HbA1c <7.0% 6 Months after Initiation of Second-Line Therapy in Patients with Uncontrolled Type 2 Diabetes Is Associated with Good Glycemic Control at 3 Years: The DISCOVER Study

Background: DISCOVER is a 3-year, observational study of people with type 2 diabetes (T2D) initiating a second-line glucose-lowering therapy in 38 countries. We assessed glycemic control after 3 years in participants with HbA1c ≥ 9.0% at baseline. Methods: Factors associated with an increased likelihood of having HbA1c < 7.0% after 3 years were assessed using a hierarchical logistic regression model. Results: Of 14 691 DISCOVER participants from 37 countries, 2233 (15.2%) had sufficient HbA1c data and HbA1c ≥ 9.0% at baseline. The majority of participants were men (58.0%), and the mean age was 54.4 years (SD: 11.2 years). The mean HbA1c at baseline was 10.4% (SD: 1.4%). After 3 years, 626 participants (28.0%) had HbA1c < 7.0% and 438 (19.6%) had HbA1c ≥ 9.0%. Time since T2D diagnosis ≥ 10 years (vs.< 5 years) was associated with a decreased likelihood of having HbA1c < 7.0% at 3 years (Figure). Second-line therapy with two or more glucose-lowering drugs (vs. insulin) and having HbA1c < 7.0% at 6 months (24.2% of patients) were associated with an increased likelihood of having HbA1c < 7.0% at 3 years. Conclusions: Less than a third of participants with HbA1c ≥ 9.0% at initiation of second-line therapy reached HbA1c < 7.0% after 3 years. Early glycemic control (HbA1c < 7.0% at 6 months) was a key factor associated with attaining this target. Disclosure: F. Bonnet: Consultant;Self;Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. H. Chen: None. A. Cooper: Employee;Self;AstraZeneca. M.B. Gomes: None. L. Ji: None. P. Leigh: Employee;Self;AstraZeneca. Employee;Spouse/Partner;Merck Sharp & Dohme Corp. L. Ramirez Gutierrez: None. M.V. Shestakova: None. I. Shimomura: Advisory Panel;Self;AstraZeneca K.K., Daiichi Sankyo, Novo Nordisk Pharma Ltd., Taisho Pharmaceutical Co., Ltd. Consultant;Self;MSD K.K., Novo Nordisk Pharma Ltd. Research Support;Self;Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau;Self;Amgen Astellas BioPharma K.K., Astellas Pharma Inc., AstraZeneca K.K., Covidien Japan Inc., Daiichi Sankyo, Eli Lilly Japan K.K., KOBAYASHI Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Nippon Chemiphar Co., Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Rohto Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. A. Siddiqui: None. F. Tang: Research Support;Self;AstraZeneca. J. Vora: Other Relationship;Self;AstraZeneca. H. Watada: Advisory Panel;Self;Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support;Self;Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau;Self;stellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. K. Khunti: Advisory Panel;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member;Self;AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support;Self;AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker's Bureau;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Funding: AstraZeneca [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Quality of Life in People with Type 2 Diabetes following Initiation of Second-Line Therapy: DISCOVER

