Dhiren Patel, PharmD, Robert Busch, MD, and Diana Issacs, PharmD, discuss recent advances in diabetes technology and their impact on patient care.

Pillars of Diabetes Care Technology

A provider toolkit with clinically relevant resources related to diagnosis and management of central precocious puberty.

CPP Provider Toolkit

Our Disease State Series was born out of the idea of providing the most practical information and resources to clinicians. In this installment, we will be focusing on thyroid disorders.

Disease State Series: Thyroid Disorders

A pair of experts in the management of diabetes review the role of insulin therapy and review the approval process for biosimilars, including the FDA's approval of the first interchangeable insulin biosimilar.

Interchangeable Insulin Biosimilars: A Game Changer in Diabetes Management

This article was originally published on 

Addressing and optimizing glucose control early on could play a major role in reducing cardiovascular risk among patients with type 2 diabetes. 

An analysis of data from the KORA study, results demonstrate achieving ideal glycemic control within the first 12 months of diagnosis was associated with an improved prognosis when assessing risk of cardiovascular events among patients with type 2 diabetes, with those achieving glucose control in the first year reducing their risk of cardiovascular events by 25% while those who failed to address elevated HbA1c experienced a 21% increase in risk.

"The conventional wisdom has been to slowly and steadily treat type 2 diabetes with diet and medicine dose-escalation over years - the period over which it took people to reduce their sugar levels after diagnosis was thought less important for major vascular protection. However, our observational study suggests that getting blood levels under control quickly – within the first 12 months after diagnosis – will significantly help reduce cardiovascular events,” said study investigator Martin Whyte, BSc, PhD, a reader in Metabolic Medicine at the University of Surrey, 

Citing data from the UK Prospective Diabetes Study that showed early glycemic control was associated with a reduction in macrovascular events, Whyte and team of colleagues sought to assess whether early glycemic control after a diagnosis of type 2 diabetes might reduce the risk of major adverse cardiovascular disease events.With this mind, investigators sought to conduct a retrospective cohort analysis of adults with type 2 diabetes from the University of Surrey’s Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, which contains primary care records from 1,595,170 people registered from 164 practices in England.

For inclusion in the investigators’ analyses, individuals needed to be newly diagnosed with type 2 diets on or after January 1, 2005, be aged at least 25 years or older at the time of diagnosis, and have HbA1c measurements at both diagnosis and after year 1 plus 5 or more measurements thereafter. For the purpose of analysis, 3 glycemic bands were created: group A, B, and C. These groups were defined as having HbA1c levels of less than 7.5%, 7.5-9.0%, and 9.0% or greater, respectively. Movement between bands from diagnosis to 1-year were used as exposures for the investigators’ analysis. The primary outcome of interest was the risk of major adverse cardiovascular events at 1-year post diagnosis, which investigators assessed using time-varying Cox proportional hazards models that included first-year transition and glycemic variability score.

Overall, 26,180 individuals were identified for inclusion. This cohort was 43.9% were female, had a median follow-up time of 1583 (IQR, 987-1737) days, a mean BMI of30.7±6.4 kg/m2, and, at the time of data extraction, a mean age of 68.7±12.6 years. Initial analysis indicated 48% of individuals began in band A and maintained that status, 16.1% improved from band C to band A, and 14.6% improved from band B to band A from diagnosis to 1-year. Investigators pointed out 7% of individuals began in band A but moved to band B or band C during the first 12 months.

Among the 26,180 patients included in the study, 4179 MACE events were recorded prior to diagnosis of type 2 diabetes and an additional 1457 events were identified in the first 12 months after diagnosis. Investigators also noted 2300 events occurred beyond the 1-year mark.

Compared to those who maintained band A status from baseline to 1-year, those who transitioned from band C to band A during the first year had a reduced risk of major adverse cardiovascular events (HR, 0.75 [95% CI, 0.60-0.94]; 

=.014). In contrast, those who maintained band C status experienced an increase in risk of major adverse cardiovascular events (HR, 1.21 [95% CI, 0.81-1.81]; 

=.34). When comparing risk based on glycemic variability score, results indicated those with the greatest levels of glycemic variability experienced an increase in risk of events (HR, 1.51 [95% CI, 1.11-2.06]; 

“Our findings support the concept that effort must be made to achieve rapid metabolic normalization after the diagnosis of diabetes in those with a low propensity to hypoglycemia,” wrote investigators.

Early and ongoing stable glycaemic control is associated with a reduction in major adverse cardiovascular events in people with type 2 diabetes: A primary care cohort study,

Articles

A University of Surrey-led study found patients achieving optimal glucose control in the first 12 months proceeding a T2D diagnosis had a lower risk of cardiovascular events than their counterparts who did not achieve optimal glucose control. 

