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What's new in endocrinology and diabetes mellitus

What's new in endocrinology and diabetes mellitus
Authors:
Kathryn A Martin, MD
Jean E Mulder, MD
Literature review current through: Feb 2022. | This topic last updated: Feb 22, 2022.

The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ADRENAL DISORDERS

Long-term survival in patients with pediatric adrenocortical carcinoma (November 2021)

For pediatric patients with adrenocortical carcinoma (ACC), there are limited data for the long-term prognosis of this rare disease. A prospective, single-arm study of approximately 80 pediatric patients with ACC described the outcomes of stage I patients treated with adrenalectomy; stage II patients treated with adrenalectomy and retroperitoneal lymph node dissection; and stage III or IV patients treated with mitotane and chemotherapy, followed by surgery as clinically indicated [1]. Five-year overall survival rates, according to stage, were 95 percent for stage I; 79 percent for stage II; 95 percent for stage III; and 16 percent for stage IV disease. Although patients with stage III disease had better outcomes relative to those with stage II disease, potentially due to receipt of mitotane and chemotherapy, we consider multiple factors (eg, grade, extent of vascular invasion) in decisions regarding systemic therapy. (See "Treatment of adrenocortical carcinoma", section on 'Management'.)

DIABETES MELLITUS

Investigational dual GIP and GLP-1 receptor agonist for type 2 diabetes (January 2022)

Tirzepatide is an investigational dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist for type 2 diabetes. In a 52-week trial comparing once-weekly subcutaneous tirzepatide with daily subcutaneous insulin glargine in almost 2000 people with type 2 diabetes (mean A1C 8.52 percent), BMI ≥25 kg/m2, and high cardiovascular risk, there was a greater reduction in A1C and weight with tirzepatide (mean difference in A1C and bodyweight for 10 mg dose of tirzepatide -0.99 percentage points and -11.4 kg, respectively) [2]. The composite cardiovascular endpoint (measured as part of a safety assessment) occurred in a similar proportion of patients in the two treatment groups (5 to 6 percent). Trials specifically designed to evaluate cardiovascular outcomes with tirzepatide are ongoing. (See "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Dual-acting GLP-1 and GIP receptor agonist'.)

Diabetes drugs and cardiovascular outcomes in at-risk adults (November 2021)

In a meta-analysis of trials comparing a GLP-1 receptor agonist (eg, liraglutide, semaglutide), SGLT2 inhibitor (eg, dapagliflozin, empagliflozin), or DPP-4 inhibitor (eg, linagliptin, sitagliptin) with placebo in people with type 2 diabetes and established cardiovascular disease (CVD), GLP-1 receptor agonists and SGLT2 inhibitors reduced the risk of all-cause and cardiovascular mortality [3]. GLP-1 receptor agonists also reduced the risk of fatal or non-fatal stroke, whereas SGLT2 inhibitors reduced the risk of heart failure hospitalizations. DPP-4 inhibitors did not reduce or increase any CVD outcomes. For patients with type 2 diabetes who are not achieving glycemic goals with metformin and in whom atherosclerotic CVD predominates, we typically add a GLP-1 receptor agonist to metformin. For similar patients in whom heart failure predominates, we typically add an SGLT2 inhibitor. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects' and "Glucagon-like peptide 1 receptor agonists for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

OBESITY

Semaglutide for obesity treatment in adults (January 2022)

The glucagon-like peptide-1 (GLP-1) receptor agonists liraglutide and semaglutide are approved for the treatment of obesity. In the STEP 8 trial, participants were assigned to receive once-weekly subcutaneous semaglutide or once-daily subcutaneous liraglutide for 68 weeks; all participants received counseling on lifestyle modification [4]. Those in the semaglutide group lost a greater percentage of body weight than those receiving liraglutide (-15.8 versus -6.4 percent). For patients who are overweight or with obesity and in whom pharmacologic therapy is warranted, we suggest using a GLP-1 receptor agonist; we prefer treatment with semaglutide since administration is once weekly and it has greater efficacy than liraglutide. (See "Obesity in adults: Drug therapy", section on 'Efficacy'.)

