This JAMA Insights explores optimal strategies for managing the adverse effects associated with incretin-based medications for obesity, including semaglutide and tirzepatide.
Importance: Type 2 diabetes involves progressive loss of insulin secretion from pancreatic β cells in the setting of insulin resistance and manifests clinically as hyperglycemia. Type 2 diabetes accounts for 90% to 95% of all cases of diabetes globally, with estimates ranging from 589 million to 828 million people worldwide. In the US, type 2 diabetes affects approximately 1 in 6 adults.
Observations: Risk factors for type 2 diabetes include older age, family history, overweight or obesity, physical inactivity, gestational diabetes, Hispanic ethnicity, and American Indian or Alaska Native, Asian, or Black race. Diabetes is diagnosed if fasting plasma glucose is greater than or equal to 126 mg/dL, hemoglobin A1C is greater than or equal to 6.5%, or 2-hour glucose during 75-g oral glucose tolerance testing is greater than or equal to 200 mg/dL. Approximately one-third of adults with type 2 diabetes have cardiovascular disease and 10.1% have severe vision difficulty or blindness. The prevalence of type 2 diabetes is 39.2% among patients with kidney failure. Although weight management is an important component of treatment for type 2 diabetes, no specific diet has been proven to be most effective for improving health outcomes. Physical activity can reduce hemoglobin A1C by 0.4% to 1.0% and improve cardiovascular risk factors (ie, hypertension and dyslipidemia). Randomized clinical trials have reported absolute reductions in microvascular disease (3.5%), such as retinopathy and nephropathy, myocardial infarction (3.3%-6.2%), and mortality (2.7%-4.9%), with intensive glucose-lowering strategies (hemoglobin A1C <7%) vs conventional treatment 2 decades after trial completion. First-line medications for type 2 diabetes include metformin and, in patients with cardiovascular or kidney comorbidities or at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors (SGLT2is). Common add-on medications include dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs, dipeptidyl peptidase-4 inhibitors, sulfonylureas, and thiazolidinediones. Approximately one-third of patients with type 2 diabetes require treatment with insulin during their lifetime. Several randomized clinical trials have demonstrated benefits of specific SGLT2i and GLP-1RA medications compared with placebo for atherosclerotic cardiovascular disease (12%-26% risk reduction), heart failure (18%-25% risk reduction), and kidney disease (24%-39% risk reduction) over 2 to 5 years. Most trial participants with type 2 diabetes were taking metformin. High-potency GLP-1RA and dual GIP/GLP-1RA medications result in weight loss of greater than 5% in most individuals with type 2 diabetes, and weight loss may exceed 10%.
Conclusions: Type 2 diabetes affects up to 14% of the global population and is associated with preventable long-term complications, such as cardiovascular disease, kidney failure, vision loss, and increased mortality. In addition to lifestyle modifications including diet, exercise, and weight management, metformin is generally first-line therapy for attainment of hemoglobin A1C targets. For individuals with type 2 diabetes and cardiovascular or kidney disease or at high cardiovascular risk, guidelines recommend early treatment with SGLT2i and/or GLP-1RA medications.
Lipoprotein(a) is a low-density lipoprotein-like particle that carries oxidized phospholipids and has proinflammatory and proatherogenic properties. In prospective studies, higher levels of lipoprotein(a) are associated with significantly higher risk of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality.1 In a meta-analysis of 29 069 patients, the incidence of ASCVD events per 1000 person-years was 80.0 (95% CI, 75.3-84.9) among people with lipoprotein(a) greater than or equal to 50 mg/dL and 55.3 (95% CI, 53.4-57.3) for people with lipoprotein(a) less than 15 mg/dL (adjusted hazard ratio, 1.35 [95% CI, 1.11-1.66]).2 A similar association of elevated lipoprotein(a) with ASCVD was observed among 460 506 participants from the UK Biobank study.3 Medications such as pelacarsen, olpasiran, and lepodisiran reduce lipoprotein(a) production in the liver and lower plasma lipoprotein(a) by up to 99%, and are currently undergoing testing in randomized clinical trials to determine whether they reduce rates of ASCVD in people with elevated lipoprotein(a).4
The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated LDL-cholesterol and non-HDL-cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid-lowering with statins outweigh potential risks such as statin-associated muscle symptoms and incident Type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. Shared decision-making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non-statin lipid-lowering therapy in older patients are sparse. Deprescribing of lipid-lowering agents may be appropriate for select patients older than 75 years with life-limiting diseases. Finally, a patient-centered approach should be taken when considering primary prevention strategies for older adults.
