A NOVEL DRUG FOR DIABETES

 UPDATED WITH COMMENTS DECEMBER 10, 2020 // Tirzepatide, a novel subcutaneously injected drug that acts via two related but separate pathways of glucose control, produced strikingly positive effects in top-line results from the phase 3, placebo-controlled study SURPASS-1 in 478 adults with type 2 diabetes, according to a December 9 press release from the manufacturer, Lilly.

The tirzepatide molecule exerts agonist effects at both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, and has been called a "twincretin" for its activity encompassing two different incretins. Phase 2 trial results caused excitement, with one physician calling the data "unbelievable" when reported in 2018.

SURPASS-1 enrolled patients who were very early in the course of their disease, had on average relatively mild elevation in glucose levels, and few metabolic comorbidities. They took one of three doses of the agent (5, 10, or 15 mg) as monotherapy or placebo for 40 weeks.

Julio Rosenstock, MD, said in the Lilly statement: "The study took a bold approach in assessing A1c targets. Not only did nearly 90% of all participants taking tirzepatide meet the standard A1c goal of less than 7%, more than half taking the highest dose also achieved an A1c less than 5.7%, the level seen in people without diabetes."

Rosenstock is principal investigator of SURPASS-1 and director of the Dallas Diabetes Research Center in Texas.

The discontinuation rate in the high-dose group was 21.5% compared with less than 10% in the two lower-dose cohorts. Lilly said most of the dropouts "were due to the pandemic and family or work reasons." The dropout rate in the placebo group was 14.8%.

These data were not included in the efficacy analysis, however, which "muddied" the analysis somewhat, one pharma analyst told BioPharma Dive.

Commenting on the new trial data, Ildiko Lingvay, MD, told Medscape Medical News: "I am very impressed with these results," which are "unprecedented for any glucose-lowering medication that has ever been tested."

Lingvay, of the Department of Internal Medicine/Endocrinology, and medical director, Office of Clinical Trials Management at UT Southwestern Medical Center, Dallas, was not involved in the study.

She added that the weight loss seen with tirzepatide "is equally impressive with greater than 10% of body weight loss above placebo achieved within 40 weeks of treatment and without any directed weight loss efforts."

If the agent is eventually approved, "I am enthusiastic about the prospect of having another very powerful tool to address both diabetes and obesity," she added.

The full results of SURPASS-1 will be presented at the American Diabetes Association 81st Scientific Sessions and published in a peer-reviewed journal in 2021.

SURPASS-1 is one of eight phase 3 studies of the drug, including five registration studies and one large 12,500-patient cardiovascular outcomes trial.

Tirzepatide Patients Lost Up to 20 lb, Side Effect Profile 'Reassuring'

In the study, patients had been recently diagnosed with type 2 diabetes (average duration, 4.8 years) and 54% were treatment-naive. Average baseline A1c was 7.9% and mean weight was 85.9 kg (189 lb).

Patients started on a subcutaneous injectable dose of tirzepatide of 2.5 mg per week, which was titrated up to the final dose — 5, 10, or 15 mg — in 2.5-mg increments given as monotherapy for 40 weeks and compared with placebo. 

Treatment with tirzepatide resulted in average reductions in A1c from baseline that ranged from 1.87% to 2.07%, depending on the dose, and were all significant compared with an increase of 0.4% with placebo.

The percentage of patients whose A1c fell to normal levels (less than 5.7%) ranged from 30.5% to 51.7%, compared with 0.9% among controls, and again, was significant for all doses.

Patients treated with tirzepatide also lost weight. Average weight reductions after 40 weeks were significant and ranged from 7.0 to 9.5 kg (15 to 21 lb) compared with an average loss of 0.7 kg (1.5 lb) among patients who received placebo.

The most common adverse events were gastrointestinal-related and mild to moderate in severity, and usually occurred during dose escalation.

Lingvay said the safety data reported are "reassuring, with side effects in the anticipated range and comparable with other medications in the GLP-1 agonist class."

And no hypoglycemic (level 2, < 54 mg/dL) events were reported, "which is impressive considering the overall glucose level achieved," she noted.

"I am eagerly awaiting the results of the other studies within the SURPASS program and hope those will confirm these initial findings and provide additional safety and efficacy information in a wider range of patients with type 2 diabetes," she concluded.

Lingvay has reported receiving research funding, advisory/consulting fees, and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target Pharma, Merck, Pfizer, Novartis, GI Dynamics, Mylan, MannKind, Valeritas, Bayer, and Zealand Pharma.

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Medscape Medical News © 2020 WebMD, LLC

DIABETES FIRST LINE TREATMENT

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide-1) receptor agonists, they advised.

Cardiovascular Disease Focus Represents a 'Major Paradigm Shift'

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It's an approach "driven by data from the cardiovascular outcome trials," that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents "a major paradigm shift," a "change from a glucose-centric approach to an approach driven by cardiovascular disease events," summed up Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC's 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D "based on cardiovascular disease risk classification," he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD Call for 'a Different Emphasis'

"There is a different emphasis" in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

"The ADA and EASD recommendations "look primarily at glucose control, with cardiovascular disease management as secondary." In contrast, the ESC guidelines "are primarily cardiovascular disease risk guidelines, with a glucose interest," Grant declared.

