Endocrinology

Diabetes

ACCORD trial: Target A1c levels for diabetes

Article Name: Effects of Intensive Glucose Lowering in Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0802743

Journal and year of publication: NEJM, 2008

Trial Design: Randomized clinical trial

Population: 10,251 patients
Key inclusion criteria:
– DMII with HbA₁c of 7.5% or more
Key exclusion criteria:
– Frequent or recent serious hypoglycemic events
– BMI > 45

Intervention Studied: Intensive therapy (HbA₁c target: below 6.0%)

Control: Standard therapy (HbA₁c target: 7.0 to 7.9%)

Outcomes:
– Occurrence of primary outcome (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes): Intensive therapy: 352 vs Standard therapy: 371 (P=0.16)
– Deaths: Intensive therapy: 257 vs Standard therapy: 203 (P=0.04)
– Hypoglycemia requiring assistance and weight gain of more than 10 kg: More frequent in the intensive-therapy group (P<0.001)

The authors concluded that “As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes.“

Citation: _{Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. PMID: 18539917; PMCID: PMC4551392.}

ADVANCE trial: Target A1c levels for diabetes

Article Name: Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/nejmoa0802987

Journal and year of publication: NEJM, 2008

Trial Design: Randomized clinical trial

Population: 11,140 patients
Key inclusion criteria:
– DMII
– 55 years or older
– History of major macrovascular or microvascular disease or at least one other risk factor for vascular disease.
Key exclusion criteria:
– Definite indication for, or contraindication to, any of the study treatments

Intervention Studied: Intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a HbA1c 6.5% or less.

Control: Standard therapy (HbA₁c target: 7.0 to 7.9%)

Outcomes:
– Mean HbA1c level: Intensive-control group: 6.5% vs Standard-control group: 7.3%
– Intensive control showed lower incidence of combined major macrovascular and microvascular events: Intensive-control group: 18.1% vs Standard-control group: 20.0%. Hazard ratio: 0.90 (95% CI:0.82 to 0.98), P=0.01
– Severe hypoglycemia, although uncommon, was more common in the intensive-control group: Intensive-control group: 2.7% vs Standard-control group: 1.5%. Hazard ratio: 1.86 (95% CI: 1.42 to 2.40), P<0.001

The authors concluded that “A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy.”

Citation: _{ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6. PMID: 18539916.}

DPP trial: Lifestyle interventions and metformin to prevent diabetes

Article Name: Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin

URL: https://www.nejm.org/doi/full/10.1056/nejmoa012512

Journal and year of publication: NEJM, 2002

Trial Design: Randomized clinical trial

Population: 3,234 patients
Key inclusion criteria:
– Age of at least 25 years with a BMI of 24 or higher (22 or higher in Asians)
– Plasma glucose concentration: Fasting: 95 to 125 mg/dL; 2 hours after a 75-g oral glucose load: 140 to 199 mg/dL
Key exclusion criteria:
– On medications known to alter glucose tolerance

Intervention Studied:
Group 1: Metformin (850 mg twice daily)
Group 2: Lifestyle-modification program (Weight loss at least a 7% or more, Physical activity of 150 minutes or more)
Group 3: Placebo

Control: See above

Outcomes:
– Incidence of diabetes (Reported in cases per 100 person-years):
Placebo group: 11.0 vs Metformin group: 7.8 vs Lifestyle group: 4.8

– Reduction of incidence of diabetes, vs placebo:
– Lifestyle intervention: Reduction by 58% (95% CI: 48 to 66%)
– Metformin: Reduction by 31% (95% CI: 17 to 43%)
– Lifestyle intervention was significantly more effective than metformin.

The authors concluded that “Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.“

Citation: _{Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403. doi: 10.1056/NEJMoa012512. PMID: 11832527; PMCID: PMC1370926.}

UKPDS 34 trial: Metformin for Type 2 diabetes

Article Name: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)

URL: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2898%2907037-8/fulltext

Journal and year of publication: The Lancet 1998

Trial Design: Randomized clinical trial

Population: 753 patients
Key inclusion criteria:
– Newly diagnosed DM II and Overweight
– FPG above 6⋅0 mmol/L
Key exclusion criteria:

Intervention Studied: Intensive blood-glucose control with metformin, aiming for FPG below 6 mmol/L (n=342)

Control: Conventional policy, primarily with diet alone (n=411)

Outcomes:
– Median HbA₁c: Conventional therapy: 8.0% vs Metformin group: 7.4%
– Risk reductions for patients on Metformin, vs Conventional therapy:
– Diabetes related endpoints: 32% (p=0.002)
– Diabetes-related death: 42% (p=0.017)
– All-cause mortality: 36% (p=0.011)

The authors concluded that “Since intensive glucose control with metformin appears to decrease the risk of diabetes related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.”