New Research Underlines the Importance of Early Interventions in Type 2 Diabetes

The US Food and Drug Administration (FDA) has granted approval to tirzepatide (Mounjaro) as an adjunct therapy to diet and exercise for improving glycemic control in adults with type 2 diabetes, according to a 

Announced on May 13, approval of the first-in-class, once-weekly dual GLP-1/GIP agonist, which is expected to be available in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg doses, is based on data from the SURPASS program.

“Given the challenges many patients experience in achieving their target blood sugar goals, today’s approval of Mounjaro is an important advance in the treatment of type 2 diabetes,” said Patrick Archdeacon, MD, associate director of the Division of Diabetes, Lipid Disorders, and Obesity in the FDA’s Center for Drug Evaluation and Research, in the FDA’s announcement.

In the SURPASS program, tirzepatide’s ability to improve glycemic control as a stand-alone agent or adjunct therapyin 5 trials comparing the agent against placebo therapy and other diabetes medications, including semaglutide and 2 long-acting insulin analogs.

In these trials, patients receiving 15 mg tirzepatide experienced a mean HbA1c reduction that was 1.6% greater than those observed with placebo when used as a stand-alone therapy and 1.5% greater than placebo therapy when used in combination with a long-acting insulin. In the trials comparing tirzepatide 15 mg against other diabetes medications, results suggested those receiving tirzepatide had an HbA1c reduction 0.5% greater than semaglutide, 0.9% more than insulin degludec, and 1.0% more than insulin glargine.

In their release, the FDA also touched upon tirzepatide’s effects on obesity and body weight. In the SURPASS program, those randomized to tirzepatide 15 mg had a mean weight loss Han was 15 pounds greater than that observed with placebo when neither were used with insulin and 23 pounds more than placebo when both were used with insulin. In trials comparing tirzepatide to other agents, use of tirzepatide was associated with weight loss that was 12 pounds greater than was observed semaglutide, 29 pounds greater than insulin degludec, and 27 greater than insulin glargine.

"Mounjaro delivered superior and consistent A1C reductions against all of the comparators throughout the SURPASS program, which was designed to assess Mounjaro's efficacy and safety in a broad range of adults with type 2 diabetes who could be treated in clinical practice. The approval of Mounjaro is an exciting step forward for people living with type 2 diabetes given the results seen in these clinical trials," said Juan Pablo Frías, MD, medical director of the National Research Institute and Investigator in the SURPASS program, in a 

In their release, the FDA noted commonly reported adverse events with tirzepatide included nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain. The FDA also noted tirzepatide caused thyroid C-cell tumors in rates but it is not known whether it causes such tumors in humans and should not be used in those with a personal or family history of medullary thyroid cancer or in patients with Multiple Endocrine Neoplasia syndrome type 2. Additionally, the agent has not been studied in patients with a history of pancreas inflammation and is not indicated for use in patients with type 1 diabetes.

Announced on May 13, the approval indicates Eli Lilly and Company's novel dual GLP-1/GIP agonist, tirzepatide (Mounjaro), for use as an adjunct to diet and exercise to improve blood sugar in adult patients with type 2 diabetes.

Tirzepatide (Mounjaro) Wins FDA Approval for Type 2 Diabetes

Patients with thyroid disorders may be at an increased risk of Parkinson disease, according to the results of a new study.

Presented at the American Academy of Clinical Endocrinology (AACE) annual meeting, results of the systematic review and meta-analysis indicate patients with hypothyroidism and hyperthyroidism were at a 1.5 times greater risk of developing Parkinson disease.

“Studies suggest patients with thyroid dysfunction may have an increased risk of developing Parkinson disease. However, the results from existing studies are inconsistent,” said Nipith Charoenngam, MD, a postdoctoral research fellow at Boston Medical Center, during his presentation. “Therefore, we aimed to investigate the association between hypo and hyperthyroidism with risk of Parkinson disease using the method of systematic review and meta-analysis.”

Citing an interest in building upon previous researching linking thyroid dysfunction and Parkinson disease, Charoenngam and a team of colleagues from Massachusetts-based institutions designed a systematic review and meta-analysis with the intent of assessing this association in eligible cohort and case-control studies published through 2021. With this in mind, investigators performed a search of the Medline and EMBASE databases form inception through December 2021, which yielded 3147 particles for potential inclusion in the analysis.

