Effective strategies are needed to facilitate the prompt diagnosis and treatment of tuberculosis in countries with a high burden of the disease.
METHODS
We conducted a cluster-randomized trial in which Ugandan community health centers were assigned to a multicomponent diagnostic strategy (on-site molecular testing for tuberculosis, guided restructuring of clinic workflows, and monthly feedback of quality metrics) or routine care (on-site sputum-smear microscopy and referral-based molecular testing). The primary outcome was the number of adults treated for confirmed tuberculosis within 14 days after presenting to the health center for evaluation during the 16-month intervention period. Secondary outcomes included completion of tuberculosis testing, same-day diagnosis, and same-day treatment. Outcomes were also assessed on the basis of proportions.
RESULTS
A total of 20 health centers underwent randomization, with 10 assigned to each group. Of 10,644 eligible adults (median age, 40 years) whose data were evaluated, 60.1% were women and 43.8% had human immunodeficiency virus infection. The intervention strategy led to a greater number of patients being treated for confirmed tuberculosis within 14 days after presentation (342 patients across 10 intervention health centers vs. 220 across 10 control health centers; adjusted rate ratio, 1.56; 95% confidence interval [CI], 1.21 to 2.01). More patients at intervention centers than at control centers completed tuberculosis testing (adjusted rate ratio, 1.85; 95% CI, 1.21 to 2.82), received a same-day diagnosis (adjusted rate ratio, 1.89; 95% CI, 1.39 to 2.56), and received same-day treatment for confirmed tuberculosis (adjusted rate ratio, 2.38; 95% CI, 1.57 to 3.61). Among 706 patients with confirmed tuberculosis, a higher proportion in the intervention group than in the control group were treated on the same day (adjusted rate ratio, 2.29; 95% CI, 1.23 to 4.25) or within 14 days after presentation (adjusted rate ratio, 1.22; 95% CI, 1.06 to 1.40).
CONCLUSIONS
A multicomponent diagnostic strategy that included on-site molecular testing plus implementation supports to address barriers to delivery of high-quality tuberculosis evaluation services led to greater numbers of patients being tested, receiving a diagnosis, and being treated for confirmed tuberculosis.
The emergence of the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 and the reduced effectiveness over time of the BNT162b2 vaccine (Pfizer–BioNTech) led to a resurgence of coronavirus disease 2019 (Covid-19) cases in populations that had been vaccinated early. On July 30, 2021, the Israeli Ministry of Health approved the use of a third dose of BNT162b2 (booster) to cope with this resurgence. Evidence regarding the effectiveness of the booster in lowering mortality due to Covid-19 is still needed.
METHODS
We obtained data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier. The mortality due to Covid-19 among participants who received the booster during the study period (booster group) was compared with that among participants who did not receive the booster (nonbooster group). A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of booster status with death due to Covid-19, with adjustment for sociodemographic factors and coexisting conditions.
RESULTS
A total of 843,208 participants met the eligibility criteria, of whom 758,118 (90%) received the booster during the 54-day study period. Death due to Covid-19 occurred in 65 participants in the booster group (0.16 per 100,000 persons per day) and in 137 participants in the nonbooster group (2.98 per 100,000 persons per day). The adjusted hazard ratio for death due to Covid-19 in the booster group, as compared with the nonbooster group, was 0.10 (95% confidence interval, 0.07 to 0.14; P<0.001).
CONCLUSIONS
Participants who received a booster at least 5 months after a second dose of BNT162b2 had 90% lower mortality due to Covid-19 than participants who did not receive a booster.
After promising initial results from the administration of a third (booster) dose of the BNT162b2 messenger RNA vaccine (Pfizer–BioNTech) to persons 60 years of age or older, the booster campaign in Israel was gradually expanded to persons in younger age groups who had received a second dose at least 5 months earlier.
METHODS
We extracted data for the period from July 30 to October 10, 2021, from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier. In the primary analysis, we compared the rates of confirmed coronavirus disease 2019 (Covid-19), severe illness, and death among those who had received a booster dose at least 12 days earlier (booster group) with the rates among those who had not received a booster (nonbooster group). In a secondary analysis, we compared the rates in the booster group with the rates among those who had received a booster 3 to 7 days earlier (early postbooster group). We used Poisson regression models to estimate rate ratios after adjusting for possible confounding factors.
RESULTS
The rate of confirmed infection was lower in the booster group than in the nonbooster group by a factor of approximately 10 (range across five age groups, 9.0 to 17.2) and was lower in the booster group than in the early postbooster group by a factor of 4.9 to 10.8. The adjusted rate difference ranged from 57.0 to 89.5 infections per 100,000 person-days in the primary analysis and from 34.4 to 38.3 in the secondary analysis. The rates of severe illness in the primary and secondary analyses were lower in the booster group by a factor of 17.9 (95% confidence interval [CI], 15.1 to 21.2) and 6.5 (95% CI, 5.1 to 8.2), respectively, among those 60 years of age or older and by a factor of 21.7 (95% CI, 10.6 to 44.2) and 3.7 (95% CI, 1.3 to 10.2) among those 40 to 59 years of age. The adjusted rate difference in the primary and secondary analyses was 5.4 and 1.9 cases of severe illness per 100,000 person-days among those 60 years of age or older and 0.6 and 0.1 among those 40 to 59 years of age. Among those 60 years of age or older, mortality was lower by a factor of 14.7 (95% CI, 10.0 to 21.4) in the primary analysis and 4.9 (95% CI, 3.1 to 7.9) in the secondary analysis. The adjusted rate difference in the primary and secondary analyses was 2.1 and 0.8 deaths per 100,000 person-days.