Despite his involvement in writing the ESC guidelines, Grant tilted toward the ADA/EASD statement as more globally relevant.

"There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease," including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

"It's important that we're not glucocentric any more, but it's equally important that we treat glucose because it has such a benefit for microvascular disease." Grant also cited metformin's long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on "knowing we're doing it right," said Grant.

Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.

'Clinical Inertia' Could Be a Danger

Cosentino played down a major disagreement between the two guidelines, suggesting that "focusing on the differences leads to clinical inertia" by the practicing community when they are unsure how to reconcile the two positions.

Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. "Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs," metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it's time to generally steer clear of sulfonylurea drugs. "We have evidence for harmful effects from sulfonylureas," Cosentino said.

"I'd dump sulfonylureas," was Grant's assessment, but he added that they still have a role for patients who need additional glycemic control but can't afford the newer drugs.

Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Medscape Medical News © 2020 WebMD, LLC

WEIGHT LOSS AND DIABETES RISK

Intentional loss of a median of just 13% of body weight reduces the relative risk of developing type 2 diabetes by around 40% in people with obesity, among many other health benefits, shows a large real-world study in half a million adults.

Other findings associated with the same modest weight loss included a reduction in the risk of sleep apnea by 22%-27%, hypertension by 18%-25%, and dyslipidemia by 20%-22%.

Christiane Haase, PhD, Novo Nordisk, Denmark, led the work, and spoke to Medscape Medical News, together with Nick Finer, MD, senior principal clinical scientist, Novo Nordisk.

"This is powerful evidence to say it is worthwhile to help people lose weight and that it is hugely beneficial. These are not small effects, and they show that weight loss has a huge impact on health. It's extraordinary," Finer asserted.

"These data show that if we treat obesity first, rather than the complications, we actually get big results in terms of health. This really should be a game-changer for those health care systems that are still prevaricating about treating obesity seriously," he added.

The size of the study, of over 550,000 UK adults in primary care, makes it unique. In the real-world cohort, people who had lost 10%-25% of their body weight were followed for a mean 8 years to see how this affected their subsequent risk of obesity-related conditions. The results were presented during the virtual European and International Congress on Obesity (ECOICO 2020).

"Weight loss was real-world without any artificial intervention and they experienced a real-life reduction in risk of various obesity-related conditions," Haase told Medscape Medical News. 

Carel le Roux, MD, PhD, from the Diabetes Complications Research Centre, University College Dublin, Ireland, welcomed the study because he says it shows those with obesity who maintained more than 10% weight loss experienced a significant reduction in the complications of obesity.

"In the study, intentional weight loss was achieved using mainly diets and exercise, but also some medications and surgical treatments. However, it did not matter how patients were able to maintain the 10% or more weight loss as regards the positive impact on complications of obesity," he highlighted.

From a clinician standpoint, "it helps to consider all the weight loss options available, but also for those who are not able to achieve weight loss maintenance, to escalate treatment. This is now possible as we gain access to more effective treatments," he added.

Also commenting on the findings, Matt Petersen, vice president of medical information and professional engagement at the American Diabetes Association, said: "It's helpful to have further evidence that weight loss reduces risk for type 2 diabetes."

However, "Finding effective strategies to achieve and maintain long-term weight loss and maintenance remains a significant challenge," he 

Large Database of Half a Million People With Obesity

For the research, anonymized data from over half a million patients documented in the Clinical Practice Research Datalink (CPRD) database, which holds information from 674 general practices in the UK, were linked to Hospital Episode Statistics and prescribing data to determine comorbidity outcomes.

At baseline, characteristics for the full study population included a median age of 54, around 50% of participants had hypertension, around 40% had dyslipidemia, and around 20% had type 2 diabetes. Less than 10% had sleep apnea, hip/knee osteoarthritis, or history of cardiovascular disease. All participants had a body mass index of 25.0–50.0 kg/m² at the start of the follow-up, between January 2001 and December 2010.

Patients may have been advised to lose weight, or take more exercise, or have been referred to a dietician. Some had been prescribed antiobesity medications available between 2001-2010. (Novo Nordisk medications for obesity were unavailable during this period.) Less than 1% had been referred for bariatric surgery.

"This is typical of real-world management of obesity," Haase pointed out.

Participants were divided into two categories based on their weight pattern during the 4-year period: one whose weight remained stable (492,380 individuals with BMI change within –5% to +5%) and one who lost weight (60,573 with BMI change –10% to –25%).

The median change in BMI in the weight-loss group was –13%. The researchers also extracted information on weight loss interventions and dietary advice to confirm intention to lose weight.

The benefits of losing 13% of body weight were then determined for three risk profiles: BMI reduction from 34.5 to 30 kg/m² (obesity class I level); 40.3 to 35 kg/m² (obesity class II level), and 46 to 40 kg/m² (obesity class III level).

Individuals with a baseline history of any particular outcome were excluded from the risk analysis for that same outcome. All analyses were adjusted for BMI, age, gender, smoking status, and baseline comorbidities.

Study strengths include the large number of participants and the relatively long follow-up period. But the observational nature of the study limits the ability to know the ways in which the participants who lost weight may have differed from those who maintained or gained weight, the authors said.

Type 2 Diabetes, Sleep Apnea Showed Greatest Risk Reductions

The researchers looked at the risk reduction for various comorbidities after weight loss compared to before weight loss. They also examined the risk reductions after weight loss compared to someone who had always had a median 13% lower weight.