For inclusion in the analysis, studies needed to consist of 1 cohort of patients with hypothyroidism or hyperthyroidism and another cohort of patients without hypothyroidism or hyperthyroidism. Additionally, cohort studies were required to report effect estimates with 95% confidence intervals comparing incident Parkinson disease between the groups. Case-control studies were considered eligible if they included cases with Parkinson Disease and controls without Parkinson Disease. Additionally, these studies were required to explore a patientshistory of hypothyroidism and/or hyperthyroidism as well as report the odds ratios for associations between presence of hypothyroidism and/or hyperthyroidism and Parkinson Disease.

Of the 3147 articles identified, a pair of independent reviews by a trio of investigators results in a group of 3 cohort studies and 6 case-control studies being deemed eligible for inclusion in the investigators’ meta-analysis. The earliest study included in the meta-analysis was a case-control study published in 1981. Outside of this study, the remaining 5 case-control studies were published from 1999-2020. The 3 cohort studies included were published in 2012, 2020, and 2021. Of note, all 6 case-control studies included patients with hypothyroidism and 5 contained patients with hyperthyroidism.

Upon analysis, results indicated there was an increased likelihood of Parkinson disease was greater among those with hypothyroidism (pooled OR, 1.56 [95% CI, 1.38-1.77], moderate heterogeneity; 

2, 66.9%) and those with hyperthyroidism (pooled OR, 1.57 [95% CI, 1.40-1.77], insignificant heterogeneity; 

2, 0.0%). Investigators pointed out funnel plots for both meta-analyses were fairly symmetric, which led them to believe there was little evidence of publication bias.

“Possible explanations include, first, the dysfunction of dopaminergic neurons in the presence of thyroid hormone deficiency. Also, oxidative stress in the neuron due to thyroid hormone excess could be the explanation for the association between hyperthyroidism and Parkinson Disease,” added Charoenngam. “Also, shared genetic predisposition and neuroinflammation in autoimmune thyroid disease could be possible explanations as well.”

This study, “Thyroid Dysfunction and Risk of Parkinson’s Disease: a Systematic Review and Meta-Analysis,” was presented at AACE 2022.

A systematic review and meta-analysis from AACE 2022 provides an overview of the potential associations between thyroid dysfunction, including both hypothyroidism and hyperthyroidism, and risk of Parkinson disease.

Thyroid Dysfunction Could Increase Risk of Parkinson Disease

New data underlines the lack of training and time dedicated to nutrition education in US endocrinology fellowships.

With the role of nutrition in care of cardiometabolic disease receiving renewed emphasis in recent years, the data, which was presented at the 

American Academy of Clinical Endocrinology (AACE) annual meeting

, underline the desire for more formal nutrition education, with 95% of respondents reporting a belief that further nutrition education was needed, but only 58% of endocrinology fellowship programs in the US offering nutrition education.

“While our population used to be plagued with communicable diseases, the leading causes of death in 2020, even taking COVID into account, were heart disease and cancer with diabetes as one of the top 10 players as well. These chronic conditions account for 90% of healthcare expenditure,” said Sandy Bassin, MD, an internal medicine resident at the Rutgers Robert Wood Johnson Medical School, during her presentation. “The Look AHEAD and Diabetes Prevention Program trials have shown beneficial effects of intensive lifestyle interventions on preventing diabetes and reducing complications amongst those with diabetes, but in our current healthcare environment only 30% of physician office visits for patients with diabetes have included nutrition counseling. Several organizations, such as the ADA, AACE, and ACGME, have also recognized this unmet need for further nutrition education.”

Citing the desire for further education in nutrition science among endocrinologists, the current study was led by Bassin and David Cohen, MD, along with colleagues from Rutgers Robert Wood Johnson Medical School to evaluate contemporary trends in education offerings within endocrinology fellowship programs in the US. To do so, investigators designed their study as a literature review of articles published from 1990-2020 and a survey of endocrinology program directors to evaluate characteristics of nutrition education used in these programs, program directors’ beliefs regarding the need for formal nutrition education, and future directions for nutrition training.

From their literature review, investigators identified 452 articles for potential inclusion. Upon further reanalysis, investigators determined none of the articles described nutrition learning experiences for fellowship trainees. A total of 152 surveys were sent to program directors from 21 different states throughout the US. From this, investigators received 38 responses, which correlates to a 25% response rate.

Analysis of surveys suggested 22 of the 38 programs (58%) offered nutrition education. Investigators pointed out 34% of programs had education offerings that were 1-5 total hours in length, the majority of these programs were primarily didactic (53%), and 39% were led by registered dietitian nutritionists. Of the 22 programs currently offering nutrition education, only 3 rated their current nutrition education as extremely effective while 95% of respondents believed further nutrition education was needed.

