determine the best way to manage PI3Ki-induced hyperglycemia and the effect of potential treatments on anti-tumor efficacy.

Euglycemic Diabetic Ketoacidosis Post Bariatric Surgery in Type II DM in the Setting of SGLT2-Inhibitor Use

Introduction: Current AACE recommendations is to stop the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity. However, case reports suggest that the pharmacologic effects of SGLT2 inhibitors persist beyond 5 half-lives of elimination (2–3 days), with glucosuria and ketonemia lasting as long as 9 to 10 days after discontinuation.Case: A 51 year old female with a past medical history of hypertension, morbid obesity, DM type II, admitted to the hospital electively for bariatric surgery. Post-op day 1, she became tachypneic and lethargic. However, alert, oriented and responding appropriately. Lab work showed blood glucose levels <200 mg/dl (70–200 mg/dl), pH 7.21 (7.35–7.45), anion gap of 36 (4–14 mol/L), bicarbonate of 3 (23–34 mmol/L), pCO2 of 6 (35–45) and Potassium of 2.6 (3.5–5.2 mmol). UA showed glucose >500 mg/dl (0 mg/dl) and ketones 80 mg/dl (0 mg/dl). She was transferred to SICU. After reviewing her home medications, she was on Canagliflozin which was stopped 2 days prior to surgery and Glargine/Lixisenatide which was stopped 2 weeks prior to surgery as recommended by her endocrinologist. Patient was then diagnosed with euglycemic DKA. She was started on an insulin drip following potassium replacement and IV fluids. Over the course of few days, she started to feel better. Her PH, bicarb, anion gap and potassium all trended toward normal limits. She was transitioned off insulin drip to basal-bolus insulin regimen and then she was discharged on post-operative day 7 with the instruction to not take any SGLT2 inhibitors.Discussion: SGLT-2 inhibitors is known to cause euglycemic DKA and ketosis. Our case brings to attention that discontinuation of SGLT2 inhibitor treatment 48 hours prior to surgery may not be adequate specially giving the half-life of the medication. The optimal timing of discontinuation remains unknown. Further studies are needed to evaluate if longer withholding period may be necessary (1).1.Yehuda Handelsman, Robert R. Henry, Zachary T. Bloomgarden, Sam Dagogo-Jack, Ralph A. DeFronzo, Daniel Einhorn, Ele Ferrannini, Vivian A. Fonseca, Alan J. Garber, George Grunberger, Derek LeRoith, Guillermo E. Umpierrez, and Matthew R. Weir (2016) AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF SGLT-2 INHIBITORS AND DIABETIC KETOACIDOSIS. Endocrine Practice: June 2016, Vol. 22, No. 6, pp. 753–762.

Capecitabine-Induced Hyperosmolar Hyperglycemic State

Abstract Capecitabine is an orally administered prodrug of 5-fluorouracil (5-FU) which is often used for treatment of solid tumour cancers such as breast cancer and gastrointestinal tumours. Common adverse effects include nausea, diarrhea, anorexia and erythrodysthesia (hand-foot syndrome). However, there have been case reports of metabolic disturbances linked to capecitabine including hyperlipidemia, and less commonly, hyperglycemia. We report a case of a new diagnosis of persistent diabetes mellitus following an acute presentation of hyperosmolar hyperglycemic syndrome (HHS) subsequent to treatment with the chemotherapy agent, capecitabine. A 72 year old female with a history of metastatic breast cancer was admitted to hospital for management of hyperglycemic hyperosmolar state (HHS) after bloodwork from her family doctor revealed an elevated random blood glucose (40.2 mmol/L). Leading up to her presentation, the patient had completed 7 cycles of capecitabine treatment for her breast cancer. Prior to her capecitabine treatment, the patient did not have a history of diabetes mellitus. However, on admission, her hemoglobin A1C (HbA1C) was found to elevated into the diabetic range. Offending medications were considered and given the temporal dysglycemia following the patient’s chemotherapy regimen, capecitabine was thought to be a probable offending agent. The patient was acutely treated for HHS, and eventually transitioned to a basal-bolus insulin regimen at discharge. Her capecitabine was held pending review with her oncology team and she was closely followed up by her family doctor. The patient’s insulin regimen was ultimately titrated down to basal insulin only. Given the increasing use of capecitabine therapy in breast cancer, it is important to recognize the risk of hyperglycemia and hyperglycemic emergencies as a potential adverse effect of this treatment. It highlights the need to ensure that blood glucose is monitored throughout treatment to prevent hyperglycemic emergencies.