Effectively, the analysis provided a measure of the effect of risk reduction due to weight loss compared to having that lower weight as a stable weight.

"The analysis asks if the person's risk was reversed by the weight loss to the risk associated with that of the lower weight level," explained Haase.

"We found that the risks of type 2 diabetes, dyslipidemia, and hypertension were reversed while the risk of sleep apnea and hip/knee osteoarthritis showed some residual risk," she added.

With sleep apnea there was a risk reduction of up to 27% (compared to before weight loss).

"This is a condition that can't be easily reversed except with mechanical sleeping devices and it is under-recognized and causes a lot of distress. There's actually a link between sleep apnea, diabetes, and hypertension in a two-way connection," noted Finer, who is also honorary professor of cardiovascular medicine at University College, London, UK.

"A reduction of this proportion is impressive," he stressed.

Dyslipidemia, hypertension, and type 2 diabetes are well-known cardiovascular risk factors. "We did not see any impact on myocardial infarction," which "might be due to length of follow-up," noted Haase.

Response of Type 2 Diabetes to Weight Loss

Most patients in the study did not have type 2 diabetes at baseline, and Finer commented on how weight loss might affect type 2 diabetes risk.

"The complications of obesity resolve with weight loss at different speeds," he said.

"Type 2 diabetes is very sensitive to weight loss and improvements are obvious in weeks to months."

In contrast, reductions in risk of obstructive sleep apnea "take longer and might depend on the amount of weight lost." And with osteoarthritis, "It's hard to show improvement with weight loss because irreparable damage has [already] been done," he explained.

The degree of improvement in diabetes due to weight loss is partly dependent on how long the person has had diabetes, Finer further explained. "If someone has less excess weight then the diabetes might have had a shorter duration and therefore response might be greater."

Lucy Chambers, PhD, head of research communications at Diabetes UK, said: "We've known for a long time that carrying extra weight can increase your risk of developing type 2 diabetes, and this new study adds to the extensive body of evidence showing that losing some of this weight is associated with reduced risk." 

She acknowledged, however, that losing weight is difficult and that support is important: "We need government to urgently review provision of weight management services and take action to address the barriers to accessing them."

Finer and Haase are both employees of Novo Nordisk. Le Roux has reported no relevant financial relationships.

ECOICO 2020. Presented September 1-4, 2020. Abstract 0497.

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SGLT2 INHIBITORS AND DKA RISK

Sodium-glucose cotransporter 2 (SGLT2) inhibitors used for the treatment of type 2 diabetes, and for heart failure, are associated with a nearly threefold increased risk for diabetic ketoacidosis (DKA), according to a newlarge database analysis.

The findings, which include data on the use of three different SGLT2 inhibitors in Canada and the United Kingdom and suggest a class effect, were published online July 27 in Annals of Internal Medicine by Antonios Douros, MD, PhD, of McGill University and the Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Quebec, Canada, and colleagues.

"Our results provide robust evidence that SGLT2 inhibitors are associated with an increased risk for DKA. Of note, increased risks were observed in all molecule-specific analyses, with canagliflozin [Invokana, Janssen] showing the highest effect estimate," they note.

And because the beneficial effects of SGLT2 inhibitors in the prevention of cardiovascular and renal disease will probably increase their uptake in the coming years, "Physicians should be aware of DKA as a potential adverse effect," Douros and colleagues write.

Analysis "Generally Confirms What Has Already Been Published"

Asked for comment, Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland, Baltimore, said that the study "generally confirms what has already been published" on the topic. He noted that overall "the risk of SGLT2 inhibitor-induced ketoacidosis is quite low in type 2 diabetes, perhaps on the order of one episode per 1000 patient-years."

However, Taylor cautioned: "Published evidence suggests that the risk of DKA is increased if patients are unable to eat," such as as when hospitalized patients are not permitted to eat.

"In that setting, it is probably prudent to discontinue an SGLT2 inhibitor. Also, it may be prudent not to prescribe SGLT2 inhibitors to patients with a history of DKA," he added.

Taylor also advised: "Although not necessarily supported by this publication, I think that caution should be exercised in prescribing SGLT2 inhibitors to insulin-dependent type 2 diabetes patients...Some-late stage type 2 diabetes patients may have severe insulin deficiency and their physiology may resemble that of a type 1 diabetes patient."

Taylor has previously advised against using SGLT2 inhibitors altogether in patients with type 1 diabetes.

Increased DKA Risk Seen Across All SGLT2 Inhibitors 

The study involved electronic health care databases from seven Canadian provinces and the United Kingdom, from which 208,757 new users of SGLT2 inhibitors were propensity-matched 1:1 to new dipeptidyl peptidase-4 (DPP-4) inhibitor users.

Of those taking an SGLT2 inhibitor, 42.3% took canagliflozin, 30.7% dapagliflozin (Farxiga/Forxiga, AstraZeneca), and 27.0% empagliflozin(Jardiance, Boehringer Ingelheim)Over a mean 0.9-year follow-up, 521 patients were hospitalized with DKA, for an overall incidence rate of 1.41 per 1000 person-years.

The rate with SGLT2 inhibitors, 2.03 per 1000 person-years, was nearly three times that seen with DPP-4 inhibitors, 0.75 per 1000 person-years, a significant difference (hazard ratio, 2.85).