When assessing ideal implementation, respondents indicated the preferred nutrition education duration should be 1-5 total hours (50%) over multiple sessions (66%), be interactive (63%, and be led by registered dietitian nutritionists (68%). Further analysis of responses indicated the most important topics for independent practice included education around diet-related behavior modification (55%), components of a healthful diet (50%), and energy expenditure/intake (47%).

“There is an unmet need for interactive, multidisciplinary nutrition education in endocrinology fellowship programs, which emphasize practical skills such as lifestyle counseling. This study provides a foundation to develop and formalize nutrition education within these fellowship programs,” added Bassin.

This study, “Nutrition Education in US Endocrinology Fellowship Programs,” was present at AACE 2022.

Results of a survey and literature review presented at AACE 2022 detail the lack of formal nutrition education available in endocrinology fellowship programs as well as the desire to see a greater emphasis placed on nutrition education in these programs.

Most Endocrinology Fellowship Programs Lack Formal Nutrition Education, Study Finds

New research presented at the American Academy of Clinical Endocrinology (AACE) annual meeting provides insight into the effects of treatment with levoketoconazole among patients with endogenous Cushing’s syndrome.

An analysis of data from a double-blind, placebo-controlled, randomized withdrawal study, results of the study demonstrate levoketoconazole provided benefits across a range of etiologies and provide evidence of levoketoconazole-specific effects through the withdrawal and reintroduction of therapy during the trial.

“This LOGICS study showed that treatment with levoketoconazole benefitted patients with Cushing’s syndrome of different etiologies and a wide range in UFC elevations at baseline by frequent normalization of mUFC and concurrent improvements in serum cholesterol,” said Maria Fleseriu, MD, professor of medicine and neurological surgery and director of the Northwest Pituitary Center at Oregon Health and Science University, during her presentation. “The benefits observed were established as levoketoconazole-specific via the loss of therapeutic effect upon withdrawal to placebo and restoration upon reintroduction of levoketoconazole.”

An orally administered cortisol synthesis inhibitor approved by the US FDA for treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome considered ineligible for surgery, levoketoconazole received approval based on results of the phase 3 open-label SONICS trial, which demonstrated . Launched on the heels of SONICS, the current trial, LOGICS, was designed as phase 3, double-blind, placebo-controlled, randomized withdrawal study aimed at assessing the drug-specificity of cortisol normalization in adult patients with Cushing’s syndrome through a comparison of the effects of withdrawing levoketoconazole to placebo against continuing treatment.

The trial began with an open-label titration maintenance phase followed by a double-blind randomized withdrawal phase and a subsequent restoration phase, with the randomized withdrawal and restoration phase both lasting 8 weeks. A total of 89 patients with Cushing’s syndrome received levoketoconazole to normalize mUFC. Of these, 39 patients on a stable dose for 4 weeks or more were included in the randomized withdrawal stage of the study. These 39, along with 5 completers of the SONICS trial, were randomized in a 1:1 ratio to continue therapy with levoketoconazole or placebo therapy, with 22 patients randomized to each arm.

The primary outcome of interest in the study was the proportion of patients with loss of mean urinary free cortisol response during the randomized withdrawal phase of the study, which was defined as an mUFC 1.5 times the upper limit of normal or greater or an mUFC 40% or more above baseline. Secondary outcomes of interest included mUFC normalization at the end of the randomized withdrawal phase of the study and changes in comorbidity biomarkers. 

Overall, 21 of the 22 patients randomized to placebo during the withdrawal stage met the primary endpoint of loss of mUFC compared to just 9 of 22 among the levoketoconazole arm of the trial (treatment difference: -54.5% [95% CI, -75.7 to -27.4]; 

=.0002). Additionally, at the conclusion of the randomization phase, mUFC normalization was observed among 11 patients in the levoketoconazole arm of the trial compared to 1 patient receiving placebo (treatment difference: 45.5% [95% CI, 19.2 to 67.9]; 

Further analysis indicated the restoration of levoketoconazole therapy was associated with a. Reversal of loss of contrail control in most patients who had been randomized to placebo. Investigators pointed out the mean change from randomized withdrawal baseline to the end of the randomized withdrawal period in total cholesterol was -0.04 mmol/L for levoketoconazole and 0.9 mmol/L for placebo (

=.0004) and the mean change in LDL-C was -0.006 mmol/L and 0.6 mmol/L, respectively (

=0.0056), with the mean increases in cholesterol observed among the placebo arm reversed during the restoration phase.

In safety analyses, results suggest the most commonly reported adverse events seen with levoketoconazole treatment, during all study phases combined were nausea and hypokalemia, which occurred among 29% and 26% of patients, respectively. Investigators also pointed out liver-related events, QT interval prolongation, and adrenal insufficiency, which were respecified adverse events of special interest occurred among 10.7%, 10.7%, and 9.5% of patients receiving levoketoconazole, respectively.

