Updated Guidelines on Management of Primary Hyperparathyroidism

Khan A, presented about primary hyperparathyroidism in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12th May 2022. The primary objective was to discuss how to diagnose and treat primary hyperparathyroidism (PHPT)and manage its complications. The diagnosis of hyperparathyroidism is usually first suspected because of:

  • An elevated serum calcium concentration
  • Calcium to creatinine clearance ratio >0.02
  • UCaX PCr / Ucr X Pca
  • FHH- inactivating mutation of casr
  • Mildly high Ca and PTH, hypocalciuria CCCR<0.01 ( sensitivity 85%, specificity 88% for FHH)

Symptomatic PHPT is correlated with skeletal and renal complications that may incorportae osteitis fibrosa cystica and/or fractures, chronic kidney disease, nephrolithiasis and/or nephrocalcinosis. Asymptomatic PHPT exhibits no overt symptoms; typically discovered by biochemical screening. Two forms of asymptomatic PHPT are described following analysis are with target organ involvement and without target organ involvement. In normocalcemic PHPT, skeletal or renal complications may or may not exist in those whose presentation fits this definition. PHPT can be evaluated with

  • Biochemical: Measure adjusted total serum calcium (ionized if normocalcemic PHPT is a consideration), phosphorus, intact PTH, 25OHD, creatinine
  • Skeletal: Three-site DXA (lumbar spine, hip, distal 1/3 radius); imaging for vertebral fractures [vertebral fracture assessment (VFA) or vertebral X-rays]; Trabecular Bone Score if available
  • Renal: eGFR or, preferably, creatinine clearance, 24-hour urinary calcium and for biochemical risk factors for stones; imaging for nephrolithiasis/nephrocalcinosis. Retrospective X-sectional study in 109 PHPT patients evaluated pre and post PTX showed that PTX prevents decline in renal function
  • Non-classical manifestations (neurocognitive, quality of life, cardiovascular): There are no data to support routine evaluation for these manifestations
  • Genetic: genetic evaluation should be considered for patients < 30 years old, those with multi-gland disease by history or imaging, and/or those with a family history of hypercalcemia and/or a syndromic disease

Theupgraded recommendations for surgical management of PHPTare: Surgery is recommended if one or more of the following is present:

  • Serum calcium > 1 mg/dL (0.25 mmol/L) above the upper limit of normal
  • Skeletal involvement: A fracture by VFA or vertebral X-ray or BMD by T-score ≤ -2.5 at any site or
  • Renal involvement: eGFR or creatinine clearance 250 mg/day in women; > 300 mg/day in men) or Nephrocalcinosis or nephrolithiasis by X-ray, ultrasound, or other imaging modality • Hypercalciuria (e.g. > 250 mg/day in women; > 300 mg/day in men)
  • Age < 50 years (no other indications are necessary; age < 50 years is a sufficient indication)
  • If no aforementioned guidelines are met, PTX is still an option with concurrence of the patient and physician and if there are no contraindications

The Ungraded Panel Recommendations  for role of non-surgical/medical management of PHPT (limited by quality of available evidence from RCT’s) are:

  • Alendronate and denosumab can be used to increase bone density if there are no contraindications
  • Cinacalcet can be used to reduce the serum calcium concentration into the normal range if there are no contraindications
  • Calcium intake/supplementation should follow the Institute of Medicine nutritional guidelines: 800 mg/day for women < 50 and men < 70 years old; 1000 mg/day for women > 50 and men > 70 years old
  • Vitamin D supplementation: the panel recommends levels of 25OHD > 30 ng/mL and < the upper limit of normal for the laboratory reference range (e.g., < 50 ng/mL)
  • Estrogen has been shown to increase BMD. Its effect on the reduction of serum calcium is inconsistent
  • Raloxifene cannot be recommended because the data are insufficient to reach any conclusions

Updated recommendations of management of PHPT during pregnancy are:

  • Mild cases should be managed by maintaining good hydration and monitoring calcium levels
  • Bisphosphonates and denosumab should not be used
  • Data are very limited on use of cinacalcet
  • Consider surgery in the 2nd trimester for patients with serum calcium > 11.0 mg/dl and for whom surgery is not contraindicated
  • Preoperative imaging should be limited to ultrasound
  • If surgery is deferred, the neonate should be closely monitored for hypocalcemia
  • If surgery is deferred, PTX should be done after delivery, and before a subsequent pregnancy

PTX is an appealing choice for asymptomatic PHPT. Those not meeting the revised guidelines or unable or unwilling to begin with surgery can be safely followed. N-BP and Dmab may yield skeletal protection. Cinacalcet decreases PTH and calcium frequently into normal range. Analysing with annual serum calcium, creatinine clearance and BMD 1-2 yrs advised.