CONCLUSIONS
Across the age groups studied, rates of confirmed Covid-19 and severe illness were substantially lower among participants who received a booster dose of the BNT162b2 vaccine than among those who did not.
The FDA approved the first interchangeable biosimilar insulin product to improve glycemic control for children and adults with diabetes, part of an effort to provide cost-effective options, according to an agency press release.
Semglee (insulin glargine-yfgn, Mylan) is both biosimilar to and interchangeable with its reference product insulin glargine (Lantus, Sanofi), a long-acting insulin analogue. As Healio previously reported, Semglee was approved as a drug product under the 505(b)(2) NDA pathway and is now deemed a biologic under section 351(a), in accordance with the Biologics Price Competition and Innovation Act.
Source: Adobe Stock
“This is a momentous day for people who rely daily on insulin for treatment of diabetes, as biosimilar and interchangeable biosimilar products have the potential to greatly reduce health care costs,” Acting FDA Commissioner Janet Woodcock, MD, said in the release. “Today’s approval of the first interchangeable biosimilar product furthers FDA’s longstanding commitment to support a competitive marketplace for biological products and ultimately empowers patients by helping to increase access to safe, effective and high-quality medications at potentially lower cost.”
A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, a biological product already approved by the FDA. An interchangeable biosimilar product may be substituted for the reference product without the intervention of the prescriber. The substitution may occur at the pharmacy, a practice commonly called pharmacy-level substitution, subject to state pharmacy laws, which vary by state. In the release, the FDA noted that biosimilars marketed in the U.S. typically have launched with initial list prices 15% to 35% lower than comparative list prices of the reference products; however, experts have debated whether biosimilar insulin products will substantially lower cost to patients.
“Access to affordable insulin is critical, and long-acting insulin products, like insulin glargine, play an important role in the treatment of types 1 and 2 diabetes mellitus,” Peter Stein, MD, director of the Office of New Drugs in the FDA’s Center for Drug Evaluation and Research, said in the release. “The FDA’s high standards for approval mean health care professionals and patients can be confident in the safety and effectiveness of an interchangeable biosimilar product, just as they would for the reference product.”
Semglee is available in 10 mL vials and 3 mL prefilled pens and is administered subcutaneously once daily. Dosing of Semglee, like Lantus, should be individualized based on the patient’s needs and should not be used during episodes of hypoglycemia or for patients with hypersensitivity to insulin glargine products.
The approval for biosimilar insulin glargine was based in part on the INSTRIDE studies, which confirmed the pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity of Semglee compared with Lantus for people with type 1 and type 2 diabetes. Mylan announced the U.S. launch of Semglee in August 2020, noting in a press release at the time that it was seeking an interchangeability designation from the FDA.
The launch came after favorable judgments on all remaining patent claims asserted by Sanofi against Mylan’s insulin glargine products.
“Although Sanofi may seek certain appeals of those judgments, Mylan is confident they will not affect commercialization,” the company stated in their release.
In March 2020, the FDA announced the formal transition of insulin and certain other biologic drugs to a new regulatory pathway that will better facilitate the development of biosimilar or interchangeable products. In an agency statement, FDA stated that a small subset of biological products approved under the Federal Food, Drug and Cosmetic Act, such as insulin and human growth hormone, will transition to being officially regulated as biological products, enabling these drugs to serve as the reference product for biosimilar or interchangeable drugs approved through the abbreviated licensure pathway. Prior to this change, the FDA required any follow-on insulins to be approved under the abbreviated new drug pathway; these insulins were not considered to be biosimilar because insulins were approved and regulated as chemical drugs.
The FDA released new materials for health care providers to enhance understanding about biosimilar and interchangeable biosimilar products, including a fact sheet about interchangeable biosimilar products, according to the agency.
When I first saw this news, my first thought was, “Can we make this the insulin for the County of Los Angeles?” Here, we still use NPH insulin in many cases, especially for people with type 2 diabetes. I am not sure that Semglee will be cheaper than the $4 a vial paid for NPH. That said, I hope with the discount coupon programs that are available, this insulin will be more affordable for people paying out of pocket.
The good thing here is price — hopefully, this drives prices down, not up. From a patient perspective, it may mean that they can easily get a less expensive insulin at the pharmacy without requiring the pharmacist to call the doctor for a substitution. However, that can also be a bad thing. There are patients, particularly with type 1 diabetes, who may feel there are differences between the brand name and the biosimilar and will not want this change, especially without a conversation with their doctor. This new biosimilar could also confuse some doctors; there will be a need for more education to stress that these two insulins are, in fact, the same.