This study, “Levoketoconazole in the Treatment of Endogenous Cushing’s Syndrome: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study,” was presented at AACE 2022.

Data presented at AACE 2022 detail levoketoconazole-specific effects observed among patients with endogenous Cushing's syndrome from the phase 3 LOGICS trial. 

Withdrawal Study Details Effects of Levoketoconazole in Cushing's Syndrome

Although blood pressure is often looked to as a predictor of adverse outcomes, including development of diabetes mellitus, new research suggests measurements of arterial stiffness may be a better predictor of diabetes risk among patients of Chinese ancestry.

An analysis of data from an ongoing, prospective study in China, results of the current study indicate arterial stiffness provided better predictive ability for diabetes than hypertension in multiple sensitivity and subgroup analyses as well as providing a greater incremental effect on the predictive value when added to a conventional risk prediction models with traditional risk factors.

“We were surprised to find that people with increased arterial stiffness were more likely to develop Type 2 diabetes, whether they had high blood pressure or not,” said senior investigator Anxin Wang, PhD, a researcher at the China National Clinical Research Center for Neurological Diseases at Beijing Tiantan Hospital in a 

statement from the American Heart Association (AHA)

. “These results provide strong evidence that measuring arterial stiffness may be a better predictor than blood pressure in determining an individual’s future risk of type 2 diabetes.”

With type 2 diabetes posing a significant threat to patient- and population-level health, prevention efforts have taken center stage for providers in endocrinology, cardiology, and internal medicine. Citing previous research suggesting arterial stiffness may be a better predictor of adverse clinical events than blood pressure and a lack of research comparing predictive ability for type 2 diabetes, Wang and a team of colleagues from the Beijing Tiantan Hospital launched the current study to assess the status of hypertension and arterial stiffness, which was measured as brachial-ankle pulse wave velocity (baPWV), in predicting future risk of type 2 diabetes in a community-based population in China.

With this in mind, investigators designed their study as an analysis of the ongoing, prospective Kailuan study. Starting in 2006, the Kailuan study has enrolled more than 100,000 patients and conducted examination surveys every 2 years. Beginning with survey cycle 3 in 2010, patients who consented to join nested studies on vascular health underwent assessments of baPWV. For the current study, investigators included those with at least 1 completed survey from 2010-2014 with synchronized data and no history of diabetes or prediabetes, yielding a cohort of 11,156 patients for inclusion in their analyses.

This cohort had a mean age of 51.53±11.62 years, 57.19% were men, the mean BMI was 24.8±3.40 kg/m2, and the mean baPWV was 1492.83±350.64 cm/s. During a follow-up period lasting a median of 6.16 (IQR, 5.02-7.00) years, a total of 768 incident cases of diabetes were identified by investigators.

Compared to those with ideal vascular function, the greatest risk of diabetes during the follow-up period was observed among those with hypertension and elevated arterial stiffness (HR, 2.42 [95% CI, 1.93-3.03]; 

 <.0001), followed by normotensive patients with elevated arterial stiffness (HR, 2.11 [95% CI, 1.68-2.66]; 

 <.0001), and those with hypertension and normal arterial stiffness (HR, 1.48 [95% CI, 1.08-2.02]; 

 <.0001). Further subgroup and sensitivity analyses yielded similar results.

Additionally, in analyses comparing the predictive value of hypertension and arterial stiffness, 

statistics in a conventional model significantly improved with the addition of arterial stiffness, from 0.690 to 0.707 (

=.0003), but did not significantly improve with the addition of hypertension (

=.0807). Investigators also pointed out the discriminatory power and risk classification of arterial stiffness appeared to be greater than hypertension, with the integrated discrimination improvement for hypertension at 0.28% (95% CI, 0.02-0.40%; 

 <.0001), while the corresponding net reclassification index was 34.59% (95% CI, 27.31-41.87%; 

<0.0001) and 40.48% (95% CI, 33.46-47.50%; 

“This finding that arterial stiffness increases the risk for developing Type 2 diabetes supports our existing understanding of cardiovascular disease and Type 2 diabetes,” said Eduardo Sanchez, MD, MPH, chief medical officer for prevention of the AHA and clinical lead for Know Diabetes by Heart, in the aforementioned statement. “We look forward to future investigations about the mechanisms between arterial stiffness and type 2 diabetes risk.”