Self-Care for the Medical Provider During a Global Pandemic

Swiner CN, talked about self care among medical provider at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12th May 2022. The learning objectives of the session were to evaluate how the COVID-19 pandemic has impacted our ability to achieve work-life balance, discuss how the superwo(man) complex and imposter syndrome affects us and summarize strategies to aid enhance work-life balance/integration. Researchers based their results on more than 20,000 respondents at 124 institutions across the country. Burnout, workload, fear of infection, anxiety or depression due to COVID-19 and the number of years in practice were correlated with intent to decrease work hours or leave. 1 in 5 doctors plan exit in 2 years, via AMA in Jan. 2022 due to stress, grief, getting sick, undervalued/underpaid, decreased support, overworked. If 1/3 of nurses and doctors leave, hospitals won’t have enough staff to care for patients. Burnout is the disorder of disengagement, disconnecting from work, friends, family & health. Burnout develops when someone is dealing with a high level of stress however doesn’t have access to adequate resources, such as social support, helpful advice, feedback from friends or colleagues, or control over how they spend their time. The impact syndrome is an internal experience of intellectual phoniness that appears to be especially prevalent and intense among a select sample of high achieving women. What can a person do is practicing positive self-talk, learn how to accept & believe compliments, make a strength list, remind yourself how great you are, realize that perfection is not realistic and ask for help. Self-preservation is very important aspect, set boundaries for your life, you are worthy & deserving and stop giving yourself away for free.

The strategies should be established to aid work/life balance and can include few things like  the roles of the support staff should be known, call patients only if essential, don’t let others take benefit of your kindness, have a procedure to keep up with findings, schedule f/u appointments instead of promising phone calls, and be an effective  communicator, go somewhere on vacay with precautions of covid norms, take mental health days, fire horrible patients, invest or start a business/write a book, hire support, pack a fun bag in your trunk, have allies and mentors. The ultimate strategy is to get a therapist.

Current and Future Treatments for Nonalcoholic Fatty Liver Disease (NAFLD)

Cusi K, talked about NAFLD in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12th May 2022. Nonalcoholic steatohepatitis (NASH) treatment is recommended in intermediate and high risk patients. Also, diabetic drugs Pioglitazone and GLP-RA were recommended in these patients of criteria. Current treatments for patients with NAFLD (not FDA approved but that can be used for patients with obesity or diabetes) were lifestyle interventions and bariatric surgery, GLP-1RA and Pioglitazone. Pioglitazone increases adiponectin (Adipose Tissue function) and reduces visceral and hepatic fat in subjects with NASH. Piogliatazone significantly decreases NASH in all patients included in RCTs (2016) and significantly lowers the risk of liver fibrosis in NASH.

 Future options to enhance the efficacy of pioglitazone and reduce weight gain are low-dose pioglitazone (15 mg/day; UF NIH study) and combination therapy: a) SGLT2i: (e.g., EMPA-REG Extend) b) GLP-1RA: (e.g., SUSTAIN-2: PIO + semagutide). Low dose pioglitazone is associated with minimal weight gain in patients with T2DM.

The dual obesity and diabetes epidemics will worsen in the coming decade and will further fuel the epidemic of NASH and liver cirrhosis. NASH cirrhosis may be prevented by early diagnosis in PCP and endocrinology clinics, but still significant clinical inertia exists. Current treatments remain underutilized to treat obesity and T2DM. They reverse the fundamental defects associated with obesity (excess fat mass; GLP-1RAs) and with T2DM (dysfunctional adipose tissue, insulin resistance; PIO) that cause NAFLD. Many treatments are in development and  potentially will be available within the next 2 years.