Citation: _{Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Erratum in: Lancet 1998 Nov 7;352(9139):1558. PMID: 9742977.}

NICE SUGAR trial: Target glucose level for critically ill patients

Article Name: Intensive versus Conventional Glucose Control in Critically Ill Patients

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0810625

Journal and year of publication: NEJM, 2009

Trial Design: Randomized clinical trial

Population: 6,104 patients
Key inclusion criteria:
– Patients admitted to ICU and expected to require treatment for 3 or more consecutive days
Key exclusion criteria:
– Admitted to ICU for treatment of DKA or hyperosmolar state.
– Patients to be eating before the end day 2 in ICU

Intervention Studied: Intensive blood-glucose control with metformin, aiming for FPG below 6 mmol/L (n=342)

Control: Conventional glucose control (Target: 180 mg/dL or less)

Outcomes:
– Death: Intensive glucose control: 27.5% of patients vs Conventional glucose control: 24.9% of patients (P=0.02)
– Severe hypoglycemia (Glucose ≤40 mg/dL): Intensive glucose control: 6.8% of patients vs Conventional glucose control: 0.5% (P<0.001)

The authors concluded that “In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter.”

Citation: _{NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24. PMID: 19318384.}

RABBIT 2 trial: Basal-bolus insulin for inpatient diabetes management

Article Name: Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes

URL: https://care.diabetesjournals.org/content/30/9/2181.long

Journal and year of publication: Diabetes, 2007

Trial Design: Randomized clinical trial

Population: 130 patients
Key inclusion criteria:
– Diagnosis of Diabetes for >3 months and are Insulin-naive ( controlled on diet and/or hypoglycemic agents)
– Admitted to medical general services
– Blood glucose level between 140 and 400 mg/dl
Key exclusion criteria:
– Intensive care unit patients
– Use of corticosteroid therapy

Intervention Studied: Glargine and glulisine

Control: Standard sliding scale insulin protocol (SSI)

Outcomes:
– Achieving a blood glucose target of <140 mg/dl: Glargine and glulisine: 66% of patients vs SSI: 38% of patients. Overall blood glucose difference of 27 mg/dl (P < 0.01)

The authors concluded that “Treatment with insulin glargine and glulisine resulted in significant improvement in glycemic control compared with that achieved with the use of SSI alone. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the management of non–critically ill, hospitalized patients with type 2 diabetes.”

Citation: _{Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007 Sep;30(9):2181-6. doi: 10.2337/dc07-0295. Epub 2007 May 18. PMID: 17513708.}

IDNT trial: ARB for diabetic nephropathy

Article Name: Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa011303

Journal and year of publication: NEJM, 2001

Trial Design: Randomized clinical trial

Population: 1,715 patients
Key inclusion criteria:
– Diagnosis of type 2 diabetes mellitus.
– Hypertension (a sitting BP >135/.85 mm Hg) or on antihypertensive agents
– Proteinuria (urinary protein excretion of at least 900 mg/ 24 hours)
Key exclusion criteria:

Intervention Studied:
1) Irbesartan (300 mg daily)
2) Amlodipine (10 mg daily)

Control: Placebo

Outcomes:
– Treatment with irbesartan was associated with lower risk of the primary composite endpoint (doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause):
– 20% lower than that in the placebo group (P=0.02)
– 23% lower than that in the amlodipine group (P=0.006)

The authors concluded that “The angiotensin-II–receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.”

Citation: _{Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. doi: 10.1056/NEJMoa011303. PMID: 11565517.}

LEADER trial: Liraglutide for Type 2 diabetes

Article Name: Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1603827

Journal and year of publication: NEJM, 2016

Trial Design: Randomized clinical trial

Population: 9,340 patients
Key inclusion criteria:
– DM type II with HbA₁c 7.0%
Key exclusion criteria:
– DM type I
– Use of GLP-1–receptor agonists, DPP-4 inhibitors, pramlintide, or rapid-acting insulin

Intervention Studied: Liraglutide

Control: Placebo

Outcomes:
– Occurrence of primary outcome (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): Liraglutide: 13.0% of patients vs Placebo: 14.9% of patients (P<0.001 for noninferiority, P=0.01 for superiority)

The authors concluded that “In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo.”