Hypertension, Arterial Stiffness, and Diabetes: a Prospective Cohort Study

An analysis of data from an ongoing, prospective cohort study in China suggests arterial stiffness, as measured by baPWV, was a better predictor of type 2 diabetes risk than blood pressure measurements. 

In Chinese Patients, Arterial Stiffness May Be Better Predictor of Diabetes than Blood Pressure

Natalie Bellini, DNP, FNP-BC, is a nurse practitioner specializing in diabetes management with the R&B Medical Group based out of Niagara Falls, NY. 

For diabetes care and education specialists, late April and early May have ushered in a whirlwind of knowledge and advances. ATTD 2022 marked the start of a conference season that includes meetings hosted by the American Association of Clinical Endocrinology (AACE), the American Diabetes Association (ADA), and the Endocrine Society within a 48-day span. Add to this, news surrounding the US FDA’s 

approval of Eli Lilly and Company’s novel dual GIP/GLP-1 receptor agonist

, tirzepatide, and the full docket of news and information to download from this brief period becomes clear.

In this episode of Diabetes Dialogue: Therapeutics, Technology, & Real-World Perspectives, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, take a deep dive into the tirzepatide approval, including discussions around the mechanism of action for the first-in-class agent, dose titrations, and where it might fit in the upcoming ADA standards of care. Later in the episode, hosts recap their experiences from 

, which saw the release of guidelines for diagnosis and management of nonalcoholic fatty liver disease (NAFLD) in primary care and endocrinology clinical settings.

previous episodes of Diabetes Dialogue: Therapeutics, Technology, & Real-World Perspectives

recap of the 15th International Conference on Advanced Technologies and Treatments for Diabetes.

Diabetes Dialogue: Therapeutics, Technology, & Real-World Perspectives is available in an audio-only format on 

Podcasts

In this episode of Diabetes Dialogue, hosts Drs. Isaacs and Bellini take a deep dive into the tirzepatide approval, including discussions around the mechanism of action, dose titrations, and where it might fit in the upcoming ADA standards of care. Later in the episode, hosts recap their experiences from AACE 2022, which saw the release of new guidelines for NAFLD.

Diabetes Dialogue: Tirzepatide in Action & AACE 2022 Recap

Data from a systematic review and meta-analysis of randomized clinical trials with tirzepatide describe the safety and efficacy of the novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist in the management of type 2 diabetes.

Leveraging data from 7 clinical trials with more than 6500 participants, results of the study provide an overview of the HbA1c lowering, incidence of hypoglycemia, and risk of discontinuation seen with various doses of tirzepatide compared against placebo therapy, basal insulins, and GLP-1 receptor agonists.

“Our meta-analysis findings can help clinicians and other diabetes stakeholders to determine the optimal place of tirzepatide among existing medications for type 2 diabetes,” wrote investigators. “We found that tirzepatide is superior in reducing HbA1c compared with other injectable therapies, in particular basal insulin and once-weekly GLP-1 RAs. In addition, tirzepatide, even at the lowest maintenance dose of 5 mg, can reduce body weight to a greater extent compared with GLP-1 RAs including subcutaneous semaglutide which, in turn, has been shown to be superior to other glucose-lowering agents.”

Approved by the US Food and Drug Administration on May 13

 for improving glycemic control in patients with type 2 diabetes, tirzepatide (Mounjaro) is being welcomed as monumental moment in the landscape of diabetes care. A first-in-class agent approved based on the SURPASS trials, with additional data backing use in obesity, endocrinologists, diabetologists, and primary care providers alike have been captivated by the agent’s potential in multiple disease states.

Spurred by Eli Lilly and Company’s announcement of their new drug application to the FDA in fall of 2021, the current systematic review and meta-analysis was designed by a team of investigators from the Aristotle University of Thessaloniki in Greece, led by Thomas Karagiannis, PhD, MSc, with the intent of providing clinicians with synthesized data from available randomized controlled trials of tirzepatide. From a search of the PubMed, Embase, Cochrane and ClinicalTrials.gov from inception through October 27, 2021 for randomized controlled trials with a duration of at least 12 weeks, investigators identified 7 trials for inclusion in their study.

The 7 trials identified for inclusion were SURPASS 1-5, a double-blind phase 2 trial comparing tirzepatide in 5, 10, and 15 mg doses to placebo or dulaglutide 1.5 mg in patients with type 2 diabetes who were drug-naive or on metformin monotherapy, and a double-blind phase 2 trial comparing tirzepatide 15 mg against placebo in patients with type 2 diabetes who were drug-naive or on metformin monotherapy. Investigator noted all studies had a parallel-group design and 3 were open-label. The duration of interventions in the trials ranged from 12-52 weeks.

