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Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes The GRADE Randomized Clinical Trial

Author/s: 
Wexler, D. J., de Boer, I. H., Ghosh, A., Younes, N., Bebu, I., Inzucchi, S. E., McGill, J. B., Mudaliar, S., Schade, D., Steffes, M., Tamborlane, W. V., Tan, M. H., Ismail-Beigi, F., GRADE Research Group

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.

Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.

Design, setting, and participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.

Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.

Main outcomes and measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.

Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.

Conclusions and relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.

Keywords 
Intention to Treat Analysis Albumins Creatinine diabetes, type 2 kidney function

The relationship between exacerbated diabetic peripheral neuropathy and metformin treatment in type 2 diabetes mellitus

Author/s: 
Hashem, Manal Mohammed, Esmael, Ahmed, Nassar, Abdelfattah Kasem, El-Sherif, Mohammed

Metformin-treated diabetics (MTD) showed a decrease in cobalamin, a rise in homocysteine, and methylmalonic acid, leading to accentuated diabetic peripheral neuropathy (DPN). This study aimed to determine whether or not metformin is a risk factor for DPN. We compared MTD to non-metformin-treated diabetics (NMTD) clinically using the Toronto Clinical Scoring System (TCSS), laboratory (methylmalonic acid, cobalamin, and homocysteine), and electrophysiological studies. Median homocysteine and methylmalonic acid levels in MTD vs. NMTD were 15.3 vs. 9.6 µmol/l; P < 0.001 and 0.25 vs. 0.13 µmol/l; P = 0.02, respectively with high statistical significance in MTD. There was a significantly lower plasma level of cobalamin in MTD than NMTD. Spearman's correlation showed a significant negative correlation between cobalamin and increased dose of metformin and a significant positive correlation between TCSS and increased dose of metformin. Logistic regression analysis showed that MTD had significantly longer metformin use duration, higher metformin dose > 2 g, higher TCSS, lower plasma cobalamin, and significant higher homocysteine. Diabetics treated with metformin for prolonged duration and higher doses were associated with lower cobalamin and more severe DPN.

Keywords 
diabetes, type 2 metformin insulin Metformin Treatment

Obesity in adults: a clinical practice guideline

Author/s: 
Wharton, Sean, Lau, David C., Vallis, Mchael, Sharma, Arya M., Biertho, Laurent, Campbell-Scherer, Denise, Adamo, Kristi, Alberga, Anela, Bell, Rhonda, Boule, Normand, Boyling, Elaine, Calam, Betty, Brown, Jennifer, Clarke, Carol, Crowshoe, Lindsay", Mary, Freedhoff, Yoni, Gagner, Michel, Grand, Cindy, Glazer, Stephen", Michael, Hahn, Margaret, Hawa, Raed, Henderson, Rita, Hong, Dennis, Hung, Pam, Janssen, Ian, Jacklin, Kristen, Johnson-Stoklossa, Carlene, Kemp, Amy, Kirk, Sra, :Kuk, Jennifer, Langlois, Marie-France, Lear, Scott, McInnes, Ashley, Macklin, David, Naji, Leen, Manjoo, Priya, Morin, Marie-Philippe, Nerenberg, Kara, Patton, Ian, Pedersen, Sue, Pereira, Leticia, Piccinini-Vallis, Helena, Poddar, Megha, Poirier, Paul, Prud'homme, Denis, Romos Salas, Ximena, Rueda-Clausen, Christian, Russell-Mayhew, Shelly, Shiau, Judy, Sherifali, Diana, Sievenpiper, John, Sockalingam, Sanjeev, Taylor, Valerie, Toth, Ellen, Twells, Laurie, Tytus, RIchard, Walji, Shahebina, Walker, Leah

  • Obesity is a prevalent, complex, progressive and relapsing chronic disease, characterized by abnormal or excessive body fat (adiposity), that impairs health.

  • People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of weight or body mass index.

  • This guideline update reflects substantial advances in the epidemiology, determinants, pathophysiology, assessment, prevention and treatment of obesity, and shifts the focus of obesity management toward improving patient-centred health outcomes, rather than weight loss alone.

  • Obesity care should be based on evidence-based principles of chronic disease management, must validate patients’ lived experiences, move beyond simplistic approaches of “eat less, move more,” and address the root drivers of obesity.

  • People living with obesity should have access to evidence-informed interventions, including medical nutrition therapy, physical activity, psychological interventions, pharmacotherapy and surgery.