Finally, the pen devices differ. Some may prefer the branded Lantus pen device vs. a Semglee pen device.
I have long wished there was an interchangeability among insulin analogues, so it was easier for switching. On the other hand, I have so many patients who get upset about switching, because they feel comfortable with what they are prescribed. This approval is good if it makes insulin less expensive and more accessible. I just want to make sure we do not limit patient choice.Anne L. Peters, MDProfessor of Clinical MedicineKeck School of Medicine of the University of Southern CaliforniaDisclosures: Peters reports financial relationships with multiple drug and devices companies.
Insulin has been around for 100 years, yet cost is a serious issue that too often leads to insulin rationing. Recently, there has been more attention to this issue, and many organizations have compiled insulin cost-savings tools like www.getinsulin.org. In June, Walmart announced it would sell ReliOn brand insulin aspart for a lower cost.
Semglee (insulin glargine) is now the first interchangeable biosimilar insulin product. It will allow pharmacists to make the direct substitution for Lantus (insulin glargine) when it is preferred by insurance providers or a lower cost option for the patient. It is widely available at the pharmacies. This product is nearly identical to Lantus and is expected to have the same outcomes on blood glucose management.
Due to the complexities of the drug pricing system and rebates from pharmaceutical companies, a lower list price does not necessarily mean that Semglee will be preferred by insurance providers. For example, insulin aspart and insulin lispro are both available as generics, yet often insurance providers prefer the brand name Novolog (Novo Nordisk) and Humalog (Lilly), respectively. Although it is a direct substitution for Lantus and is expected to have identical effects unit per unit, patients should know that they still have the choice to continue using Lantus if they prefer. Their prescriber can also choose to not allow for the substitution when writing the prescription.
Overall, it is great to see we are moving in the right direction with insulin affordability, but there is still much work to be done to ensure no one has to ever ration insulin.Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES, FADCES, FCCPEndocrine Clinical Pharmacy SpecialistCGM and Remote Monitoring Program CoordinatorCo-Director Center of Excellence for Endocrine Disorders in PregnancyCleveland Clinic Endocrinology & Metabolism InstituteDisclosures: Isaacs reports she has received consultant and speaker fees from Abbott, Dexcom, Insulet, Medtronic, and Novo Nordisk.
PERSPECTIVE
Satish Garg, MD
This is a good thing. Interchangeable means that a pharmacist can now automatically substitute the branded insulin for the patient with the biosimilar, without making a phone call to the doctor or the insurance company. I hope, as more players enter the market, that cost for biosimilar insulins will go down. It is the same insulin. That said, about 10% of patients do not want to change what they have been using for years; however, most of the time, the cost savings will drive people to accept it.Satish Garg, MDProfessor of Medicine and MediatricsBarbara Davis Center for Diabetes, University of Colorado Denver
Patients with type 1 diabetes presenting with symptoms of diabetic ketoacidosis may instead have ketosis due to cannabis hyperemesis syndrome, and several criteria can help avoid a misdiagnosis, according to data published in Diabetes Care.
Physicians mostly rely on pH and bicarbonate levels to diagnose and classify DKA and make floor vs. ICU admission decisions, Halis Kaan Akturk, MD, assistant professor of medicine and pediatrics at the Barbara Davis Center for Diabetes at the University of Colorado and communications director of the American Diabetes Association, Diabetes Technology Interest Group, and colleagues wrote. In a single-center analysis, the researchers found that relying only on pH and bicarbonate can be misleading with cannabis users with type 1 diabetes.
Akturk is an assistant professor of medicine and pediatrics at the Barbara Davis Center for Diabetes at the University of Colorado and communications director of the American Diabetes Association, Diabetes Technology Interest Group.
“Cannabis use has been increasing among people with type 1 diabetes and we observed frequent ED visits with symptoms similar to diabetic ketoacidosis,” Akturk told Healio. “In this study, we wanted to compare the metabolic parameters of cannabis users and nonusers presenting to the ED with symptoms of DKA. We considered any patients with a positive urine drug screen for cannabis as a cannabis user, and those with a negative urine drug screen as nonusers.”
Akturk and colleagues analyzed electronic medical records data from 68 patients with type 1 diabetes followed at the Barbara Davis Center for Diabetes who were seen in the ED with a DKA diagnosis between January 2016 and January 2021 (172 DKA events). Researchers compared mean levels of venous pH, serum bicarbonate, anion gap and beta-hydroxybutyrate between cannabis users and nonusers, using linear mixed models.
Cannabis users had higher pH (mean, 7.42 vs. 7.09) and bicarbonate (mean, 19.2 mmol/L vs. 9.1 mmol/L) compared with nonusers (P < .0001).
The area under the receiver operating characteristic curve for a positive cannabis urine test result predicting cannabis hyperemesis syndrome was 0.9892.
“There were significant differences in metabolic parameters to distinguish between cannabis users and nonusers,” Akturk said. “Non-cannabis users present with high anion gap metabolic acidosis in DKA as expected, but cannabis users present with additional metabolic alkalosis likely due to recurrent vomiting associated with cannabis hyperemesis syndrome.”