From these trials, investigators obtained data related to a cohort of 6609 participants for inclusion in their analyses. At baseline, the mean age of this cohort was 58 years, the mean body weight was 91.5 kg, and the mean HbA1c was 8.2%. The primary outcome of interest for the investigators’ current analyses were the change in HbA2c from baseline. Secondary outcomes of interest included change in body weight and safety outcomes.

Results demonstrated a dose-dependent superiority for lowing HbA1c was observed with the 5, 10, and 15 mg doses of tirzepatide against all comparators, with mean differences ranging from -1.62% to -2.06% against placebo, -0.29% to -0.92% against GLP-1 receptor agonists, and -0.70% to -1.09% against basal insulin regimens. Similarly, superior reductions in bodyweight were observed with tirzepatide against all comparators, with investigators highlighting reductions versus GLP-1 receptor agonists ranging from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg.

When assessing the safety of tirzepatide, results indicated the incidence of hypoglycemia observed with tirzepatide was similar to the incidence rate observed with placebo therapy and lower than rates observed with basal insulin. Investigators pointed out nausea was more frequent with tirzepatide than placebo therapy, especially with tirzepatide 15 mg (OR, 5.60 [95% CI, 3.12 to 10.06]). Tirzepatide 15 mg was also associated with increased incidence of vomiting (OR, 5.50 [95% CI, 2.40 to 12.59]) and diarrhea (OR, 3.31 [95% CI, 1.40 to 7.85]). Investigators also pointed out tirzepatide 15 mg was associated with a higher discontinuation rate due to adverse events regardless of comparator, but all tirzepatide doses were considered safe in terms of serious adverse events and mortality.

“The findings of this meta-analysis of seven RCTs suggest a dose-dependent superiority of all three tirzepatide maintenance doses on glycemic control, not only vs placebo but also vs long-acting GLP-1 RAs and basal insulin regimens. All tirzepatide doses were superior to all comparators in terms of reducing body weight,” wrote investigators.

Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis

A systematic review and meta-analysis of 7 trials provide a detailed overview of the reductions in HbA1c and body weight, as well as the safety, of tirzepatide in various doses compared against placebo and other diabetes medications from clinical trials.

Review Details Efficacy, Safety of Tirzepatide in T2D from Clinical Trials

A secondary analysis of data from a randomized clinical trial suggests participation in home-based exercise programs could aid in improving functional abilities following hip fracture in older patients.

An analysis of the HIPFRA trial, which assessed the effects of a 12-month home-based, physiotherapist-supervised exercise program, results of the study indicate participation in such a program was associated with improved physical performance and ability to complete daily living activities among patients aged 60 years or older.

“It is worthwhile to invest in rehabilitation exercise for older people after hip fracture. Better functioning benefits the individual and also society,” said lead investigator Paula K. Soukkio, MSc, of the South Karelia Social and Health Care District in Finland, 

A parallel-group randomized controlled trial, the Effects of Long-term Intensive Home-based Physiotherapy on Older People With an Operated Hip Fracture or Frailty (HIPFRA) study was conducted from December 9, 2014-December 31, 2019 with the aim of comparing the effects of exercise and usual care in patients from southern Finland. With a population of 121 randomized patients, the trial’s primary analyses concluded participation in an exercise program was not associated with a significant increase in days lived at home or mortality at 24 months between the study arms. For the secondary analyses, HIPFRA investigators sought to assess the effects of randomization to the 12-month home-based physiotherapist-supervised, progressive exercise program on functioning performance and physical activity compared to randomization to usual care.

As part of the trial’s protocol, patients underwent assessment at baseline and again at months 3, 6, and 12. These assessments included Lawton's Instrumental Activities of Daily Living (IADL), Short Physical Performance Battery (SPPB), handgrip strength, and self-reported frequency of sessions of leisure-time physical activity, which served as the primary outcomes of interest for the secondary analyses. Investigators pointed out these were analyzed using mixed-effects models.

At baseline, the exercise arm and usual care arm had the mean IADL scores of 17.1 (SD, 4.5) and 17.4 (SD, 5.1), mean SPPB scores of 3.9 (SD, 1.6) and 4.2 (SD, 1.8), and handgrip strength of 17.7 (SD, 8.9) kg and 20.8 (SD, 8.0) kg, respectively.