Immunotherapy-Related Autoimmune Diabetes Mellitus and Exogenous Insulin Antibody Syndrome in a Patient With Metastatic Oral Squamous Cell Carcinoma

Introduction: Exogenous insulin antibody syndrome (EIAS) is a rare condition characterized by wide glycemic excursions and recurrent hypoglycemia in the presence of high insulin antibody titers. It has been described in diabetic patients treated with exogenous insulin. Programmed death ligand 1 (PD-L1) inhibitors are known to cause autoimmune diabetes mellitus, but PD-L1-related EIAS has not yet been reported to our best knowledge. Case Description: A 63 years old Caucasian man with history of recurrent oral squamous cell cancer presented to emergency room with polyuria, polydipsia, nausea, and vomiting 3 months after initiation of immunotherapy (Durvalumab and cetuximab). He had no prior history of diabetes mellitus or hypoglycemia. He was admitted to hospital for management of diabetic ketoacidosis (Anion gap of 24 mEq/L, venous blood glucose of 805 mg/dL, Venous PH of 7.12, large urine ketone, A1C of 8.9%). After a brief hospital stay, the patient was discharged home on insulin glargine and metformin. His immunotherapy was resumed after hospital discharge. When the patient was seen by Endocrinologist in the clinic, metformin was discontinued and prandial insulin lispro was added. This basal-bolus insulin regimen improved his glycemic control initially. However, without significant changes in his lifestyle or medical condition, he developed worsening postprandial hyperglycemia and recurrent fasting hypoglycemia. Up-titration of his mealtime insulin did not lower postprandial hyperglycemia but possibly worsened fasting hypoglycemia. EIAS was suspected after reviewing his continuous glucose monitoring data. Further work up at this point revealed mildly elevated glutamic acid decarboxylase antibodies (5.9 units/mL, normal range 0.5 - 5.0) and markedly elevated insulin antibody level (77.0 µU/mL, normal range <5). His blood C-peptide was undetectable when his venous blood glucose was 252 mg/dl. In addition, his total insulin level (198 uU/mL) was much higher than his free insulin level (38 uU/mL) following an insulin lispro injection. The patient was diagnosed with EIAS. Switching insulin lispro to insulin aspart while he was on a different immunotherapy medication (Pembrolizumab) immediately reduced his average blood glucose and reduced his total daily insulin dosage by more than 50%. This improvement in glycemic control with insulin aspart only lasted for about 1 week. Unfortunately, the patient’s squamous cancer progressed on immunotherapy. He was referred to hospice care and passed away. Conclusion: Evaluation for EIAS would be reasonable in insulin-treated diabetic patients who develop wide glucose excursions and unexplained fasting hypoglycemia while on immunotherapy.

Predicting the Need for Basal-Bolus Insulin in Hospitalized Patients With Hyperglycemia: Is Sliding Scale Sometimes the Answer?

Uncontrolled blood glucose (BG) is associated with increased risk of infection, complications, and mortality in hospitalized patients. American Diabetes Association guidelines currently recommend basal insulin for all hospitalized, non-critically ill patients requiring insulin and state that “use of only a sliding scale insulin regimen in the inpatient hospital setting is strongly discouraged”. In practice, however, sliding scale only is used not infrequently. Here, we challenge the recommendation for universal basal insulin use and leverage machine learning to predict which inpatients would indeed benefit from basal insulin at time of admission.Querying inpatient electronic health record data for hospitalizations between 2008–2020, we identified a cohort of 16,868 unique patients who achieved a day of “good control”, defined as ≥ 3 BGs that were within 100–180 mg/dL without any values outside that range. Inclusion criteria were adult inpatients receiving subcutaneous insulin with BG of 100-180mg/dL on one calendar day. If patients had more than one “good day”, the first day of their most recent hospitalization was chosen. We excluded patients ordered for insulin pumps, insulin infusion, any insulin type that is rarely used (ordered < 25 times), TPN or PPN, or tube feeds. We also excluded patients with missing weights.We aimed to predict which patients would require > 6 units of insulin. We chose this threshold clinically, as patients with a total daily dose (TDD) of insulin < 6 units could reasonably be managed on sliding scale insulin alone. Using the threshold of 6 units, we used an ensemble machine learning method, called SuperLearner, to model a binary classification for high vs. low insulin users. Features included in the algorithm were collected prior to prediction time, including weight, height, age, sex, race, insurance status, A1c categories (normal, high, panic high, and missing), creatinine, diet, steroid use in prior 48 hours, admission BG, summary statistics of BG, numerous counts of relevant lab values in quantiles, history of basal insulin use, and counts of major diagnosis code groups. Prior insulin doses were not considered to better simulate admission insulin dosing.Compared to using only weight in the model, with an area under the receiver operating curve (AUROC) of 0.59, our machine learning algorithm showed excellent predictive ability, with an AUROC of 0.85 (95% CI: 0.84 - 0.87) and area under the precision recall curve (AUPRC) of .65 (95% CI: 0.64 - 0.68) vs 0.29 with the weight-only model. Although it will need to be validated prospectively, our algorithm could be used to emphasize basal-bolus insulin on admission in patients predicted to require more insulin, whereas those predicted to require less could be started on sliding scale insulin or considered for oral anti-hyperglycemics.