Background: Symptom relief, prolonging survival and avoiding complications are key goals in treating type 2 diabetes (T2D), but health-related quality of life (HRQoL) may be as or more important to patients. We used DISCOVER, a global observational study of people with T2D initiating a second-line glucose-lowering therapy, to examine factors associated with HRQoL over 3 years of follow-up. Methods: HRQoL was assessed using the 36-item Short-Form Health Survey (SF-36) v2 mental and physical component summary (MCS;PCS) scores (higher scores = better HRQoL) and the Hypoglycemia Fear Survey II (HFS-II;higher scores = greater fear). Factors associated with HRQoL over time were assessed using longitudinal multivariable regression models. Results: Of 14 691 DISCOVER patients from 37 countries, baseline and ≥ 1 follow-up MCS, PCS and HFS-II scores were available for 7880, 7854 and 5387 patients, respectively. Over time, SF-36 scores decreased (change per 6 months from baseline: MCS −0.04 [95% CI: −0.05 to −0.04];PCS −0.03 [95% CI: −0.03 to −0.02]), and HFS-II scores increased (change: 0.10 [95% CI: 0.09 to 0.12]). Many factors were associated with HRQoL (Table). Conclusions: HRQoL worsened during follow-up. Patient-, disease- and treatment-related factors were associated with HRQoL differences. Assessing factors associated with HRQoL over time may inform interventions to improve this important outcome. Disclosure: A. Nicolucci: Consultant;Self;AstraZeneca. H. Chen: None. A. Cooper: Employee;Self;AstraZeneca. M.B. Gomes: None. L. Ji: None. K. Khunti: Advisory Panel;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member;Self;AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support;Self;AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker's Bureau;Self;Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp & Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. M.N. Kosiborod: Consultant;Self;Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support;Self;AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P. Leigh: Employee;Self;AstraZeneca. Employee;Spouse/Partner;Merck Sharp & Dohme Corp. L. Ramirez: None. M.V. Shestakova: None. I. Shimomura: Advisory Panel;Self;AstraZeneca K.K., Daiichi Sankyo, Novo Nordisk Pharma Ltd., Taisho Pharmaceutical Co., Ltd. Consultant;Self;MSD K.K., Novo Nordisk Pharma Ltd. Research Support;Self;Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, MSD K.K., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau;Self;Amgen Astellas BioPharma K.K., Astellas Pharma Inc., AstraZeneca K.K., Covidien Japan Inc., Daiichi Sankyo, Eli Lilly Japan K.K., KOBAYASHI Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Kirin Co., Ltd., Mitsubishi T nabe Pharma Corporation, MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Nippon Chemiphar Co., Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Rohto Pharmaceutical Co., Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. A. Siddiqui: None. F. Tang: Research Support;Self;AstraZeneca. J. Vora: Other Relationship;Self;AstraZeneca. H. Watada: Advisory Panel;Self;Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support;Self;Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau;Self;Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. S.V. Arnold: None. Funding: AstraZeneca [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

HbA1c Level in Severe COVID-19 Patients Is Not Only a Marker of Glycemic Status but Also of Acute Erythrocyte Damage

Introduction: COVID-19 can trigger either transient stress-induced state, or newly onset diabetes mellitus (DM). It is well known that HbA1c serves as an indicator of glycemic status 12 weeks before the acute disease. Aim: To examine glycemic status at admission and 6 weeks after hospital discharge in patients with confirmed COVID-19 but no previous DM-history. Methods: Of 155 patients hospitalized with COVID-19 and pneumonia 111 persons had no previous DM-history. The levels of HbA1с, fasting and admission plasma glucose (FPG and APG) were measured at admission and 6 weeks after the discharge. The severity of COVID-19 was confirmed by CT scan, SpO2, serum IL-6, CRP, D-dimer. Results: All 111 patients had normal FPG and APG values. According to HbA1c level all the patients were divided into two groups: A) HbA1c≤6.0% (n=64, median 5,8%) and B) HbA1c>6,0% (n=47, median 6,4%). Our particular interest was focused on the group B due to the discrepancy of high HbA1c level and normal FPG and APG. Group B patients were retested for glycemic status in 6±1 week after the discharge. Surprisingly the median HbA1c level dropped down from 6,4% to 5,7% in such a short period of time with no antidiabetic drugs. COVID-19 severity markers were significantly higher in the group B. Conclusions: We suggest two explanations for this faster than expected HbA1c decrease: 1) patients with HbA1c>6,0% will progress to DM later, and, therefore, a longer follow-up is needed;2) SARS-CoV-2 virus has extensively glycosylated spike(S)-protein that may bind to erythrocytes. High-pressure liquid chromatography (the standard method for HbA1c) probably fails to separate the glycated 1-β-chain of hemoglobin from glycated viral spikes. In this case, abnormally high HbA1c in COVID-19 patients with no DM-history may serve as a marker of severe viral erythrocyte damage rather than a marker for the glucose control. This hypothesis is confirmed by the prompt (in 6 weeks) normalization of HbA1c level following the virus elimination.

[Diabetes and COVID-19: analysis of the clinical outcomes according to the data of the russian diabetes registry].