The researchers suggested diagnostic criteria for what they termed “hyperglycemic ketosis due to cannabis hyperemesis syndrome,” or HK-CHS. In addition to high venous blood glucose, high anion gap and high beta-hydroxybutyrate levels, other criteria would include a pH of at least 7.4 and bicarbonate of at least 15 mmol/L in presence of ketosis in patients presenting with symptoms of DKA.
“For patients with type 1 diabetes presenting with symptoms of DKA and an unusual metabolic profile, such as an unexpectedly high pH and high bicarbonate that shows alkalosis, cannabis use should be considered,” Akturk said. “Most hospitals classify and place patients with diabetic ketoacidosis based on their pH and bicarbonate levels based on American Diabetes Association classification criteria, so cannabis users presenting with type 1 diabetes may be misclassified based on current classification system.”
The researchers suggest screening urine toxicology for cannabis in adults with type 1 diabetes who present to the ED with a blood glucose of at least 250 mg/dL, beta-hydroxybutyrate of at least 0.6 mmol/L and a pH of at least 7.4 with bicarbonate of at least 15 mmol/L.
“This cutoff would predict 98% of HK-CHS events,” Akturk said.
Heart failure and type 2 diabetes are exquisitely intertwined. Their shared pathophysiology can accelerate debilitating outcomes for patients that clinicians struggle to prevent and treat.
People with type 2 diabetes are two to four times more likely to develop heart failure (HF) than a person without type 2 diabetes, according to data from the American Heart Association (AHA). But HF itself is also a risk factor for type 2 diabetes, with insulin resistance often the mechanism linking the two.
“It is a vicious cycle — insulin resistance can lead to diabetes, diabetes increases the risk for HF, and HF can then exacerbate insulin resistance — makingdiabetes more difficult to manage,” Silvio E. Inzucchi, MD, professor of medicine at Yale University School of Medicine and Yale-New Haven Hospital, told Endocrine Today. “This is a really interesting bidirectional relationship between diabetes and HF.”
Ongoing trials are assessing SGLT2 inhibitor effects in HF hospitalization, heart failure with preserved ejection fraction, advanced CKD with and without diabetes, and post-MI without diabetes, according to Silvio E. Inzucchi, MD.
Photo courtesy of Silvio E. Inzucchi. Printed with permission.
Until recently, cardiologists, and to some extent, endocrinologists managing diabetes, had few good options for these patients, apart from angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitor drugs, beta-blockers, mineralocorticoid antagonists and diuretics. The treatment landscape is quickly evolving.
Since the 2015 landmark EMPA-REG OUTCOME trial of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim and Eli Lilly), data have revealed surprises for a class of diabetes drugs designed initially to lower blood glucose.
Instead, SGLT2 inhibitors may hold the keys to not just preventing HF, but treating existing HF, even for people without diabetes.
“The EMPA-REG OUTCOME trial changed the field dramatically when it came out in 2015,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Endocrine Today. “Those results showed large and significant reductions for hospitalization for HF, and for that matter, also in CV death. That changed the way we were conducting diabetes trials. Until then, the goal was just to show diabetes drugs were safe from a CV standpoint, not increasing [myocardial infarction] risk. The bar was raised after that trial — to actually influence CV outcomes.”
In the 6 years since EMPA-REG OUTCOME, SGLT2 inhibitors have emerged as foundational pillars in the treatment of people with HF. New trial data show the class benefits extend to people with and without diabetes, and several studies are currently evaluating SGLT2 inhibitors for people with HF with preserved ejection fraction (HFpEF), a population with substantially fewer effective treatment options.
“I keep hearing the words ‘pillars of care’ with respect to SGLT2 inhibitors and diabetes with HF, and that should be a pillar of care,” Ileana L. Piña, MD, MPH, FAHA, FACC, professor of medicine at Wayne State University and clinical professor of medicine at Central Michigan University, told Endocrine Today. “If you are prescribing an ACE inhibitor and a beta-blocker, why not start the SGLT2 inhibitor at the same time? You don’t have to worry about blood pressure. You don’t have to worry about heart rate. The side effects are minimal, and it is once a day. Why wait?”
‘This is backward science’
When SGLT2 inhibitors were first assessed in large trials as part of an FDA requirement to prove CV safety for any new diabetes agent, most researchers hoped for just that — CV safety.
“This was during an era where there were concerns about thiazolidinediones and their clear, negative impact on HF risk, and then also the saxagliptin (Onglyza, AstraZeneca) study SAVOR-TIMI 53, which found a surprising increased risk for hospitalization for HF from a DPP-IV inhibitor that had been considered pretty bland on everything in terms of CV risk, neither good nor bad,” Inzucchi said. “There had also been some observational data that suggested even insulin itself could be deleterious for HF risk, although that has since been disproven. There was a lot of concern in the diabetes community in the first decade of the 21st century that we needed a medication that not only would show safety for hospitalization for HF, but actually improved rates for hospitalization for HF.”