Citation: _{Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13. PMID: 27295427; PMCID: PMC4985288.}

PIONEER 1 trial: Semaglutide for Type 2 diabetes

Article Name: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes

URL: https://diabetesjournals.org/care/article/42/9/1724/36289/PIONEER-1-Randomized-Clinical-Trial-of-the

Journal and year of publication: ADA, 2019

Trial Design: Randomized clinical trial

Population: 703 patients with T2DM
Key inclusion criteria:
– Diagnosed with DMII and on treatment with diet/exercise for at least 30 days
– HbA_1c: 7.0–9.5%
Key exclusion criteria:
– History of pancreatitis
– Personal or family history of medullary thyroid carcinoma or MEN type 2
– Estimated GFR <60 mL/min/1.73 m2
– Proliferative retinopathy or maculopathy requiring acute treatment

Intervention Studied: Oral semaglutide (at a dose of 3 mg, 7 mg, or 14 mg)

Control: Placebo

Outcomes:
– Oral semaglutide reduced HbA_1c (placebo-adjusted treatment differences at wk 26): With 3 mg: -0.6% vs with 7 mg: – 0.9% vs with 14 mg: -1.1% (P < 0.001 for all)
– Oral semaglutide reduced body weight: With 3 mg: −0.1 kg vs with 7 mg: −0.9 kg vs with 14 mg: −2.3 kg (P < 0.001)
– Most common side effects: Mild-to-moderate transient GI events

The authors concluded that “In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA_1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.”

Citation: _{Aroda, V. R., Rosenstock, J., Terauchi, Y., Altuntas, Y., Lalic, N. M., Morales Villegas, E. C., Jeppesen, O. K., Christiansen, E., Hertz, C. L., Haluzík, M., & PIONEER 1 Investigators (2019). PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes care, 42(9), 1724–1732.}

EMPA-REG trial: Empagliflozin for Type 2 diabetes

Article Name: Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1504720

Journal and year of publication: NEJM, 2015

Trial Design: Randomized clinical trial

Population: 7020 patients
Key inclusion criteria:
– DM Type II with BMI of 45 or less and eGFR of at least 30 ml/min/1.73 m²
– Established cardiovascular disease
Key exclusion criteria:
– Bariatric surgery within the past two years and other GI surgeries that induce chronic malabsorption
– Treatment with systemic steroids
– ACS, stroke, or transient ischemic attack within 2 months prior

Intervention Studied: Empagliflozin (10 mg or 25 mg)

Control: Placebo

Outcomes:
– The primary outcome occurrence (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke): Empagliflozin: 10.5% of patients vs Placebo: 12.1% of patients (P=0.04 for superiority)

The authors concluded that “Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.”

Citation: _{Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. doi: 10.1056/NEJMoa1504720. Epub 2015 Sep 17. PMID: 26378978.}

CANVAS trial: Canagliflozin for Type 2 diabetes

Article Name: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1611925

Journal and year of publication: NEJM, 2017

Trial Design: Randomized clinical trial

Population: 10,142 patients
Key inclusion criteria:
– Diagnosis of type 2 DM with HbA₁c between ≥7.0% and ≤10.5%
– History of, or high risk of, cardiovascular disease
Key exclusion criteria:
– History of DKA, DM I, or DM secondary to pancreatitis or pancreatectomy
– On an AHA AND not on a stable regimen for at least 8 weeks

Intervention Studied: Canagliflozin

Control: Placebo

Outcomes:
– Primary outcome (Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.): Placebo: 31.5 per 1000 patient-years vs Canagliflozin: 26.9 per 1000 patient-years (P<0.001 for noninferiority, P=0.02 for superiority)

The authors concluded that “In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal.”