BACKGROUND: Data on the national level and worldwide show a higher rate of mortality in patients with diabetes mellitus (DM) due to COVID-19, which determines the high relevance of risk factor analysis for outcomes in DM patients to substantiate the strategy for this category of patients. AIM: To assess the effect of clinical and demographic parameters (age, gender, body mass index (BMI), glycemic control (HbA1c), and antidiabetic and antihypertensive drugs, including ACE inhibitors and ARBs) on clinical outcomes (recovery or death) in patients with type 2 DM. MATERIALS AND METHODS: A retrospective analysis of the Russian Register of Diabetes database was performed, including patients with type 2 DM (n=309) who suffered pneumonia/COVID-19 in the period from 01.02.2020 to 27.04.2020 and the indicated outcome of the disease (recovery or death) RESULTS: The percentage of lethality was determined to be 15.2% (47 of 309 people). The degree of lethality was found to be significantly higher in males (OR=2.08; 95% CI 1.1–3.9; p=0.022) and in patients on insulin therapy (OR=2.67; 95% CI; 1.42–5.02; p=0.002), while it was significantly lower in patients with an age <65 years (OR=0.34; 95% CI 0.18–0.67; p=0.001) and in patients receiving metformin (OR=0.26; 95% CI 0.14–0,5; p<0.0001), antihypertensive therapy (OR=0.43; 95% CI 0.22–0.82; p=0.009), β-blockers (OR=0.26; 95% CI 0.08–0.86; p=0.018), diuretics (OR=0.4; 95% CI 0.17–0.93; p=0.028) and renin-angiotensin system blockers (ACE inhibitors or ARBs) (OR=0.36; 95% CI 0.18–0.74; p=0.004). A tendency to an increase in lethality at higher rates of HbA1c and BMI was present, but it did not reach a statistical significance. Differences between patients receiving insulin therapy and those who were not receiving the insulin therapy were observed as follows: a significantly longer duration of type 2 DM (13.4 vs. 6.8 years, respectively; p<0.0001), worse overall glyacemic control (HbA1c: 8.1% vs. 7.0%, resp.; p<0.0001), and three times more frequent failure to achieve the HbA1c goal by more than 2.5% (14.7% vs. 5.9%, resp.; p=0.04). CONCLUSION: The identified risk factors for lethality in patients with type 2 DM indicate that good glycemic control and previous treatment with metformin and antihypertensive drugs (including RAS blockers) could reduce the frequency of deaths. In patients on insulin therapy, a higher lethality degree was associated with worse glycemic control.

THE ROLE OF RENIN-ANGIOTENSIN SYSTEM AND ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) IN THE DEVELOPMENT AND COURSE OF VIRAL INFECTION COVID-19 IN PATIENTS WITH DIABETES MELLITUS

The role of renin-angiotensin system (RAS) in general and angiotensin-converting enzyme 2 (ACE2) in particular in the pathogenesis and course of viral infection caused by SARS-CoV-2 (COVID-19) is of particular interest. This is due not only to the fact that ACE2 is a receptor for the virus the target cells. RAS hyperactivation in patients with arterial hypertension, cardiovascular disease and diabetes mellitus, is considered one of the most important factors for a more severe infection in persons with concomitant pathology. In addition, the effects of PAS blockage with angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) remains one of the most discussed topics in the literature on COVID-19. This review presents the data on the interaction between the virus and the main components of RAS and the factors influencing their expression level, the impact of ACE inhibitors and ARBs therapy on the disease outcome, and presents the perspectives of the treatment with recombinant ACE 2.

COVID-19 AND KIDNEYS

COVID-19 poses a real threat to patients with comorbid conditions such as diabetes mellitus (DM), hypertension, cardiovascular, renal or hepatic disorders. Kidney damage is very likely in people with diabetes who have undergone a new infection, and the risk of developing acute renal injury is associated with mortality. Potential mechanisms of kidney involvement in the clinical picture of the disease may include cytokine damage, cross-organ damage, and systemic effects that determine the treatment strategy. These mechanisms are closely interrelated and are important for individuals on extracorporeal therapy and kidney transplants. Autopsy data provide evidence of SARS-CoV-2 virus invasion into kidney tissue with damage to tubular epithelium cells and podocytes, and red blood cell aggregation in severely COVID-19 patients. By including individuals with chronic kidney disease in planned COVID-19 research protocols, an evidence base for effective and safe treatments can be generated.

COURSE AND TREATMENT OF DIABETES MELLITUS IN THE CONTEXT OF COVID-19

In 2020, the world is facing a historically unparalleled public health challenge associated with the invasion of the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This is also a challenge for the healthcare systems worldwide. Patients with diabetes mellitus (DM) are most vulnerable to COVID-19 because of the peculiarities of their immune response to a virus attack and due to their high susceptibility to viral activity because of hyperglycemia and other comorbid conditions and obesity that often accompany DM. The severity of the COVID-19 disease requires a mandatory review of the usual anti-hyperglycemic therapy. Maintaining optimal glycemic control and preventing the development of ketoacidosis remain extremely important;therefore, insulin becomes the priority drug for glycemic control in most cases. The search for new drugs to fight against the coronavirus infection continues with new randomised clinical drug trials being launched. Innovative anti-diabetic agents are also being tested as candidates for potentially effective anti-coronavirus agents.