OSTEOPOROSIS

Zoledronic acid after denosumab therapy for osteoporosis (November 2021)

Zoledronic acid (ZA) is often administered to prevent rapid bone loss and reduce risk of vertebral fractures associated with delay in dosing or discontinuation of denosumab therapy for osteoporosis. The efficacy of ZA varies among studies, in part due to the variable duration of prior denosumab therapy. In a multicenter prospective study of 47 postmenopausal patients who received a single ZA infusion six months after the last denosumab injection, lumbar spine bone density at 12 months decreased significantly in the group that received >3 years of denosumab treatment but was maintained in those who had received ≤3 years of denosumab [5]. Patients who have received >3 years of denosumab may require a second infusion of ZA to prevent bone loss after denosumab discontinuation. (See "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)

Dietary calcium and fracture prevention in institutionalized older adults (October 2021)

Evidence supporting a benefit of calcium and/or vitamin D supplementation in older adults is conflicting. Fracture benefit of nutrient supplementation appears to be greater among institutionalized or hospitalized than community-dwelling individuals. In a cluster randomized trial evaluating the initiation of dairy products (eg, milk, yogurt, or cheese to provide an additional 562 mg/day of calcium and 12 g/day of protein) in over 7000 institutionalized, vitamin D-supplemented, older adults (mean age 86 years) who were consuming approximately 700 mg of calcium/day, the incidence of total fractures, hip fractures, and falls was lower in the dairy product than control group (mean follow-up 12.6 months) [6]. This supports our recommendation to increase intake of dairy products or calcium-rich foods if dietary calcium intake is below recommended levels (1200 mg/day for older adults). If not possible, optimal intake can be achieved with a combination of diet plus supplements. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Calcium and vitamin D'.)

THYROID DISORDERS

Combination T4 and T3 therapy versus T4 alone for primary hypothyroidism (February 2022)

Some hypothyroid patients remain symptomatic after T4 replacement normalizes thyroid stimulating hormone. In a crossover trial evaluating T4 alone, combined T4 and T3, or desiccated thyroid extract in 75 hypothyroid patients previously treated with a stable dose of T4, there was no difference among the three groups in patient preference or scores on the thyroid symptom or general health questionnaires [7]. However, the 20 patients with the most symptoms at baseline had a strong preference for combination therapy or thyroid extract over T4 alone and had significant improvement in the scores. Analysis of this subgroup did not reveal any significant differences in etiology of hypothyroidism, serum thyroid tests while taking T4, or presence of polymorphisms in the deiodinase 2 gene. Although we do not suggest the routine use of combined T4 and T3, selected patients may benefit from a trial of the combination, using doses of T4 and T3 that mimic normal physiology. (See "Treatment of primary hypothyroidism in adults", section on 'Is there a role for T3?'.)

Defining subclinical hypothyroidism in older adults (October 2021)

There is disagreement about the appropriate upper limit of normal for serum thyroid stimulating hormone (TSH) in older adults. Although there is an age-related shift toward higher TSH concentrations in older adults, age-based normal ranges for TSH are not widely implemented. In one study of over 2000 adults >70 years of age, the likelihood of a diagnosis of subclinical hypothyroidism (defined as an elevated TSH with a normal free T4) decreased from 29 to 3 percent if age-specific rather than uniform normal reference ranges were used [8]. We suggest not treating older adults for subclinical hypothyroidism for a TSH above the upper limit of normal up to and including 6.9 mU/L, since TSH values in the range are age appropriate. (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Epidemiology'.)

REFERENCES

  1. Rodriguez-Galindo C, Krailo MD, Pinto EM, et al. Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol. J Clin Oncol 2021; 39:2463.
  2. Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021; 398:1811.
  3. Kanie T, Mizuno A, Takaoka Y, et al. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev 2021; 10:CD013650.
  4. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022; 327:138.
  5. Makras P, Appelman-Dijkstra NM, Papapoulos SE, et al. The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation. J Clin Endocrinol Metab 2021; 106:e4155.
  6. Iuliano S, Poon S, Robbins J, et al. Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial. BMJ 2021; 375:n2364.
  7. Shakir MKM, Brooks DI, McAninch EA, et al. Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism. J Clin Endocrinol Metab 2021; 106:e4400.
  8. Zhang Y, Sun Y, He Z, et al. Age-specific thyrotropin references decrease over-diagnosis of hypothyroidism in elderly patients in iodine-excessive areas. Clin Endocrinol (Oxf) 2021.
Topic 8354 Version 10977.0

References

1 : Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal Lymph Node Dissection, and Chemotherapy: The Children's Oncology Group ARAR0332 Protocol.

2 : Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

3 : Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis.

4 : Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.

5 : The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation.

6 : Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial.

7 : Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism.

8 : Age-specific thyrotropin references decrease over-diagnosis of hypothyroidism in elderly patients in iodine-excessive areas.