Savitha Subramanian
For all the CV outcomes trials, the primary outcome was major adverse CV events, typically defined as nonfatal stroke, nonfatal MI and CV death. However, trialists prospectively collected HF outcomes and centrally adjudicated them.
“In the early trials we were doing, which were focused on making sure new diabetes drugs were not increasing the risk for heart attack, there was actually a lot of HF occurring. Rates for HF were at least as high as the risk for MI,” Bhatt said. “It turned out HF was much more common than we appreciated in patients with diabetes who did not have overt HF to begin with. Therefore, it became important to try to find ways to reduce that risk for HF.”
The data, beginning with EMPA-REG OUTCOME, would speak for itself. Across all CV outcome trials for empagliflozin, dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) and ertugliflozin (Steglatro, Merck), hospitalization for HF was significantly reduced by 30% to 35% among people who received the drugs. The onset of benefit was rapid, with curves among those who received the drug vs. those who received placebo separating dramatically within a few weeks.
The numbers left researchers searching for a mechanism that could explain such substantial benefit.
“A lot of scientists say this is backward science, going from the bedside to the bench,” Darren K. McGuire, MD, MHSc, professor of medicine in the division of cardiology, Dallas Heart Ball Chair for Research on Heart Disease in Women and Distinguished Teaching Professor at the University of Texas Southwestern Medical Center, Dallas, told Endocrine Today. “We are taking an observation that has been consistent across trials, across different patient populations and across different compounds in the class, and we are going back to the science to try and figure out what is going on.”
Finding the why
Mikhail Kosiborod
Initially, there were many glucose-based hypotheses offered to explain the surprising HF benefits observed, McGuire said. One such theory: If a patient is hyper-filtering glucose — and hyper-reclaiming glucose — they are also hyper-reclaiming sodium.
“That sets off a whole cascade of kidney mechanisms that modify systemic physiology,” McGuire said. “HF stimulates the renin angiotensin aldosterone system and the sympathetic nervous system, increases BP, may also increase heart rate, expands plasma volume. There are all these pernicious effects. When you block those, you can restore the kidney back to normal physiology. There is a lot of plausibility to the idea of a secondary kidney-mediated mechanism.”
That premise, however, requires something to be “broken” to fix, McGuire said. Subsequent SGLT2 inhibitor trials performed specifically with patients with established HF, like DAPA-HF and EMPEROR-Reduced, would demonstrate a comparable HF effect for dapagliflozin and empagliflozin independent of diabetes status. When it came to HF benefit, a class of drugs developed for type 2 diabetes worked just as well for people who did not have diabetes.
“[SGLT2 inhibitors] do act as diuretics, but it is believed that the body adapts to that early effect after a while,” Bhatt said. “While it is still controversial, that is not believed to be the dominant mechanism of action. However, it probably does account for at least some of the benefit.”
Inzucchi said researchers observed that the typical mechanisms that kick in with the use of traditional diuretics, such as activation of the sympathetic nervous system and the renin angiotensin system, may not occur when an SGLT2 inhibitor is used — at least not to the same extent.
“It is almost as if the body is tricked into not having this typical, but ultimately counterproductive, response when plasma volume is reduced with an SGLT2 inhibitor as opposed to conventional diuretics,” Inzucchi said. “But there is also evidence for other factors that may be playing a role.”
Other theories persist. Some suggest SGLT2 inhibitors cause a shift in energy utilization by the heart or an increase in the production of ketone bodies by the liver, better “fueling” the heart.
Still other theories relate to direct effects on the heart.
Deepak L. Bhatt
“There are studies looking at the left ventricular muscle function and direct heart effects, not just from a volume overload standpoint,” Savitha Subramanian, MD, associate professor in the division of metabolism, endocrinology and nutrition and medical director of the lipid clinic at the University of Washington School of Medicine, told Endocrine Today. “There may be effects on cardiac muscle, volume, function, things we are only beginning to understand. Europeans are already including SGLT2 inhibitors in their HF management, and the U.S. has to catch up.”
HFpEF: ‘Right now, we have nothing’
CV outcomes trials and meta-analyses demonstrated SGLT2 inhibitors address a triple goal of treatment for HF with reduced EF (HFrEF) — to live longer, stay out of the hospital and reduce debilitating symptoms while improving quality of life.
Whether the class of drugs can do the same for people with HFpEF, however, remains an open and intriguing question.
“The outcomes for people with HF with preserved ejection fraction are nearly as poor as those with HF with reduced ejection fraction,” Mikhail Kosiborod, MD, FACC, FAHA, vice president for research and Ben McCallister, MD, Endowed Chair in Cardiovascular Research at Saint Luke’s Mid America Heart Institute, and professor of medicine at the University of Missouri-Kansas City School of Medicine, told Endocrine Today. “Risk for death or hospitalization is very high, and quality of life is very poor. The pathophysiology of HFpEF is different than HFrEF, but the symptoms are frequently very similar.”