The physiological basis of insulin therapy in people with diabetes mellitus

Insulin therapy has been in use now for 100 years, but only recently insulin replacement has been based on physiology. The pancreas secretes insulin at continuously variable rates, finely regulated by sensitive arterial glucose sensing. Pancreatic insulin is delivered directlyin the portal blood to insulinize preferentially the liver. In the fasting state, insulin is secreted at a low rate to modulate hepatic glucose output. After liver extraction (50%), insulin concentrations in peripheral plasma are 2.4–4 times lower than in portal, but still efficacious to restrain lipolysis. In the prandial condition, insulin is secreted rapidly in large amounts to increase portal and peripheral concentrations to peaks 10–20 times greater vs the values of fasting within 30–40 min from meal ingestion. The prandial portal hyperinsulinemia fully suppresses hepatic glucose production while peripheral hyperinsulinemia increases glucose utilization, thus limitating the post-prandial plasma glucose elevation. Physiology of insulin indicates that insulin should be replaced in people with diabetes mimicking the pancreas, i.e. in a basal-bolus mode, for fasting and prandial state, respectively. Despite the presently ongoing limitations (subcutaneous and peripheral rather than portal and intravenous insulin delivery), basal-bolus insulin allows people with diabetes to achieve A1c in the range with minimal risk of hypoglycaemia, to prevent vascular complications and to ensure good quality of life.

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND, a Randomized, Pragmatic Trial.

OBJECTIVEBEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control.RESEARCH DESIGN AND METHODSParticipants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months.RESULTSBaseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group.CONCLUSIONSBEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

Basal-bolus insulin therapy fails to control glucocorticoidinduced hyperglycemia in patients with severe COPD exacerbation

Basal-bolus insulin therapy fails to control glucocorticoidinduced hyperglycemia in patients with severe COPD exacerbation

Management of older hospitalized patients with type 2 diabetes using linagliptin: Lina-Older study.

Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice. We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used. Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001). The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Fasting and postprandial plasma glucose contribution to glycated haemoglobin and time in range in people with type 2 diabetes on basal and bolus insulin therapy: Results from a pooled analysis of insulin lispro clinical trials

AimsTo investigate the interrelations between glycaemic metrics of fasting plasma glucose (FPG), postprandial glucose (PPG), glycated haemoglobin (HbA1c), and percentage of time in target range 3.9 to 10.0 mmol/L (%TIR) in patients on insulin therapy.Materials and methodsA pooled analysis was conducted using datasets extracted from an integrated database of insulin lispro clinical trials (Eli Lilly and Company). Studies in patients with type 2 diabetes on basal‐bolus or basal‐plus insulin therapy, and with ≥7‐point self‐monitored blood glucose profiles were included in the analysis. A multivariate regression model was used to quantify the contribution of FPG and PPG change to the change in HbA1c and %TIR. In addition, a linear regression model was used to describe the relationship between %TIR and HbA1c.ResultsFive studies encompassing 1572 patients met the criteria for inclusion. On average, a 1‐mmol/L change in FPG was associated with 2.7 mmol/mol (0.25%) change in HbA1c (range 2.0 to 2.8 mmol/mol [0.18%–0.26%]; all P <0.0001), and a 1‐mmol/L change in PPG with 1.8 mmol/mol (0.16%) change in HbA1c (range 1.2 to 2.1 mmol/mol [0.11%–0.19%]; all P <0.01). Furthermore, a 1‐mmol/L reduction in FPG and PPG was associated with an increase in TIR of 6.5% (range 5.8%–9.2%) and 5.3% (range 4.1%–8.7%), respectively, all P <0.0001. A decrease in HbA1c of 10.9 mmol/mol (1%) corresponded with an increase in TIR of 8.3%, on average.ConclusionsIn patients with type 2 diabetes on basal‐bolus or basal‐plus insulin therapy, management of both FPG and PPG is important for achievement of HbA1c and TIR goals.

