The Best Approach for Diabetes Control—Treat for Glucose or Obesity?

Two leading experts debate the evidence and explore the benefits of initiating a blood glucose-directed or obesity-centric management treatment plan, pointing out the strengths in choosing one disease approach over the other.

With John L. Leahy, MD, and W. Timothy Garvey, MD

Waiting rooms are filled with the more than 30 million adults who have diabetes,1 as well as patients coming for a myriad of reasons of whom 40% will present with obesity.2 Of course, the two conditions have a tendency to overlap, introducing a persistent challenge to you, their clinicians.

If you have diabetes, which should you worry more about--your blood sugar or your weight?

Which condition should be tackled first as the optimal therapeutic approach to these oft concomitant conditions—Is it better to take a glucose-centric approach in a person with obesity or to establish an adiposity-centered management plan to address the type 2 diabetes? That was the topic of a spirited debate held during ObesityWeek 2019, in Las Vegas, Nevada, between two of leading experts in diabetes and weight management.

W. Timothy Garvey, MD, Butterworth Professor of Medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham who advocated for an obesity-centered treatment, while John (Jack) L. Leahy, MD, professor of medicine and co-chief of endocrinology, diabetes and metabolism at the University of Vermont College of Medicine in Burlington, argued in favor of leading with a diabetes-first approach. 3

Each clinician previewed their arguments in pre-meeting interviews with EndocrineWeb.  Both offered a rationale for taking their stated position and offered highlights of the evidence from their planned presentations in support of their respective stances.

Given the Complications of Diabetes, Focus on Blood Glucose Management

"I think it's pretty clear that in an obese patient who has diabetes, you are dealing with a health issue that should take precedence over the body weight," Dr. Leahy said. While acknowledging that there is a strong connection between the two, he added:  if the obesity had been treated earlier, the diabetes might have been avoided so it is now necessary to help the patient achieve glucose control.

"Obesity medicine people will say 'Fix their weight and that will fix their diabetes.' I'm not so sure. My argument [to focus on glucose first] stems from epidemiology and that includes what we know about the importance of diabetes control," he said. Another crucial reason: we have a great array of antidiabetes medications that will address the consequences of type 2 diabetes as much as support better blood glucose control. "We know a lot about these drugs which come with very few contraindications."

Perhaps the turning point in effective diabetes management occurred in 2008, when the Food and Drug Administration mandated that all new diabetes drugs must undergo formal cardiovascular disease (CVD) outcome studies.4 In the decade-plus since, we have benefited from a robust accumulation of data from these trials. "We have an incredible amount of information about the safety and efficacy of the newer diabetes drugs, which doesn't really exist in the obesity world. I don't think there is the same kind of demonstrated evidence about the power of obesity treatments out there."

Yet, both approaches—focusing primary on blood glucose or obesity—clearly have value, he said. "But if you have to choose one or the other, if you really want to fix the patient's health, you need to focus on getting their blood sugar under control." This choice is made a bit easier in that, fortunately, some of the same drugs that work to improve blood glucose also support weight loss.

Focus on What Arises First—Obesity as the Driver of Type 2 Diabetes

"Obesity and diabetes are integrally linked," Dr. Garvey said. "When you have a person with overweight or obesity and they have developed diabetes, I'm looking at diabetes as a complication of the obesity."

Thus, the aim ought to be to prevent or treat all of the obesity-related complications; no diabetes drug is going to do that, he said. "While you can put the diabetes into remission, you don't cure it. But first the patient must be able to achieve some weight loss, and the more weight loss the better in terms of lowering hemoglobin A1c (HbA2c)."

We also know that in successfully treating the obesity, the result will be to achieve a cascade of other health improvements, he said, beginning with better glycemic control but also to improve sleep apnea, reduce pain such as is caused by arthritis, and promote better physical functioning and overall quality of life. Also, conditions such as non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) will improve. "Weight loss of just five to 10% will get the fat out of their livers," he said.

And like some antidiabetes medications, weight loss confers renal protection, he says; without the added concerns about side effects. There are also proven benefits demonstrated by bariatric surgery, not the least of which has been to put T2D into remission, Dr. Garvey said.

A Glucose First Treatment Approach Is Supported by Substantial Evidence

In building his case, Dr. Leahy relied on a strong, evidenced-based presentation of ''hard clinical outcomes" that may be achieved by taking a diabetes-focused management in the patient. He argued that proven positive health effects must trump surrogate measures, such the benefits of achieving changes in HbA1c, weight, CVD risk factors, and those based on subgroup analyses.