Ileana L. Pina
Two large trial programs are exploring the benefits of SGLT2 inhibitors in HFpEF. EMPEROR-Preserved is assessing the effects of empagliflozin related to CV death or hospitalization of adults with HFpEF. DELIVER is assessing the effect of dapagliflozin on reducing CV death or worsening HF of adults with HFpEF. Results from both trials are expected in the near future.
Two smaller trials offered a glimpse of the possible benefits in this population. Data from the SCORED and SOLOIST trials, presented at the AHA Scientific Sessions in November, showed that sotagliflozin (Lexicon), a novel dual SGLT1/SGLT2 inhibitor, reduced risk for CV death and hospitalization or urgent visits for HF compared with placebo. In SOLOIST, benefits were significant by about 1 month in an acute population; for the more chronic outpatient population in SCORED, benefit was still observed by 3 months, Bhatt said when presenting the data.
“What Dr. Bhatt showed at AHA was if you consider the totality of data from SCORED and SOLOIST in patients with HFpEF, it looks very favorable,” Kosiborod said. “Although it may not be definitive yet for SGLT2 inhibitors in HFpEF, these early results from well-designed randomized clinical trials of sotagliflozin are promising.”Open questions are a bit different for HFpEF, experts said. If there is a benefit with SGLT2 inhibitors, the question remains will benefit be driven predominantly by reductions in hospitalizations for HF, a reduction in CV death, or a combination of both. Also unanswered is the effects on symptom burden and quality of life.
“All of those are important questions, and it is too early to tell,” Kosiborod said. “It is extraordinarily difficult to reduce CV death in the HFpEF population, because it is so multifactorial. But even if we were to come out of these trials with the message that SGLT2 inhibitors show a meaningful reduction in hospitalizations — even without a reduction in mortality — it would still be incredibly important. HFpEF is now a majority of the people with HF, at least in the U.S. We have little to offer them today in terms of disease-modifying therapies. If we see that SGLT2 inhibitors provide a combination of benefits — reduction in hospitalizations and CV death — in HFpEF, that would be amazing, but we have to remember that, right now, we have almost nothing.”
Cross-specialty conversations
With multiple large trials now complete and more underway, evidence is compelling for HF benefits with SGLT2 inhibitors. The biggest challenge now is not just a need for additional data, but implementation science, Bhatt said.
“We need to make sure that patients who currently have guideline or labeled indications for SGLT2 inhibitors are actually getting them,” Bhatt said. “If they are not getting them, what are the barriers, economic or otherwise, that we need to overcome? These are drugs that have the potential to have a large impact on people with diabetes, and especially in diabetes plus either HF or chronic kidney disease. Barring contraindications, it is hard to see why they should not be on this type of medicine.”
To spread that message, cross-specialty collaboration and conversations are important, Subramanian said.
“In our area, there are maybe a handful of cardiologists who are comfortable starting these drugs. I call them the very brave cardiologists,” Subramanian said. “But cardiologists take care of so many different problems. There is counseling needed for these patients. If they are on other medications, those need to be adjusted. The successful cardiology groups that do this well have a pharmacist who handles the medication titration. Even though clinical research did not show an increase in urinary tract infection or Fournier’s gangrene, that is not real-world. There is real risk.”
Hesitancy to prescribe SGLT2 inhibitors remains an issue, either due to lack of comfort or understanding. Endocrinologists working together with cardiologists could help bridge that barrier, Subramanian said.
“In our setting, in an academic practice, it has been variable,” Subramanian said. “Very few cardiologists are comfortable. Often they will send a message through the electronic chart saying, ‘Hey, I’m interested in starting this patient on this drug, what do you think?’ It is a conversation, and dialogue is important.”
McGuire agreed.
“One of the things we must do as cardiologists is stop considering SGLT2 inhibitors ‘diabetes drugs,’” McGuire said. “As I have said since EMPA-REG OUTCOME, these are CV medications, with a side effect of glucose-lowering. We as cardiologists should become more and more comfortable prescribing them, completely independent of glucose considerations. That is an evolution that is occurring.”Click to enlarge
A new clinical care delivery model that prioritizes prevention and treatment of HF can help speed implementation of newer therapies, such as SGLT2 inhibitors, Kosiborod said.
“We built our own cardiometabolic center 2.5 years ago, and the results in terms of quality improvement were so compelling that we have started a national organization — the Cardiometabolic Center Alliance — helping other health care organizations build their own centers of excellence,” Kosiborod said. “I hope this process continues to accelerate. We just can’t wait for decades for efficacious therapies to be adopted in practice, especially for highly morbid conditions like heart failure.”
More to learn
As more trial data continue to reveal new chapters for the SGLT2 inhibitor story, researchers are anxious to learn what more the drugs could potentially do. In addition to trials assessing SGLT2 inhibitor effects for people with HFpEF, there are studies evaluating those hospitalized for HF, as well as patients with advanced chronic kidney disease with and without diabetes and patients post-MI who do not have diabetes.
“There are at least two, if not three studies using SGLT2 inhibitors looking at an early use, either in hospital or soon upon discharge,” Inzucchi said. “Why might that be helpful? Well, the benefit emerges rapidly.. Patients who are just discharged are vulnerable, and getting them potentially lifesaving therapy as soon as possible is probably important.”