By individual SGLT2 inhibitor, the hazard ratios compared with DPP-4 inhibitors were 1.86 for dapagliflozin, 2.52 for empagliflozin, and 3.58 for canagliflozin, all statistically significant. Stratification by age, sex, and incident versus prevalent user did not change the association between SGLT2 inhibitors and DKA.

Asked about the higher rate for canagliflozin, Taylor commented: "It is hard to know whether there are real and reproducible differences in the risks of DKA among the various SGLT2 inhibitors. The differences are not huge and the populations are not well matched."

But, he noted, "If canagliflozin triggers more glucosuria, it is not surprising that it would also induce more ketosis and possibly ketoacidosis."

He also noted that the threefold relative increase in DKA with canagliflozin versus comparators is consistent with Janssen's data, published in 2015. 

"It is, of course, reassuring that both [randomized clinical trials] and epidemiology produce similar estimates of the risk of drug-induced adverse events. Interestingly, the incidence of DKA is approximately threefold higher in the Canadian [data] as compared to Janssen's clinical trials."

Taylor also pointed out that in the Janssen studies the risk of canagliflozin-induced DKA appeared to be higher among patients with anti-islet antibodies, suggesting that some may have actually had autoimmune (type 1) diabetes. "So, the overall risk of SGLT2 inhibitor-induced DKA may depend at least in part on the mix of patients."

In the current study, individuals who never used insulin had a greater relative increase in DKA with SGLT2 inhibitors compared with DPP-4 inhibitors than did those who did use insulin (hazard ratios, 3.96 vs 2.24 both vs DPP-4 inhibitors).

However, just among those taking SGLT2 inhibitors, the absolute risk for DKA was higher for those with prior insulin use (3.52 vs 1.43 per 1000 person-years). 

The results of sensitivity analyses were consistent with those of the primary analysis.

The study was funded by the Canadian Institutes of Health Research and supported by ICES. Douros has reported receiving a salary support award from Fonds de recherche du Quebec – sante. Taylor was previously employed at Bristol-Myers Squibb. He is currently a consultant for Ionis Pharmaceuticals and has reported receiving research support provided to the University of Maryland School of Medicine by Regeneron. 

Ann Intern Med. Published online July 27, 2020. Abstract

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PREVENTION OF TYPE 2 DIABETES

Adults at high risk for type 2 diabetes who had received either lifestyle intervention or metformin in the 3-year Diabetes Prevention Program (DPP) and continued in the Diabetes Prevention Program Outcomes Study (DPPOS) were less likely to develop diabetes than patients in the placebo group over an average 22-year follow-up.  

DPPOS chair David M. Nathan, MD, and other study investigators presented findings last week during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

At the end of the DPP, conducted in 1996-2001, patients in the lifestyle-intervention or metformin group were 58% and 31% less likely to have incident diabetes, respectively, than patients in the placebo group.

Now, 22 years after they enrolled in the DPP, patients were on average 72 years old and those in the original lifestyle intervention or metformin group were 25% and 18% less likely to have diabetes, respectively.

And participants who did not develop diabetes had significantly lower rates of eye, kidney, and major cardiovascular disease, at 57%, 37%, and 39%, respectively, according to a statement from the ADA.

"What we have shown is that diabetes prevention is possible," Nathan, from Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News in an interview.

Unique Long-Term Study 

The DPP participants were at very high risk for diabetes, Nathan stressed.

"Their glucose levels were rising. They were overweight, if not obese, and we also overrecruited in ethnic and racial groups that are at particularly high risk — African Americans, Hispanic Americans, American Indians, and Asian Americans."

This unique, long-term study showed "a pretty remarkable — and not unexpected, some may say — reduction in eye disease, kidney disease, and major cardiovascular disease in people who did not develop diabetes," he noted.

"I think it is important for providers and patients with prediabetes to know that even after 22 years, adults at high risk for diabetes have continued to benefit from metformin or prior intensive lifestyle modification in preventing or delaying" diabetes, Christine Lee, MD, told Medscape Medical News in an email.

Lee is program director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Lifestyle Modification Better for Prevention in Adults > 60 Years

In the DPP, 3234 patients at high risk of developing diabetes were randomized to receive placebo or metformin (850 mg twice a day) or an intensive lifestyle counseling program that aimed for 7% weight loss and 150 minutes of moderate exercise per week.

At the end of the DPP, 88% of participants (including those who had developed diabetes) entered the DPPOS; those who were taking metformin stayed on it and all three groups received less intensive lifestyle counseling.As reported earlier, 15 years after enrolling in the DPP, 55% of participants in the lifestyle group and 56% of those in the metformin group had developed diabetes, compared with 62% of those in the placebo group.

At 22 years, 75% of patients from the DPP who were still alive were still participating in the DPPOS.

"The new findings did not show that taking metformin can prevent cancer, cardiovascular disease, or diseases of the eyes and kidney caused by diabetes," Lee pointed out.

However, "the data suggest that there may be some preventive effects of metformin for these outcomes in adults younger than 45 years [eg, a trend to less stroke], but these outcomes were more infrequent in this younger age group and further studies are needed before conclusions can be made for this age group."

"Conversely, there appeared to be a greater risk for kidney disease with metformin in older adults," she continued.