In patients with type 2 diabetes, attaining an optimal HbA1c is the prime treatment goal with diabetes, he said, as this is the best way to reduce the life-threatening complications known to arise in most anyone with long-term diabetes. In order to mitigate the risk factors such as acute myocardial infarction  in those with type 2 diabetes, addressing glycated hemoglobin is at the top of the list.5

First, in a recent cohort study of 271,174 patients with type 2 diabetes (compared to 1.3 million matched controls) who were followed for 5.7 years to assess for five risk factors, the investigators found as that a glycated hemoglobin level that fell outside the target range was the strongest predictor of acute myocardial infarction and stroke.5

Add to that the striking evidence for CVD and renal protection achieved with the newer type 2 diabetes pharmaceuticals—this has been ground-breaking, Dr. Leahy said, citing 20 cardiovascular disease outcomes trials that have been reported over the course of the past decade.6  Furthermore, there are other convincing studies, including one very recently published, that demonstrated renoprotection from the newer antidiabetes medications, which conferred a low rate of serious adverse events along with good safety and efficacy in older adults.7,8

Another strong argument for a glucose-centric approach, he said, is that achieving relevant clinical outcomes specific to diabetes are less good with obesity-centric therapies. He cited the Look AHEAD findings in which intensive lifestyle intervention led to meaningful weight loss but did not reduce the rate of cardiovascular events in overweight or obese adults with T2D.9

As for the pushback about anti-hyperglycemic agents causing weight gain, Dr. Leahy pointed out that these drugs have not been associated with adverse clinical outcomes.10  A case in point—When a comparison of individuals treated with combination therapy (insulin degludec and liraglutide) against each medication alone was made, weight loss ranged from 0.5 kg to 3.0 kg but the final HbA1c declined to 6.4%-7.0%.10

Dr. Leahy's final argument: Hyperglycemia-based care is easier to deliver and follow than obesity-centric care in the real world setting. We need to manage patients where they are, and weight control is much harder to achieve than glucose control.

Obesity Has the Potential to Reverse Type 2 Diabetes, Delivering Dual Benefits

"The more weight loss achieved, the better, in terms of lowering HbA1c,” said Dr. Garvey, citing the results of the DIRECT trial that assessed outcomes achieved with intensive weight management.11 At the end of the first year, 40% of the participants achieved remission of their diabetes. “In fact, of those who lost 15% of their starting weight, 86% were in disease remission at 12 months," he said. That’s an ideal two-for-one benefit for these individuals.

In looking more closely at the findings reported out of the DIRECT study, 11 the intervention group lost an average of 10 kilograms over the 12 months, compared to 1 kg for those in the control group. Also, levels of HbA1c declined by 0.9% in the treated group but rose slightly (0.1%) in the individuals receiving the sham therapy.

Dr. Garvey also mentioned that at the end of the study, there was a decline in the number of antihypertensive medications of 0.06 needed by those in the intervention group whereas the need for blood pressure medications increased 0.1) among those in the control group. A measure of growing significance—change in quality of life scores—rose 7.2 points among patients receiving the intensive weight management intervention while this score declined by 2.9 points in those in the control group.11

As if to counter the lack of clinical robustness given to weight loss medications, Dr. Garvey confirmed that there are several weight loss-promoting drugs have all been tested for efficacy and safety, specifically mentioning orlistat, phentermine/topiramate ER, lorcaserin, naltrexone SR/bupropion SR, and liraglutide/high-dose (3 mg a day).

Any weight loss achieved by patients taking these medications has been accompanied by numerous positive health benefits—besides putting diabetes into remission and lowering HbA1c. Dr. Garvey pointed to results of the Sleep AHEAD study, in which those who lost 10% of their starting weight had a marked decrease in sleep apnea.12

In individuals who achieved a weight loss of 5 to 10%, they experienced a demonstrated improvement in liver function (ie, NASH and NAFLD),13 he said; in particular, Promrat et al reported that percent weight reduction correlated significantly with improvements in the NASH histological activity score (NAS).13

When weight loss was realized in patients with T2D, these individuals also reported a reduction in pain scores and disability while improving overall physical function,14  Dr. Garvey said, citing the Look AHEAD findings. So weight loss may reduce the symptoms of peripheral neuropathy, based on results of the Look AHEAD trial. These results were boosted by a significant decrease in questionnaire-based diabetic peripheral neuropathy, which was associated with the magnitude of weight loss achieved.15

As the data keeps building on the benefits of bariatric surgery, this approach was found superior to pharmacotherapy alone in individuals with T2D—as reported in the STAMPEDE trial,16 with medical therapy plus bariatric surgery achieving much better glycemic control in a significantly greater number of patients than with only medical therapy.

While the diabetes drugs have research supporting their effects on renoprotection, intensive lifestyle changes leading to a net weight loss are also beneficial to kidney function,17 as the Look AHEAD research group reported.

Dr. Garvey reasons that the bottom line remains—the diabetes is a complication of obesity, so efforts to address patient health should begin with weight management.

Dr. Leahy reports honoraria for advisory boards of Merck and Novo-Nordisk  Dr. Garvey is sm advisor to Novo-Nordisk, American Medical Group Association, BOYDSense, Gilead, Amgen, Boehringer-Ingelheim, Sanofi, and the Milken institute.

 

Continue Reading:
Hemoglobin A1c Not Reliable in Diagnosing Type 2 Diabetes
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