Another study, DARE-19, evaluated the effect of dapagliflozin as a treatment for COVID-19 progression, complications and death among adults with CV, metabolic or renal risk factors. AstraZeneca announced in April that the trial did not meet its primary endpoints of organ dysfunction/all-cause death and change in clinical status. But the biggest lesson may be not to write off this drug class a treatment for a single condition, Kosiborod said.
“People like to compartmentalize drugs and interventions. We say drug A is for headache, drug B is for HF, drug C is for diabetes, drug D for kidney disease,” Kosiborod said. “What we see with SGLT2 inhibitors is just a wonderful demonstration of how this way of thinking is erroneous. We think we are done with SGLT2 inhibitors, and they have probably been one of the most extensively researched medications in the history of medicine. Yet, we are likely just scratching the surface.
“There are reasons to believe this class could have benefits through a variety of mechanisms in other disease states. Even in the cardiovascular field, after all these trials, there are many remaining questions,” Kosiborod said. “We should not repeat mistakes of the past.”
Losing 15% of body weight should be a primary treatment goal for most people with type 2 diabetes and could help lead to diabetes remission, according to two speakers.
Ildiko Lingvay, MD, MPH, MSCS, a professor of medicine at the University of Texas Southwestern Medical Center in Dallas, and Priya Sumithran, MBBS (Hons), FRACP, PhD, a senior research fellow in the department of medicine at the University of Melbourne in Australia, said health care professionals treating people with diabetes should be trained in obesity management to prepare for a future of diabetes treatment where weight loss is a major focus.
Lingvay is a professor of medicine at the University of Texas Southwestern Medical Center in Dallas.
“The treatment of obesity should be the future of diabetes treatment,” Lingvay said during a press conference at the European Association for the Study of Diabetes virtual meeting. “It is now our responsibility to work at making it the present of diabetes treatment.”
According to estimates included in a review article published in The Lancet, 40% to 70% of people with type 2 diabetes have obesity, and about 20% to 40% have cardiovascular disease. This leads to three subgroups of people with type 2 diabetes: adiposity-related diabetes, diabetes with CVD and isolated hyperglycemia. Lingvay said treatment should be tailored specifically toward those subtypes.
“We propose a gluco-centric approach for those with beta-cell dysfunction and isolated hyperglycemia, a cardio-centric approach in those with CVD, and a weight-centric approach in everybody else,” Lingvay said.
Weight loss of 15% as primary goal
In the review article, researchers detailed specific targets for each of the three diabetes subtypes. For isolated hypoglycemia, the primary target should be an HbA1c of less than 7%. For diabetes with CVD, treatment should center on the use of proven cardio-protective agents. For adiposity-related diabetes, adults should aim for 15% or more weight loss. Adiposity-related diabetes should center around weight-loss interventions and anti-obesity agents.
Researchers selected a 15% weight-loss goal due to evidence showing weight loss at that level can induce diabetes remission. For adults with type 2 diabetes participating in the Diabetes Remission Clinical Trial (DiRECT), each 1 kg of weight lost was associated with 32% greater odds for diabetes remission at 1 year (95% CI, 1.23-1.41; P < .0001). Of participants who lost 15 kg or more body weight, 86.1% had diabetes remission after 1 year.
A similar association was found in a study analyzing 5,928 adults with type 2 diabetes who underwent bariatric surgery. In the study, weight loss of 10% to 15% was associated with a greater likelihood for diabetes remission compared with those who lost 5% of weight or less (HR = 1.97; 95% CI, 1.47-2.64).
Sumithran noted losing 15% or more weight is challenging. Lifestyle change plus pharmacotherapy is typically associated with weight loss of 5% to 8%. Bariatric surgery, which is invasive and not scalable for a larger population, typically results in weight loss greater than 15%. This leaves a gap in obesity treatment, but Sumithran said, new and combination pharmacotherapy, such as semaglutide (Wegovy, Novo Nordisk) and tirzepatide (Eli Lilly) could fill the gap, can induce weight loss of 15%.
“Type 2 diabetes remission is achievable for many people, particularly if they can achieve weight loss of 10% or more, and particularly if they can sustain that weight loss,” Sumithran said. “New medications are demonstrating that these targets are increasingly achievable in large numbers of participants. This presents an opportunity for how we think about treating diabetes.”
Implementing an obesity-centered approach
With weight management and type 2 diabetes closely intwined, changes will be required in clinical care, according to Lingvay. Health care professionals who treat people with diabetes will need to be trained on obesity management if they are not already, and practices may need specialized staff to assist with weight-related elements of the new diabetes treatment strategy.
“Right now, a relatively small group of physicians or providers actually address obesity or know how to treat obesity,” Lingvay said. “That will have to change. Every provider that treats diabetes would need to know how to address obesity, how to treat obesity, what available options are there, how to implement them, the benefits, how to coach the patient. Then it takes that office environment to be successful.
“All of that has to change, and it’s not going to be a quick change, it’s going to take time to get there,” Lingvay said. “But I’m optimistic that if we spread the message and people understand the benefits of this approach and the greater benefit over just focusing on blood sugar, then this will come naturally.”