Therefore, "when balancing that risk [from metformin]" with prior, and newer, results that respectively show lifestyle modification works better than metformin for preventing diabetes in older adults, and can also decrease the risk of frailty in this same group, "patients ages 60 and older at high risk for diabetes should focus on intensive lifestyle modification for diabetes prevention," according to Lee.

Metformin is not approved for diabetes prevention in the United States, and it is unlikely that any of the several manufacturers of generic metformin would file a new drug application for this use with the US Food and Drug Administration, according to Nathan.

Widespread Prediabetes, Few Referrals for Community DPPs

In the United States, an estimated 30 million people have diabetes (mostly type 2), including about 7 million not yet diagnosed, Nathen said, and another 90 million have prediabetes.

More research is needed to be able to identify which patients with prediabetes are most vulnerable to developing diabetes and would benefit most from prevention interventions, he stated.

Similarly, Lee said that the current findings "highlight the importance of trying to further understand differences in how metformin or lifestyle modification work in adults at high risk for diabetes."

"Research to better identify who can benefit most from metformin or lifestyle will help providers offer patient-centered approaches for diabetes prevention," she said.

In the meantime, and as previously reported, the US Preventive Services Task Force and the ADA recommend screening and lifestyle counseling to achieve weight loss and reduce diabetes risk in high-risk adults, and diabetes prevention programs are covered by Medicare, many commercial health plans, and some Medicaid and state employee health plans.

About 2 years ago, the Center for Medicare and Medicaid Services began funding the diabetes prevention lifestyle program for qualifying Medicare beneficiaries at high risk of diabetes, said Nathan, and the program is available in many US communities.

And as previously reported, the turnkey lifestyle program to prevent diabetes by the US Centers for Disease Control and Prevention (CDC) replicates the DPP intervention and is offered by 244 YMCAs at more than 1100 locations.

Patients receive coaching from trained individuals about making long-term dietary changes, increasing physical activity, and overcoming challenges to maintaining weight loss and a healthy lifestyle. Counseling is given in 22 sessions over 1 year.

However, few physicians are referring patients with prediabetes to the program. According to a 2019 CDC study, only 5% of individuals with prediabetes and 0.4% of those with an elevated risk of diabetes had been told by their physician to participate in a diabetes prevention program (JAMA Netw Open. 2019;2:E193160).

DPPOS is supported by the NIDDK, National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute on Aging, National Eye Institute, Office of Research on Women's Health, and CDC. Merck supplied the metformin.  

ADA 2020 Scientific Sessions. June 16, 2020.   

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DIABETES INCREASE RISK OF COLORECTAL CANCER

The increased risk of colorectal cancer associated with type 2 diabetes in people under age 50 is close in magnitude to the risk with a family history of the disease, according to a Swedish registry study.

Dr. Mahdi Fallah of the German Cancer Research Center (DKFZ) in Heidelberg told Reuters Health by email the findings are important so that for now, "risk-adapted colorectal cancer screening can be offered to diabetic patients earlier than the general population, or at least as soon as they become eligible for colorectal cancer mass screening."

"So far, we know that diabetic patients should be screened earlier, but we do not know exactly how many years earlier," he acknowledged. To investigate this further, he said, his team will use the same approach they described June 3 in Gastroenterology, which yielded starting ages for colorectal cancer screening based on family history. (https://bit.ly/2MORKSq)

Dr. Fallah and colleagues studied data from more than 12 million individuals born after 1931 and their parents, including 559,375 diabetic patients and 162,226 CRC patients.

As reported May 21 in the American Journal of Gastroenterology, a type 2 diabetes diagnosis before age 50 was associated with a 1.9-fold increased risk of CRC before age 50 versus a 1.3-fold risk of CRC at/after age 50.

A diagnosis before age 50 in those with a family history of CRC was associated with a 6.9-fold risk of CRC before age 50 and a 1.9-fold risk of CRC at/after age 50.

Further, diabetic patients had a similar lifetime risk of CRC before age 50 (0.4%) as those with only a family history (0.5%) - double that of the general population (0.2%).

Study co-leader Dr. Elham Kharazmi, also of DKFZ, said by email: "Researchers with valid information on diabetic patients (especially by diabetes type), family history of colorectal cancer, and colorectal cancer outcome are encouraged to investigate the mechanism behind the association we found. This may eventually lead to prevention of early-onset colorectal cancer, which is globally on the rise among young adults."

Dr. Trilokesh Kidambi, director of the Colon Cancer Screening Program at City of Hope in Duarte, California, commented in an email to Reuters Health, "There is little doubt that these results are valid, as many of the patients I see with early-onset colon cancer or large, precancerous polyps do have a history of diabetes and other features of the metabolic syndrome."

"The primary limitation of this study is that it was unable to delineate the direct effect of diabetes on colon cancer risk and to separate this from other components of the metabolic syndrome such as obesity and high cholesterol, which are associated with and can contribute to risk of diabetes development," he said. "In other words, diabetes may represent the end product of several metabolic factors that increase a patient's risk of developing colon cancer, as well as other well-known medical problems."

"Additionally, it is not clear if duration (i.e., the number of years the patient's body has been exposed to higher blood sugar levels and changes in insulin levels) or severity (how well controlled the blood sugar has been) of diabetes influences the risk of colon cancer, which is critical to apply this type of data to the patients we see in practice," he said.