The Risks and Benefits of Other Therapies

Stanton RC, talked about ACE inhibitors and ARB in diabetic kidney disease in a session at American Association of Clinical Endocrinology (AACE) Annual Meeting 2022 on 12th May 2022. The aims of the session were to discuss the new ideas on the dosing of ACEi and ARBs for managing Diabetic Kidney Disease, evaluate the risks and benefits of newer hypoglycemic drugs for treatment of diabetic kidney disease (DKD), evaluate proposed mechanisms underlying renoprotection given by newer hypoglycemic drugs for DKD. Renin-Angiotensin-Aldosterone System Inhibitors are pillar of treatment for DKD. Decreasing urine albumin level is a goal for slowing progression of kidney disease and reducing CV Risk. Liraglutide lowers urine albumin level but no change in eGFR. Dulaglutide is reported to be reno-protective in AWARD-7 study but only in macro-albuminuria (UACR >300 mg/g). Based on AMPLITUDE-O Trial, Efpeglenatide is recently reported to improve kidney outcomes. GLP1 Agonists have CV benefits, lead to lowering of the urine albumin level, and appear to slow rate of decline in eGFR. FLOW Study with Semaglutide (Estimated enrollment of 3508; to be completed in 2024) will certainly aid in determining reno-protective effects of GLP-1 RA. DPP-4 Inhibitors had no clear unique renal benefit; although there may be subgroups that benefit such as people with high urine protein levels. As per CREDENCE trial, Canagliflozin slowed decline in eGFR and improved albuminuria. Dapagliflozin showed CV and renal benefits in CKD in diabetic and non-diabetic patients. The CREDENCE and DAPA-CKD Results (EMPA Kidney was recently stopped early due to positive results) combined with the positive cardiovascular results are understandably extremely exciting for new treatments for people with DM, Heart Disease, and CKD. The risks involved with SGLT2i were euglycemic ketoacidosis, genital mycotic infections, UTI, extracellular fluid volume depletion. SGLT2 Inhibitors provide highly significant benefits for people with CV disease. All recent guidelines are recommending their use as first line agents with Metformin if Diabetic Kidney Disease is present. Combination of SGLT2 Inhibitor with RAAS Inhibition may be more reno-protective as compared to either alone.

There is a world-wide epidemic of DKD. Early detection and aggressive interferences can slow the evolution and development of DKD. Currently, a very exciting era of discovery is proceeding that will continue to lead to new mechanistic insights and new treatments to manage this very serious complication of diabetes mellitus.


 Achievement of HbA1c <6.5% with ≥5% Weight Loss and without Hypoglycemia in Patients with Type 2 Diabetes Treatment with Tirzepatide: A Post Hoc Analysis of the SURPASS 1-5 Studies

Thieu V, presented a study on Tirzepatide in a session at American Association of Clinical Endocrinology on 12th May, 2022.  Tirzepatide is a once weekly GIP/GLP-1 receptor agonist for the treatment of people with type 2 diabetes (T2D) and in phase 3 clinical trials, it showed substantial reductions in HbA1c and body weight.

In this post-hoc analysis, evaluation of SURPASS 1 to 5 studies were done to achieve a triple composite of HbA1c <6.5% with ≥5% weight loss without clinically significant hypoglycaemia or severe hypoglycaemia. At the end of the treatment, HbA1c and weight were evaluated.

The efficacy data analysis set included data from randomly assigned participants who were exposed to at least one drug. End of treatment HbA1c and weight were evaluated at week 40 (SURPASS 1, 2, 5) and week 52 (SURPASS 3, 4). Hypoglycaemia was evaluated post baseline up to Week 40 (SURPASS-1, -2, -5) or Week 52 (SURPASS-3, -4).

Of the participants in SURPASS 1 to-5 treated with any dose of tirzepatide, 46-79% of patients achieved HbA1c< 6.5% with ≥5% weight loss in comparison to 2-44% of patients treated with placebo or active comparators. HbA1c <6.5% with no hypoglycemia was achieved in 58-85% of patients as compared to 8-63% of patients treated with placebo or active comparators. 39-77% achieved the triple endpoint of HbA1c <6.5%, ≥5% weight loss, and no hypoglycemia.