Citation: _{Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. doi: 10.1056/NEJMoa1611925. Epub 2017 Jun 12. PMID: 28605608.}

CREDENCE trial: Canagliflozin for diabetic nephropathy

Article Name: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1811744

Journal and year of publication: NEJM, 2019

Trial Design: Randomized clinical trial

Population: 4,401 patients
Key inclusion criteria:
– Aged 30 years or older with DM II with HbA1C of 6.5 to 12.0%
– CKD: GFR of 30 to <90 ml/min/1.73 m²BSA
– Albuminuria (urinary albumin-to-creatinine ratio: >300 to 5000)
Key exclusion criteria:
– Suspected nondiabetic kidney disease
– Patients treated with immunosuppression for kidney disease
– History of dialysis or kidney transplantation

Intervention Studied: Canagliflozin, 100 mg daily

Control: Placebo

Outcomes:
– Primary outcome (composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15): canagliflozin group: 43.2 per 1000 patient-years vs Placebo group: 61.2 per 1000 patient-years (HR: 0.70, 95% CI: 0.59 to 0.82, P=0.00001)

The authors concluded that “In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years.“

Citation: _{Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14. PMID: 30990260.}

DCCT trial/EDIC: Diabetes Control and Complications Trial

Article Name: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study at 30 Years: Overview

URL: https://diabetesjournals.org/care/article/37/1/9/31789/The-Diabetes-Control-and-Complications-Trial

Journal and year of publication: ADA, 2014

Trial Design: Cohort study post-RCT

Population: 1,441 patients with T1DM
Key inclusion criteria:
– Age 13–39 years with type 1 diabetes.
– Fasting c-peptide concentrations <0.2 nmol/L.
– Generally healthy without CV disease, HTN, or dyslipidemia
Key exclusion criteria:
– Those with neuropathy requiring treatment

Intervention Studied: Intensive therapy (INT): Levels of glycemia as close to the nondiabetic range as safely possible

Control: Conventional therapy (CON): Maintaining a safe asymptomatic glucose control

Outcomes:
INT had the following advantages:
– 35–76% reduction in the early stages of microvascular disease
– Median HbA_1c: INT: 7% vs CON: 9%.
Major adverse effects:
– Threefold increased risk of hypoglycemia with INT
– Not associated with a decline in cognitive function or quality of life.
EDIC (Epidemiology of Diabetes Interventions and Complications (EDIC) observational follow-up) showed:
– The reduction in early-stage complications during the DCCT translated into substantial reductions in severe complications and CVD.

The authors concluded that “DCCT/EDIC has demonstrated the effectiveness of INT in reducing the long-term complications of T1DM and improving the prospects for a healthy life span.”

Citation: _{Nathan, D. M., & DCCT/EDIC Research Group (2014). The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes care, 37(1), 9–16. https://doi.org/10.2337/dc13-2112}

EDIC trial: Intensive diabetic treatment for Type 1 diabetes

Article Name: Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa052187

Journal and year of publication: NEJM, 2005

Trial Design: Randomized clinical trial

Population: 1,441 patients
Key inclusion criteria:
– Type 1 DM and 13 to 40 years old

Intervention Studied: Intensive therapy (goal HbA1c as less than 6.05 percent)

Control: Conventional therapy (prevent symptoms of hyperglycemia and hypoglycemia)

Outcomes:
– Risk of cardiovascular event reduced with Intensive treatment by 42% (P=0.02)

The authors concluded that “Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.“

Citation: _{Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25):2643-53. doi: 10.1056/NEJMoa052187. PMID: 16371630; PMCID: PMC2637991.}

DIAMOND trial: Continuous glucose monitoring for Type 1 diabetes

Article Name: Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections

URL: https://jamanetwork.com/journals/jama/fullarticle/2598770

Journal and year of publication: JAMA, 2017

Trial Design: Randomized clinical trial

Population: 158 patients
Key inclusion criteria:
– Type 1 DM 25 years and older
– Multiple daily insulin injections
– HbA1c level of 7.5% to 10.0%
– Desire to lower A1C such as a goal of 7%

Intervention Studied: Continuous Glucose Monitoring (CGM)

Control: Usual care

Citation: Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, Kollman C, Kruger D, McGill JB, Polonsky W, Toschi E, Wolpert H, Price D; DIAMOND Study Group. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. JAMA. 2017 Jan 24;317(4):371-378. doi: 10.1001/jama.2016.19975. PMID: 28118453.

Citation: _{Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, Kollman C, Kruger D, McGill JB, Polonsky W, Toschi E, Wolpert H, Price D; DIAMOND Study Group. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. JAMA. 2017 Jan 24;317(4):371-378. doi: 10.1001/jama.2016.19975. PMID: 28118453.}

Other

TRUST trial: Treatment for subclinical hypothyroidism

Article Name: Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1603825

Journal and year of publication: NEJM, 2017

Trial Design: Randomized clinical trial

Population: 737 patients
Key inclusion criteria:
– Age of 65 years or more with persistent subclinical hypothyroidism
– Thyrotropin level 4.60 to 19.99 mIU/L
Key exclusion criteria:
– Current levothyroxine, antithyroid drugs, amiodarone, or lithium
– Thyroid surgery or radioactive iodine within 12 months
– Dementia

Intervention Studied: Levothyroxine adjusted according to the thyrotropin level

Control: Placebo with mock dose adjustments

Outcomes:
– Mean (±SD) thyrotropin levels: Placebo: 5.48 mIU/L vs Levothyroxine: 3.63 mIU/L (P<0.001)
– Hypothyroid Symptoms score (at 1 year): No difference between groups
– Tiredness score (at 1 year): No difference between groups

The authors concluded that “Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism.”