"I would use this data as yet another reason to motivate my diabetic patients to try and control their disease through diet, exercise and medications, and if a diabetic patient came to my office with concerning gastrointestinal symptoms, I would have a lower threshold to perform a colonoscopy," Dr. Kidambi concluded.

SOURCE: https://bit.ly/2B2NhJ4 American Journal of Gastroenterology, online May 21, 2020.

DIABETES AND COVID19

Patients with diabetes may be at extra risk for coronavirus disease (COVID-19) mortality, and doctors treating them need to keep up with the latest guidelines and expert advice.

Most health advisories about COVID-19 mention diabetes as one of the high-risk categories for the disease, likely because early data coming out of China, where the disease was first reported, indicated an elevated case-fatality rate for COVID-19 patients who also had diabetes.

In an article published in JAMA, Zunyou Wu, MD, and Jennifer M. McGoogan, PhD, summarized the findings from a February report on 44,672 confirmed cases of the disease from the Chinese Center for Disease Control and Prevention. The overall case-fatality rate (CFR) at that stage was 2.3% (1,023 deaths of the 44,672 confirmed cases). The data indicated that the CFR was elevated among COVID-19 patients with preexisting comorbid conditions, specifically, cardiovascular disease (CFR, 10.5%), diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6%), and cancer (5.6%).

The data also showed an age-related trend in the CFR, with patients aged 80 years or older having a CFR of 14.8% and those aged 70-79 years, a rate of 8.0%, while there were no fatal cases reported in patients aged 9 years or younger (JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648).

Those findings have been echoed by the U.S. Centers of Disease Control and Prevention. The American Diabetes Association and the American Association of Clinical Endocrinologists have in turn referenced the CDC in their COVID-19 guidance recommendations for patients with diabetes.

Guidelines were already in place for treatment of infections in patients with diabetes, and at this stage, it seems that the same guidelines would extend to those patients who are also diagnosed with COVID-19, which is caused by the novel coronavirus, SARS-CoV-2.

In general, patients with diabetes – especially those whose disease is not controlled, or not well controlled – can be more susceptible to more common infections, such as influenza and pneumonia, possibly because hyperglycemia can subdue immunity by disrupting function of the white blood cells.

Glucose control is key

An important factor in any form of infection control in patients with diabetes seems to be whether or not a patient's glucose levels are well controlled, according to comments from members of the editorial advisory board for Clinical Endocrinology News. Good glucose control, therefore, could be instrumental in reducing both the risk for and severity of infection.

Paul Jellinger, MD, of the Center for Diabetes & Endocrine Care, Hollywood, Fla., said that, over the years, he had not observed higher infection rates in general in patients with hemoglobin A_1c levels below 7, or even higher. However, "a bigger question for me, given the broad category of 'diabetes' listed as a risk for serious coronavirus complications by the CDC, has been: Just which individuals with diabetes are really at risk? Are patients with well-controlled diabetes at increased risk as much as those with significant hyperglycemia and uncontrolled diabetes? In my view, not likely.Alan Jay Cohen, MD, agreed with Dr. Jellinger. "Many patients have called the office in the last 10 days to ask if there are special precautions they should take because they are reading that they are in the high-risk group because they have diabetes. Many of them are in superb, or at least pretty good, control. I have not seen where they have had a higher incidence of infection than the general population, and I have not seen data with COVID-19 that specifically demonstrates that a person with diabetes in good control has an increased risk," he said.

"My recommendations to these patients have been the same as those given to the general population," added Dr. Cohen, medical director at Baptist Medical Group: The Endocrine Clinic, Memphis.

Herbert I. Rettinger, MD, also conceded that poorly controlled blood sugars and confounding illnesses, such as renal and cardiac conditions, are common in patients with long-standing diabetes, but "there is a huge population of patients with type 1 diabetes, and very few seem to be more susceptible to infection. Perhaps I am missing those with poor diet and glucose control."

Philip Levy, MD, picked up on that latter point, emphasizing that "endocrinologists take care of fewer patients with diabetes than do primary care physicians. Most patients with type 2 diabetes are not seen by us unless the PCP has problems [treating them]," so it could be that PCPs may see a higher number of patients who are at a greater risk for infections.

Ultimately, "good glucose control is very helpful in avoiding infections," said Dr. Levy, of the Banner University Medical Group Endocrinology & Diabetes, Phoenix.

For sick patients

Guidelines for patients at the Joslin Diabetes Center in Boston advise patients who are feeling sick to continue taking their diabetes medications, unless instructed otherwise by their providers, and to monitor their glucose more frequently because it can spike suddenly.

Patients with type 1 diabetes should check for ketones if their glucose passes 250 mg/dL, according to the guidelines, and patients should remain hydrated at all times and get plenty of rest.

"Sick-day guidelines definitely apply, but patients should be advised to get tested if they have any symptoms they are concerned about," said Dr. Rettinger, of the Endocrinology Medical Group of Orange County, Orange, Calif.

If patients with diabetes develop COVID-19, then home management may still be possible, according to Ritesh Gupta, MD, of Fortis C-DOC Hospital, New Delhi, and colleagues (Diabetes Metab Syndr. 2020 Mar 10;14[3]:211-2. doi: 10.1016/j.dsx.2020.03.002).