Keywords 
obesity Stigmas diabetes, type 2 diabetes Gallbladder disease non-alcoholic fatty liver disease Gout

Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity

Author/s: 
Aminian, A, Zajicheck, A, Arterburn, DE, Wolski, KE, Brethauer, SA, Schauer, PR, Kattan, MW, Nissen, SE

IMPORTANCE:

Although metabolic surgery (defined as procedures that influence metabolism by inducing weight loss and altering gastrointestinal physiology) significantly improves cardiometabolic risk factors, the effect on cardiovascular outcomes has been less well characterized.

OBJECTIVE:

To investigate the relationship between metabolic surgery and incident major adverse cardiovascular events (MACE) in patients with type 2 diabetes and obesity.

DESIGN, SETTING, AND PARTICIPANTS:

Of 287 438 adult patients with diabetes in the Cleveland Clinic Health System in the United States between 1998 and 2017, 2287 patients underwent metabolic surgery. In this retrospective cohort study, these patients were matched 1:5 to nonsurgical patients with diabetes and obesity (body mass index [BMI] ≥30), resulting in 11 435 control patients, with follow-up through December 2018.

EXPOSURES:

Metabolic gastrointestinal surgical procedures vs usual care for type 2 diabetes and obesity.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the incidence of extended MACE (composite of 6 outcomes), defined as first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure, nephropathy, and atrial fibrillation. Secondary end points included 3-component MACE (myocardial infarction, ischemic stroke, and mortality) and the 6 individual components of the primary end point.

RESULTS:

Among the 13 722 study participants, the distribution of baseline covariates was balanced between the surgical group and the nonsurgical group, including female sex (65.5% vs 64.2%), median age (52.5 vs 54.8 years), BMI (45.1 vs 42.6), and glycated hemoglobin level (7.1% vs 7.1%). The overall median follow-up duration was 3.9 years (interquartile range, 1.9-6.1 years). At the end of the study period, 385 patients in the surgical group and 3243 patients in the nonsurgical group experienced a primary end point (cumulative incidence at 8-years, 30.8% [95% CI, 27.6%-34.0%] in the surgical group and 47.7% [95% CI, 46.1%-49.2%] in the nonsurgical group [P < .001]; absolute 8-year risk difference [ARD], 16.9% [95% CI, 13.1%-20.4%]; adjusted hazard ratio [HR], 0.61 [95% CI, 0.55-0.69]). All 7 prespecified secondary outcomes showed statistically significant differences in favor of metabolic surgery, including mortality. All-cause mortality occurred in 112 patients in the metabolic surgery group and 1111 patients in the nonsurgical group (cumulative incidence at 8 years, 10.0% [95% CI, 7.8%-12.2%] and 17.8% [95% CI, 16.6%-19.0%]; ARD, 7.8% [95% CI, 5.1%-10.2%]; adjusted HR, 0.59 [95% CI, 0.48-0.72]).

CONCLUSIONS AND RELEVANCE:

Among patients with type 2 diabetes and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MACE. The findings from this observational study must be confirmed in randomized clinical trials.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT03955952.

Keywords 
diabetes, type 2 weight loss obesity bariatric surgery metabolic surgery

Standards of Medical Care in Diabetes—2019 Abridged for Primary Care Providers

Author/s: 
American Diabetes Association

The American Diabetes Association’s (ADA’s) Standards of Medical Care in Diabetes is updated and published annually in a supplement to the January issue of Diabetes Care. The ADA’s Professional Practice Committee, which includes physicians, diabetes educators, registered dietitians (RDs), and public health experts, develops the Standards. The Standards include the most current evidence-based recommendations for diagnosing and treating adults and children with all forms of diabetes. ADA’s grading system uses A, B, C, or E to show the evidence level that supports each recommendation.

  • A—Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered

  • B—Supportive evidence from well-conducted cohort studies

  • C—Supportive evidence from poorly controlled or uncontrolled studies

  • E—Expert consensus or clinical experience

This is an abridged version of the 2019 Standards containing the evidence-based recommendations most pertinent to primary care. The tables and figures have been renumbered from the original document to match this version. The complete 2019 Standards of Care document, including all supporting references, is available at professional.diabetes.org/standards.

Keywords 
standard of care guidelines diabetes diabetes, type 2 A1C

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

Author/s: 
Emanuele, N.V., Reaven, P.D., Wiitala, W.L., Bahn, G.D., Reda D.J., McCarren, M., Duckworth, W.C., Hayward, R.A., VADT Investigators

BACKGROUND

We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.

METHODS

We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.

RESULTS

There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).

CONCLUSIONS

Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)

Keywords 
diabetes glucose gangrene veterans military personnel heart failure stroke amputation diabetes, type 2
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