New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
METHODS
We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29.
RESULTS
A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group.
CONCLUSIONS
Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.
Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain.
METHODS
We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19–related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19–related medically attended visit or death from any cause by day 28.
RESULTS
A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19–related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group.
CONCLUSIONS
Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo.
Ms. G. perched on the exam table across from me. Her hair was now graying like mine. It had been a long time since our last visit, spanning the Covid-19 pandemic, more than a year with no hairstyling to mask how much we had aged.
At routine annual exams, I have always asked my patients to tell me how they have been since we last met and what issues they most want us to discuss. Now I also ask how they’ve been during such a difficult and stressful time.
Ms. G. answered that she was peaceful: she knew God was protecting her, although she accepted that she also had to do her part to stay healthy. Then she told me that both her son and her mother had died just before the pandemic and her father had died the previous year.
Ms. G. and I have known each other for many years. I knew that her family lived far away. She talked often about her son, who had been paralyzed in a devastating accident years earlier.
After a year in which I sometimes felt overwhelmed by the accumulating losses that my patients have suffered, I was struck by Ms. G.’s quiet acceptance. She said she was grateful that her son had died before Covid so she could fly out to say goodbye. He wasn’t cremated until she had seen his body, and no one had put makeup on him, so she saw him just as he was; she sat with him and knew he was with God, no longer suffering.
As we talked, the tears started rolling down my cheeks. My flimsy plastic visor fogged up until I pulled it off, then laid my glasses next to it on the desk. We sat together and talked about faith, about suffering, about strength.
But there is an inevitable moment in primary care visits when even heartbreaking stories end, when we remember we need to recheck the blood pressure or do the Pap smear, make a plan to adjust the diabetes medication, or just acknowledge that the appointment is running longer than its allotted slot and there are other patients waiting.
This time I hesitated. I find it harder to disagree than to empathize, and in my nonprofessional life, I avoid conflict whenever possible. But my work requires disagreement and persuasion, in fact centers on motivational interviewing as I try to counter what my patients are hearing in the media or from their families and friends. Each day, I encourage someone who is reluctant to take a medicine to treat their cholesterol or osteoporosis, or I refuse to prescribe hydroxychloroquine for Covid-19 or a narcotic for chronic pain. Each time, I think about how to persuade without losing trust.
I knew that Ms. G. had not yet been vaccinated against Covid. And I have seen so many people sick, have read the literature documenting the vaccine’s incredible efficacy and safety, have rested my belief in the power of science. But Ms. G. poured out the reasons she didn’t believe in the vaccine: it doesn’t work against the variants, if you get the vaccine you won’t wear a mask, and more. Most important, God would keep her safe. She didn’t need this vaccine.
The moment felt fragile, as the emotional tone shifted; our disagreement loomed as I put my glasses back on and logged back into the computer. I thought about Ms. G.’s vulnerability to infection and my responsibility to help her stay healthy. And how her decision would have ripple effects on others, might harm those she most loved and feed the spread of sickness in her community.
I thought about Ms. G.’s strength — how the faith that I felt inclined to battle against was fundamental to her well-being and her ability to thrive despite unimaginable loss. I considered how to honor her ability to make choices about her health without abdicating my role as a source of medical expertise. Reciting the facts, I described the minuscule risk of a serious adverse effect from the vaccine, versus the significant risk of Covid, but Ms. G.’s skeptical expression was easy to recognize even above her mask. And so I told her that I respected her beliefs, and I reflected back her earlier assertion that she would do her part to stay healthy. I told her about my experience getting vaccinated and asserted my belief in the vaccine’s efficacy. I asked her to think about it, because I wanted the best for her, wanted her to stay safe. I tried to plant the seed for change.
Mulling over our conversation, I keep thinking about trust. I circle back to this tension between trusting and disagreeing, to the question of how to maintain a relationship in the face of profoundly different beliefs and choices. I have had similar conversations, over and over, with patients who don’t want to get the Covid vaccine — about their mistrust of medical institutions and providers, of science, of politicians; their feeling of being pressured; and their fear of being harmed. One distraught young woman had been warned by her family that the vaccine would make her infertile. And I think about the racism and misogyny that have so often shaped medical care in our country, and the ways in which such experiences color our relationships and our individual decisions about our health.
No matter how much I want to convince Ms. G. to get vaccinated, I know that in medicine, relationship and trust are fundamental to healing. I uncomfortably juggle these two conflicting imperatives and try not to let my frustration turn into anger. And so I stepped back to let Ms. G. think about what to do next. After our visit, I sent her this essay, with the hope that we might, together, navigate this collision of persuasion, faith, and trust.
Four months later, Ms. G. remains unvaccinated. She graciously thanked me for writing to her and gave me permission to share our story. And she has come back to see me twice. Each time, she is double-masked and open to my other treatment recommendations. And although I continue to wonder what more I could do, I believe that what we can both do is continue to talk. Amid the strident vaccination rhetoric that surrounds us, our dialogue feels like a meaningful and therapeutic exchange.
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