Dr. Rettinger agreed, noting that home management would be feasible as long as "everything is going well, that is, the patient is not experiencing respiratory problems or difficulties in controlling glucose levels. Consider patients with type 1 diabetes who have COVID-19 as you would a nursing home patient – ever vigilant."

Dr. Gupta and coauthors also recommended basic treatment measures such as maintaining hydration and managing symptoms with acetaminophen and steam inhalation, and home isolation for 14 days or until the symptoms resolve. However, the ADA warns in its guidelines that patients should "be aware that some constant glucose monitoring sensors (Dexcom G5, Medtronic Enlite, and Guardian) are impacted by acetaminophen (Tylenol), and that patients should check with finger sticks to ensure accuracy [if they are taking acetaminophen]."

In the event of hyperglycemia with fever in patients with type 1 diabetes, blood glucose and urinary ketones should be monitored often, the authors wrote, cautioning that "frequent changes in dosage and correctional bolus may be required to maintain normoglycemia." Dr Rettinger emphasized that "hyperglycemia, as always, is best treated with fluids and insulin and frequent checks of sugars to be sure the treatment regimen is successful."

In regard to diabetic drug regimens, patients with type 1 or 2 disease should continue on their current medications, advised Yehuda Handelsman, MD. "Some, especially those on insulin, may require more of it. And the patient should increase fluid intake to prevent fluid depletion. We do not reduce antihyperglycemic medication to preserve fluids.

"As for hypoglycemia, we always aim for less to no hypoglycemia," he continued. "Monitoring glucose and appropriate dosage is the way to go. In other words, do not reduce medications in sick patients who typically need more medication.Dr. Handelsman, medical director and principal investigator at Metabolic Institute of America, Tarzana, Calif., added that very sick patients who are hospitalized should be managed with insulin and that oral agents – particularly metformin and sodium-glucose transporter 2 inhibitors – should be stopped.

"Once the patient has recovered and stabilized, you can return to the prior regimen, and, even if the patient is still in hospital, noninsulin therapy can be reintroduced," he said.

"This is standard procedure in very sick patients, especially those in critical care. Metformin may raise lactic acid levels, and the SGLT2 inhibitors cause volume contraction, fat metabolism, and acidosis," he explained. "We also stop the glucagon-like peptide receptor–1 analogues, which can cause nausea and vomiting, and pioglitazone because it causes fluid overload.

"Only insulin can be used for acutely sick patients – those with sepsis, for example. The same would apply if they have severe breathing disorders, and definitely, if they are on a ventilator. This is also the time we stop aromatase inhibitor orals and we use insulin."

Preventive measures 

In the interest of maintaining good glucose control, patients also should monitor their glucose levels more frequently so that fluctuations can be detected early and quickly addressed with the appropriate medication adjustments, according to guidelines from the ADA and AACE. They should continue to follow a healthy diet that includes adequate protein and they should exercise regularly.

Patients should ensure that they have enough medication and testing supplies – for at least 14 days, and longer, if costs permit – in case they have to go into quarantine.

General preventive measures, such as frequent hand washing with soap and water, practicing good respiratory hygiene by sneezing or coughing into a facial tissue or bent elbow, also apply for reducing the risk of infection. Touching of the face should be avoided, as should nonessential travel and contact with infected individuals.

Patients with diabetes should always be current with their influenza and pneumonia shots.

Dr. Rettinger said that he always recommends the following preventative measures to his patients and he is using the current health crisis to reinforce them:

Possible therapies 

There are currently no drugs that have been approved specifically for the treatment of COVID-19, although a vaccine against the disease is currently under development.

Dr. Gupta and his colleagues noted in their article that there have been reports of the anecdotal use of antiviral drugs such as lopinavir, ritonavir, interferon-beta, the RNA polymerase inhibitor remdesivir, and chloroquine.

However, Dr. Handelsman said that, as far as he knows, none of these drugs has been shown to be beneficial for COVID-19. "Some [providers] have tried Tamiflu, but with no clear outcomes, and for severely sick patients, they tried medications for anti-HIV, hepatitis C, and malaria, but so far, there has been no breakthrough."

Dr. Cohen, Dr. Handelsman, Dr. Jellinger, Dr. Levy, and Dr. Rettinger are members of the editorial advisory board of Clinical Endocrinology News. Dr. Gupta and Dr. Wu, and their colleagues, reported no conflicts of interest.

This story originally appeared on MDedge.com.

NEW GUIDELINES FOR DIABETES CARE

Today I'm going to continue my overview of the 2020 American Diabetes Association (ADA) Standards of Medical Care in Diabetes.

Pharmacologic approaches to the management of glycemia in patients with type 2 diabetes (T2D) are discussed in section 9. This section is mistitled, because diabetologists in 2020 are now looking at two things: glycemic management, to be sure, but also cardiovascular risk reduction. As everyone now knows, our diabetes drugs do two things: They lower glucose levels and they lower the risk for cardiovascular events, heart failure, and progression to chronic kidney disease (CKD). So the world of cardiology and the world of diabetes are getting closer.