Citation: _{Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, Kean S, Kelly M, Krebs D, Langhorne P, McCarthy G, McCarthy V, McConnachie A, McDade M, Messow M, O’Flynn A, O’Riordan D, Poortvliet RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland HA, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J; TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3. PMID: 28402245.}

SOS trial: Bariatric surgery for obesity

Article Name: Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa066254

Journal and year of publication: NEJM, 2007

Trial Design: Randomized clinical trial

Population: 4,047 patients
Key inclusion criteria:
– Age at application 37-57 years
– BMI ≥ 34 kg/m2 for men, ≥ 38 kg/m2 for women
Key exclusion criteria:

Intervention Studied: Bariatric surgery (surgery group)

Control: Conventional treatment (matched control group)

Outcomes:
– Weight change:
– Average weight change in control subjects was less than ±2% (up to 15 years)
– Maximum weight losses in the surgical subgroups: (1-2 years):
– Gastric bypass(1-2 years): 32% At 10 years: 25%
– Vertical-banded gastroplasty (1-2 years): 25% At 10 years: 16%
– Banding: 20% At 10 years: 14%
– Deaths: Surgery group:101 deaths vs Control group: 129 deaths (P=0.01)

The authors concluded that “Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.”

Citation: _{Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, Lindroos AK, Lönroth H, Näslund I, Olbers T, Stenlöf K, Torgerson J, Agren G, Carlsson LM; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007 Aug 23;357(8):741-52. doi: 10.1056/NEJMoa066254. PMID: 17715408.}

Vitamin D and Calcium for prevention of bone fractures

Article Name: Vitamin D3 and Calcium to Prevent Hip Fractures in Elderly Women

URL: https://www.nejm.org/doi/full/10.1056/NEJM199212033272305

Journal and year of publication: NEJM, 1992

Trial Design: Randomized clinical trial

Population: 3270 patients
Key inclusion criteria:
– 69 to 106 years of age (mean [±SD], 84±6)
– Ambulatory
– No serious medical conditions
Key exclusion criteria:
– Used drugs known to alter bone metabolism in the past year
– Like corticosteroids, thyroxine, or anticonvulsant drugs

Intervention Studied: 1.2 g of elemental calcium and 800 IU of vitamin D₃

Control: Placebo

Outcomes:
– Fractures (after 18 months of supplementation):
– Hip fractures: 43% lower with calcium and vit D supplementation, vs placebo (P = 0.043)
– Nonvertebral fractures: 32% lower with calcium and vit D supplementation, vs placebo (P = 0.015)
– Proximal femur bone density: Vitamin D₃—calcium group: increased 2.7% vs Placebo: Decreased 4.6% (P<0.001)

The authors concluded that “Supplementation with vitamin D₃ and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women.”

Citation: _{Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 1992 Dec 3;327(23):1637-42. doi: 10.1056/NEJM199212033272305. PMID: 1331788.}

Bisphosphonates for osteoporosis

Article Name: Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

URL: https://www.nejm.org/doi/full/10.1056/NEJM199511303332201

Journal and year of publication: NEJM, 1995

Trial Design: Randomized clinical trial

Population: 994 patients
Key inclusion criteria:
– Women, postmenapausal or 45 to 80 years with osteoporosis
Key exclusion criteria:
– Other causes of osteoporosis, Like glucocorticoids use, or other disorders of bone and mineral metabolism, vitamin D deficiency, Paget’s disease, or hyperparathyroidism
– History of hip fracture

Intervention Studied: Alendronate

Control: Placebo

Outcomes:
– Mean (±SE) differences in bone mineral density between those using alendronate and placebo (at 3 years) : Spine: 8.8±0.4% ; Femoral neck: 5.9±0.5%
(P<0.001 for all comparisons)
– With alendronate, there was a association with 48% reduction in proportion of women with new vertebral fractures; Alendronate: 3.2% vs Placebo: 6.2% (P = 0.03)

The authors concluded that “Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.”