Importance: Obesity affects approximately 21% of US adolescents and is associated with insulin resistance, hypertension, dyslipidemia, sleep disorders, depression, and musculoskeletal problems. Obesity during adolescence has also been associated with an increased risk of mortality from cardiovascular disease and type 2 diabetes in adulthood.
Observations: Obesity in adolescents aged 12 to younger than 18 years is commonly defined as a body mass index (BMI) at the 95th or greater age- and sex-adjusted percentile. Comprehensive treatment in adolescents includes lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Lifestyle modification therapy, which includes dietary, physical activity, and behavioral counseling, is first-line treatment; as monotherapy, lifestyle modification requires more than 26 contact hours over 1 year to elicit approximately 3% mean BMI reduction. Newer antiobesity medications, such as liraglutide, semaglutide, and phentermine/topiramate, in combination with lifestyle modification therapy, can reduce mean BMI by approximately 5% to 17% at 1 year of treatment. Adverse effects vary, but severe adverse events from these newer antiobesity medications are rare. Surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy) for severe adolescent obesity (BMI ≥120% of the 95th percentile) reduces mean BMI by approximately 30% at 1 year. Minor and major perioperative complications, such as reoperation and hospital readmission for dehydration, are experienced by approximately 15% and 8% of patients, respectively. Determining the long-term durability of all obesity treatments warrants future research.
Conclusions and relevance: The prevalence of adolescent obesity is approximately 21% in the US. Treatment options for adolescents with obesity include lifestyle modification therapy, pharmacotherapy, and metabolic and bariatric surgery. Intensive lifestyle modification therapy reduces BMI by approximately 3% while pharmacotherapy added to lifestyle modification therapy can attain BMI reductions ranging from 5% to 17%. Surgery is the most effective intervention for adolescents with severe obesity and has been shown to achieve BMI reduction of approximately 30%.
Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.
Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.
Conclusions and relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.
Objective: To assess the benefits and harms of lipid-lowering therapies used to prevent or manage cardiovascular disease including bile acid sequestrants (BAS), ezetimibe, fibrates, niacin, omega-3 supplements, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, and statins.
Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed.
Objective: To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point).
Design: Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028).
Setting: Eight Scandinavian referral centers.
Patients: From 1998 to 2005, 191 patients with mild PHPT were included.
Intervention: Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS).
Measurements: Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually.
Results: After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group).
Limitation: During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew.
Conclusion: Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities.
IMPORTANCE An estimated 13% of all US adults (18 years or older) have diabetes, and 34.5%
meet criteria for prediabetes. The prevalences of prediabetes and diabetes are higher in older
adults. Estimates of the risk of progression from prediabetes to diabetes vary widely, perhaps
because of differences in the definition of prediabetes or the heterogeneity of prediabetes.
Diabetes is the leading cause of kidney failure and new cases of blindness among adults in the
US. It is also associated with increased risks of cardiovascular disease, nonalcoholic fatty liver
disease, and nonalcoholic steatohepatitis and was estimated to be the seventh leading cause
of death in the US in 2017. Screening asymptomatic adults for prediabetes and type 2
diabetes may allow earlier detection, diagnosis, and treatment, with the ultimate goal of
improving health outcomes.
OBJECTIVE To update its 2015 recommendation, the USPSTF commissioned a systematic
review to evaluate screening for prediabetes and type 2 diabetes in asymptomatic,
nonpregnant adults and preventive interventions for those with prediabetes.
POPULATION Nonpregnant adults aged 35 to 70 years seen in primary care settings who have
overweight or obesity (defined as a body mass index 25 and 30, respectively) and no
symptoms of diabetes.
EVIDENCE ASSESSMENT The USPSTF concludes with moderate certainty that screening for
prediabetes and type 2 diabetes and offering or referring patients with prediabetes to
effective preventive interventions has a moderate net benefit.
CONCLUSIONS AND RECOMMENDATION The USPSTF recommends screening for prediabetes
and type 2 diabetes in adults aged 35 to 70 years who have overweight or obesity. Clinicians
should offer or refer patients with prediabetes to effective preventive interventions.
(B recommendation)
Background: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected.
Methods: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016.
Results: At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups.
Conclusions: Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.).