Upon analysis, results indicated the age- and sex-adjusted mean changes in IADL at 12 months were 3.7 (95% CI, 2.8 to 4.7) in the exercise arm and 2.0 (95% CI, 1.0 to 3.0) in the usual care arm (between-group difference, 

=.016). For SPPB, the age- and sex-adjusted mean changes at 12 months were 4.3 (95% CI, 3.6 to 4.9) in the exercise arm and 2.1 (95% CI, 1.5 to 2.7) in the usual care arm (between-group difference, 

 <.001). For handgrip strength, the age- and sex-adjusted mean changes at 12 months were 1.2 kg (0.3 to 2.0) in the exercise arm and 1.0 kg (-1.9 to 0.2) in the usual care arm (between-group difference, 

 <.001). Investigators pointed out there were no significant differences observed in regard to changes from baseline in frequency of leisure-time activity sessions between the study arms.

In their conclusion, investigators listed considerations for future trials and underlined the importance of further research into the effects of different exercise-based interventions in subgroups of patients with hip fracture.

“Future trials should include longer follow-up periods to determine whether booster exercise sessions every few months, for example, would help maintain the effects on functioning achieved by exercise interventions,” wrote investigators. “In addition, future trials should evaluate the effects of alternative home-based exercise implementation strategies, such as remote rehabilitation or exercise programs, on functioning and physical performance in patients with surgical repair of hip fracture."

Effects of a 12-month home-based exercise program on functioning after hip fracture–Secondary analyses of an RCT,

Journal of the American Geriatrics Society.

A secondary analysis of the HIPFRA trial indicates participation in a home-based exercise program was associated with increased functional ability and physical performance in adult patients recovering from hip fracture. 

Exercise Program Following Hip Fracture Linked to Improved Functional Ability in Older Adults

New data from an analysis of data from more than 100,000,000 million patients with heart failure is providing clinicians with insight into the impact of diabetic ketoacidosis on risk of poor outcomes and complications among patients with heart failure.

Results of the analysis, which levered data from both the National Inpatient Sample (NIS) database and the Nationwide Readmission Database (NRD), indicate diabetic ketoacidosis was associated with a 61% increase in likelihood of in-hospital mortality, 56% increase in likelihood of major adverse cardiovascular events, and a 12% increase in likelihood of 30-day readmission in adjusted analyses.

“Our study concludes that the presence of diabetic ketoacidosis is associated with poor outcomes and increases the risk of complications. The higher rate of readmission in heart failure populations emphasizes the importance of proper post-hospitalization management,” said Navya Konindala, MD, an internal medicine resident with Memorial Healthcare System, during her presentation.

With an interest in assessing the impact of diabetic ketoacidosis on risk of poor outcomes in patients with heart failure, Konindala and colleagues from the Memorial Healthcare System in Pembroke Pines, Florida designed their study as a retrospective cohort analysis of data from the NIS and NRD recorded between 2016 and 2018. Using ICD-10 diagnosis codes to identify patients and a discharge-level weight analysis to produce a national estimate, investigators identified 106,709,435 patients with heart failure and 314,840 with diabetic ketoacidosis for inclusion in their analyses.

Upon analysis, incidence rates for in-hospital mortality (6.52% vs 4.74%), major cardiovascular events (14.77% vs 9.53%), acute kidney injury (60.29% vs 31.06%), deep vein thrombosis (2.52% vs 2.25%) were all greater among those with diabetic ketoacidosis than their counterparts without DKA, but investigators noted patients with diabetic ketoacidosis had a lower prevalence of atrial fibrillation (16.14% vs 27.87%). Additionally, patients with diabetic ketoacidosis were also younger and had a longer mean length of stay (7.51±0.088 vs 6.18±0.004 days) than their counterparts without DKA.

In analyses adjusting for age, sex, race, chronic kidney disease, and comorbid burden, diabetic ketoacidosis was associated with increased in-hospital mortality (OR, 1.61 [95% CI, 1.48-1.74]; 

 <.0001) and higher incidence of MACE (OR, 1.56 [95% CI, 1.48-1.65]; 

 <.0001). In analyses assessing risk of readmission, results indicated readmission was more common among those with DKA, with 16.69% of those with diabetic ketoacidosis being readmitted within 30 days compared to 14.72% without diabetic ketoacidosis. In analyses adjusted for age, sex, and CKD, diabetic ketoacidosis was associated with increased likelihood of readmission within 30 days (OR, 1.12 [95% CI, 1.08-1.15]; 

“Further studies are needed to untangle the risk factors and develop a standard management of diabetic ketoacidosis in heart failure populations,” added Konindala.

This study, “The Impact of Diabetes Ketoacidosis on Heart Failure: An Analysis of National Inpatient Sample Study 2016-2018,” was presented at AACE 2022.

Diabetic ketoacidosis increased the likelihood of in-hospital mortality by 61%, the likelihood of major adverse cardiovascular events by 56%, and a likelihood of 30-day readmission by 12% among patients hospitalized with heart failure in the US.