Citation: _{Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. doi: 10.1056/NEJM199511303332201. PMID: 7477143.}

FLEX trial: Duration of bisphosphonates for osteoporosis

Article Name: Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

URL: https://jamanetwork.com/journals/jama/fullarticle/204789

Journal and year of publication: JAMA, 2006

Trial Design: Randomized clinical trial

Population: 1,099 patients
Key inclusion criteria:
– Women assigned to receive alendronate during FIT study who completed at least 3 years of treatment during the trial
Key exclusion criteria:

Intervention Studied: Alendronate 5 mg or 10 mg

Control: Placebo

Outcomes:
– When compared to alendronate, switching to placebo for 5 years resulted in:
Declines in BMD of the hip: −2.4% (95%CI: −2.9% to −1.8%) (P<.001) ; and the spine : −3.7% (95%CI: −4.5% to −3.0%) (P<.001)
– Mean levels for both groups remained at or above pretreatment levels 10 years earlier.
– Cumulative risk of fractures: No significant difference in nonvertebral fractures, but clinically recognized vertebral fractures were significantly lower risk for alendronate continuing group.

The authors concluded that “Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years.”

Citation: _{Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006 Dec 27;296(24):2927-38. doi: 10.1001/jama.296.24.2927. PMID: 17190893.}

FREEDOM trial: Denosumab for osteoporosis

Article Name: Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0809493

Journal and year of publication: NEJM, 2009

Trial Design: Randomized clinical trial

Population: 7,868 patients
Key inclusion criteria:
– Women aged 60 to 90 years
– Bone mineral density T score < −2.5 at lumbar spine or total hip
Key exclusion criteria:
– Conditions that influence bone metabolism

Intervention Studied: Denosumab

Control: Placebo

Outcomes:
– Incidence of new radiographic vertebral fracture: Denosumab: 2.3% vs Placebo: 7.2% (P<0.001)
– Incidence of hip fracture: Denosumab: 0.7% vs Placebo: 1.2% (P=0.04)
– Incidence of nonvertebral fracture: Denosumab: 6.5% vs Placebo: 8.0% (P=0.01)

The authors concluded that “Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis.”

Citation: _{Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756-65. doi: 10.1056/NEJMoa0809493. Epub 2009 Aug 11. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914. PMID: 19671655.}

WHI trial: HRT for postmenopausal women

Article Name: Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. Principal Results From the Women’s Health Initiative Randomized Controlled Trial

URL: https://jamanetwork.com/journals/jama/fullarticle/195120

Journal and year of publication: JAMA, 2002

Trial Design: Randomized clinical trial

Population: 16,608 patients
Key inclusion criteria:
– Age 50 to 79 years at initial screening, postmenopausal
Key exclusion criteria:
– Prior breast cancer
– Acute MI, stroke, or transient ischemic attack in the previous 6 months
– Known chronic active hepatitis or severe cirrhosis

Intervention Studied: Conjugated equine estrogens (0.625 mg/d) + medroxyprogesterone acetate (2.5 mg/d)

Control: Placebo

Outcomes:
– Estimated hazard ratios, for combined estrogen plus progestin vs placebo:
Coronary heart disease: 1.29 (95% CI: 1.02-1.63)
Breast cancer: 1.26 (95% CI: 1.00-1.59)
Stroke: 1.41 (95% CI: 1.07-1.85)
PE: 2.13 (95% CI: 1.39-3.25)
Colorectal cancer: 0.63 (95% CI: 0.43-0.92)
Endometrial cancer: 0.83 (95% CI: 0.47-1.47)
Hip fracture: 0.66 (95% CI: 0.45-0.98)
Death due to other causes: 0.92 (95% CI: 0.74-1.14)

The authors concluded that “Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women. All-cause mortality was not affected during the trial. The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.“

Citation: _{Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. doi: 10.1001/jama.288.3.321. PMID: 12117397.}

Do you think there are some important trials we should add to our site? Please contact us at landmarktrials@gmail.com with the trial name, link, and why you think it is a landmark paper!

Disclaimer: Please note that articles mentioned on this site are the property of their respective journals. The information from these articles was presented on this site under the Fair Use legal doctrine (Section 107 of the Copyright Act) as the data shared was limited in quantity, factual in nature, already published, and for the purpose of relaying and teaching socially beneficial medical knowledge. The work was attributed to the journals that published them with citations and links provided.

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