The cardiologists have changed their guidelines, essentially throwing out metformin and instead using GLP-1 receptor agonists and SGLT2 inhibitors as first-line therapy in patients who have other high-risk characteristics such as existing CKD, atherosclerotic cardiovascular disease (CVD), or heart failure. The ADA still sticks with metformin as the first-line therapy for patients with T2D, but they also say that if a patient has those high-risk characteristics (established CVD, CKD, or heart failure), don't bother looking at the A1c; go ahead and also start them on a GLP-1 receptor agonist or an SGLT2 inhibitor.

So it's not a stepwise treatment approach. If a patient fits those categories, you should start them on two therapies: metformin plus a drug to help their cardiovascular risk. That's a new concept. We don't come out and say to start with dual combination therapy, but in essence that's what we mean.

What if a patient has an A1c of 6.8% and has atherosclerotic CVD? Should I put them on metformin and at the same time add a GLP-1 receptor agonist? I might not give this person metformin, even though that's my opinion, not what the ADA is saying in these guidelines. You have to take these guidelines and then use common sense. I believe that if you have a patient with atherosclerotic CVD, CKD, or heart failure, or who is high risk, your goal is to get that person on a medication that prevents further damage and that lowers further risk for atherosclerotic CVD or the others. That is important.

A1c Still Matters

Now, glycemia does matter. Many of the patients you're going to be treating will have a higher A1c at diagnosis, and you will want to start them on metformin to lower their glucose levels. But again, in patients who are in that category with cardiovascular risk, you will need to add another agent right away, whereas you would not necessarily add a second agent in patients with glycemia alone.

Some cardiologists with whom I've spoken say, "We don't really care that much about glycemia. Why does A1c matter?" A1c matters a lot to a patient because a higher A1c is associated with an increased risk for microvascular complications. And I can tell you, my patients don't want to have retinopathy, nephropathy, or painful neuropathy. Most people I know, including physicians, don't want to have an A1c of 9% if they can have an A1c below 7%. So, glycemia matters. We need to use medications to improve those outcomes, but we also want to use medications that reduce cardiovascular riskWhen patients need a GLP-1 receptor agonist or an SGLT2 inhibitor, you need to ask yourself, Is this a patient in whom atherosclerotic cardiovascular disease predominates or is this a patient in whom heart failure and/or CKD predominate?

For patients who have had a known atherosclerotic CVD event or an indicator of high atherosclerotic CVD risk—they're 55 years or older with coronary, carotid, or lower-extremity artery stenosis of greater than 50%, or left ventricular hypertrophy—they should be preferentially started on a GLP-1 receptor agonist with proven CVD benefit on the label.

For patients in that heart failure/CKD category, particularly if they have a left ventricular ejection fraction < 45% or if they have CKD (defined as an estimated glomerular filtration rate [eGFR] of 30-60 mL/min/1.73 m² or a urine albumin-creatinine ratio > 30, and particularly those who have a urine albumin-creatinine ratio > 300), use an SGLT2 inhibitor, for which there is evidence of improvement in heart failure or CKD in the cardiovascular outcomes trials.

We know that there will be reasons why patients can't necessarily be on the drug you want them to be on. For example, patients who have a significantly reduced eGFR may not be able to use an SGLT2 inhibitor. In that case, you'd use a GLP-1 receptor agonist. You can also go through the algorithm and combine the two drugs. This is basically the framework we use to think about this, in terms of which agent to use and how to choose among them.

Cardiovascular Disease and Risk Management

Section 10 specifically discusses cardiovascular disease and risk management. For the second time in a row, this section has been endorsed by the American College of Cardiology. It is important to have all of us on the same page, particularly when we're teaching in primary care.

This section provides very detailed information on the cardiovascular outcomes trials and includes tables and summaries of the data. Hopefully this will enable everyone to understand the data used to support some of the newer recommendations.

Caring for Older Adults

Section 12 discusses diabetes treatment in older adults. It talks about the importance of assessing for cognitive decline and impairment. Sometimes it's hard to know at what level a patient can function, particularly if they're living by themselves and having to make complicated decisions about diabetes management.

The section includes a discussion about costs—the cost of insulin and the cost of these newer agents, and how we determine what's best for a patient in the context of the patient's life and finances. For the first time, this section also talks about older adults with type 1 diabetes and their special challenges.

Children and Adolescents

The section on children and adolescents discusses individualizing targets, managing cardiovascular risk in children and adolescents, and retinopathy screening, which may be less often than previously recommended. If you're taking care of pediatric patients, I suggest looking at this section

Diabetes in Pregnancy

Section 14, on managing diabetes in pregnant women, emphasizes the need for preconception care. This isn't always possible because we know that not all pregnancies are planned. But certainly, for any woman who has the potential for getting pregnant, it's important to discuss this.

The Standards talk about the use of continuous glucose monitoring during pregnancy. This is an area with good data, but we need more. I personally use continuous glucose monitoring in my pregnant patients and have found that these women do quite well. Again, that is an area where a lot more research is needed. The standards also cover postpartum care and managing diabetes in that challenging setting.

Those are the major changes in the ADA Standards of Care. I encourage everyone to read more about these changes. We've made living updates to the Standards throughout the year and intend to continue throughout the next year.

Anne L. Peters, MD, is a professor of medicine at the University of Southern California (USC) Keck School of Medicine and director of the USC clinical diabetes programs. She has published more than 200 articles, reviews, and abstracts and three books on diabetes, and has been an investigator for more than 40 research studies. She has spoken internationally at over 400 programs and serves on many committees of several professional organizations.