Dapagliflozin: an effective adjunctive treatment in type 1 diabetes.

IntroductionMany people with type 1 diabetes (T1DM) continue to run high HbA1c levels with an associated elevated risk of cardiovascular events and increased mortality. We describe here how adjunctive prescription of an SGLT2 inhibitor has improved the glycaemic control of several people with T1DM, where the new technology has been intensively deployed.MethodsWe report outcomes of six adults with T1DM who have been given dapagliflozin in East Cheshire, UK. Initiation was with education/support from the diabetes specialist nurses. All had an HbA1c of 70 mmol/mol (8.6%) or more before this was initiated. All had been monitoring glycemia with a FreeStyle Libre monitor for at least 6 months prior to this.ResultsThe age range was 30–68 years. The mean duration of T1DM was 23.3 ± 5.5 years. All were on a basal-bolus regime. Over a 6 month period, HbA1c fell from 78.5 mmol/mol (9.3%) to 55 mmol/mol (7.2%). The greatest reduction in HbA1c was 57 mmol/mol (7.4%). Analysis of the FreeStyle Libre blood glucose records showed that the proportion of blood glucose readings on target (4–10 mmol/L) increased from 33.1 to 65.2% with the addition of dapagliflozin(P = 0.007). The proportion of blood glucose readings above target (>10 mmol/L) decreased from 68.0 to 26.4%, 6 months after initiation of dapagliflozin (P = 0.005). There was no increase in symptomatic hypoglycemia.ConclusionDapagliflozin as adjunctive therapy to basal-bolus regime insulin in individuals with T1DM was well tolerated and improved glycemic control with no increase in hypoglycemia. We provide further evidence of the value of this intervention.

A Model-Based Insulin Dose Optimization Algorithm for People With Type 1 Diabetes on Multiple Daily Injections Therapy.

Multiple daily injections (MDI) therapy is the most common treatment for type 1 diabetes (T1D) including basal insulin doses to keep glucose levels constant during fasting conditions and bolus insulin doses with meals. Optimal insulin dosing is critical to achieving satisfactory glycemia but is challenging due to inter- and intra-individual variability. Here, we present a novel model-based iterative algorithm that optimizes insulin doses using previous-day glucose, insulin, and meal data. Our algorithm employs a maximum-a-posteriori method to estimate parameters of a model describing the effects of changes in basal-bolus insulin doses. Then, parameter estimates, their confidence intervals, and the goodness of fit, are combined to generate new recommendations. We assessed our algorithm in three ways. First, a clinical data set of 150 days (15 participants) were used to evaluate the proposed model and the estimation method. Second, 60-day simulations were performed to demonstrate the efficacy of the algorithm. Third, a sample 6-day clinical experiment is presented and discussed. The model fitted the clinical data well with a root-mean-square-error of 1.75 mmol/L. Simulation results showed an improvement in the time in target (3.9-10 mmol/L) from 64% to 77% and a decrease in the time in hypoglycemia (< 3.9 mmol/L) from 8.1% to 3.8%. The clinical experiment demonstrated the feasibility of the algorithm. Our algorithm has the potential to improve glycemic control in people with T1D using MDI. This work is a step forward towards a decision support system that improves their quality of life.

Mauriac syndrome: a rare cause of massive hepatomegaly

Mauriac syndrome or glycogen hepatopathy (GH) is an uncommon complication of poorly controlled type 1 diabetes mellitus commonly occurring in adolescents. It has become even less common after the emergence of advances on diabetes treatment, but still exists. It manifests as growth failure, hepatomegaly, elevated liver enzymes, and accumulation of glycogen in hepatocytes related to poorly controlled diabetes and a glucose trap in the liver. GH has got good prognosis and fast resolution after adequate glycemic control, with no progression to end-stage liver disease. We report a 10-year-old boy with poorly controlled type I diabetes mellitus (on pre-mix insulin), hepatomegaly, and extremely high levels of liver transaminases. He underwent a liver biopsy elsewhere which showed glycogen deposits. He was referred to our institution for confirmation of diagnosis of glycogen storage disorder. Clinical examination revealed short stature, moon facies, and protuberant abdomen with hepatomegaly of 8 cm below the right costal margin. After exclusion of other causes of hepatitis, we controlled his sugars using basal bolus insulin regimen. Clinical exome sequencing revealed no abnormal mutations in the enzymes linked to glycogen metabolism. In an about 8 weeks, his transaminases normalized and hepatomegaly regressed.