The results suggests that higher number of patients treated with tirzepatide achieved HbA1c <6.5% with ≥5% weight loss and without hypoglycemia compared to placebo, semaglutide 1 mg or basal insulin. The triple endpoint of HbA1c, weight loss and no hypoglycaemia was achieved by more than 50% of patients for tirzepatide 10 and 15 mg dose.


Diabetes Mellitus and COVID-19: A Not So Sweet Combination

Khine A, presented a study on severity of COVID-19 infection and HbA1c levels in a session at American Association of Clinical Endocrinology on 12th May, 2022. The risk factors for increased severity of COVID-19 infection are diabetes mellitus and hyperglycaemia. However, the connection between DM and COVID-19 is not well understood.

The objective of the current study is to investigate whether there is any correlation between HbA1c levels and COVID-19 infection severity. The primary outcomes assessed was mortality and the secondary outcomes assessed were need for intubation, need for intensive care unit (ICU) level of care, increased hospital length of stay.

The study was conducted as a retrospective cohort study with a total of 317 patients. The results of the study suggest that there is no significant correlation between elevated HbA1c and severity of COVID-19 infection. No significant correlation with found with mortality, need for intubation, need for ICU level of care and increased hospital length of stay.

The study concludes that further studies are needed to identify possible predictors of COVID-19 severity in order to appropriately manage these patients.


Use of Sulfonylurea Based on Diet Recall

Panchal D, presented a study on use of sulfonylurea base on diet in a session at American Association of Clinical Endocrinology on 12th May, 2022. When it comes to possibility of hypoglycemia, sulfonylureas are the most potent oral diabetes agents and to avoid hypoglycaemia, sulfonylurea agent has to be selected based on diet composition and pattern of the patient.

In this study, sulfonylurea group of drugs were offered to type 2 diabetes patients not able to achieve glycemic goal with maximum tolerated dose with two non-sulfonylurea group of oral anti-diabetes agents for 3 months. Sulfonylureas were used based on patients’ diet, particularly meal pattern and carbohydrate percentage in each meal. A total of 286 patients were included in this trial. These patients were divided into three groups:

  • Group A with three major meals per day consists of 228 patients
  • Group B with two major meals per day consists of 42 patients
  • Group C with one major meal per day consists of 16 patients

The results of the study suggest that 72.7% (281) patients were able to achieve target HbA1c at 3 month and 88.1% (254) patients achieved target HbA1c at six months.

The study concludes that the use of sulfonylurea drugs as per the diet pattern particularly meal pattern and percent of carbohydrate, can achieve glycaemic control with minimum risk of hypoglycaemia in type 2 diabetes patients.


Energy Metabolism in a Weight Reduced State

Jakicic J, presented a study on the components of energy expenditure in a session at American Association of Clinical Endocrinology on 12th May, 2022.  The components of energy expenditure are voluntary structured physical activity, voluntary non- structured physical activity, non-voluntary physical activity, thermic effect of food, and resting energy expenditure.

The 24-hour physical activity spectrum consists of low-energy expenditure at the extreme left and high-energy expenditure at the extreme right. The spectrum consists of sleep, sedentary behavior, light intensity physical activity, moderate intensity physical activity, and vigorous intensity physical activity.

With moderate dietary restriction, physical activity can enhance short-term weight loss by 20-25% which is above what can be achieved with the moderate dietary restriction alone. If there is a severe dietary restriction, physical activity will have minimum effect on weight loss above what can be achieved with severe dietary restriction.

When it comes to sleep, get adequate amounts of volume and quality of sleep, decrease sedentary behavior to increase light moderate and vigorous intensity physical activity. Light physical activity includes engaging in lifestyle, household, and occupational activity to enhance light intensity physical activity. Moderate and vigorous intensity physical activity engaging in leisure-time moderate-to-vigorous physical activity, and when possible, increase moderate-to-vigorous household and occupational physical activity.  

The given results suggest that as physical activity increases in terms of moderate to vigorous physical activity, weight loss occurs. The 24-hour physical activity spectrum consists of low energy expenditure activities and high-energy expenditure activities.