Let’s Get Real: Where’s the Evidence?

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Column Editor: Walter J. Pories, MD, FACS

Dr. Pories is professor of surgery at the Brody School of Medicine, East Carolina University, Greenville, North Carolina. Dr. Chapman is professor of surgery at the Brody School of Medicine, East Carolina University, Greenville, North Carolina.

This month: Where’s the Evidence?

by Walter J. Pories, MD, FACS; and G. Lynis Dohm, PhD
Dr. Dohm is Professor of Physiology at the Brody School of Medicine, East Carolina University, Greenville, North Carolina.

Funding: No funding was provided in the preparation of this manuscript.
Financial disclosures: Drs. Pories and Dohm report no conflicts of interest relevant to the content of this column.

Bariatric Times. 2013;10(10):8–9.

Our colleagues were right in demanding evidence. The claims that an intestinal operation could reverse type 2 diabetes (T2DM) were, frankly, not easy to believe. Everyone knew that T2DM was a progressive and cruel disease. Diet and exercise might help in early and mild cases, but the long-term outcomes were the predictable amputations, blindness, renal failure, and early mortality. The claim that these immutable catastrophes could be avoided with a simple operation on the gut is still hard to believe.

Actually, the remarkable documentation in the first patient  three decades ago that the gastric bypass produced rapid and full remission of T2DM was already suprising but strong proof. A rock doesn’t fall upwards. No other therapy had ever produced such results.

But our colleagues were correct in requiring proof and we responded. Four prospective, randomized, clinical trials[1–4] have now reported dramatic remissions of T2DM following metabolic surgery. In addition, other studies documented reductions in mortality,[5] lessening of the associated comorbidities,6 and even sharp drops in the prevalence of solid cancers within five years.[7] In contrast, there is remarkably little proof that the medical therapies work. Despite a broad variety of new drugs and approaches, T2DM continues to be the primary cause of blindness, amputation, and renal failure as well as a major factor in myocardial infarctions and strokes.[8] The evidence for the need of insulin is indisputable with T1DM, but we cannot find a single prospective, clinical trial that tests two regimens: one with insulin versus another without the hormone at equal stages of T2DM. If any of our readers know of such a study, (i.e., insulin vs. no insulin, in man), please send it to us ([email protected]).

It is curious that both forms of diabetes, T1DM and T2DM, are treated with insulin when they are totally different entities. Patients with T1DM are unable to produce enough insulin, while those with T2DM are hyperinsulinemic with insulin levels that can rise to nine times the normal rate in advanced disease (i.e., cases with fasting blood glucose levels >140mg/dL).[9] Except for metformin, the most effective anti-diabetic drug, which decreases hyperglycemia primarily by suppressing hepatic gluconeogenesis, all of the other medications focus on increasing insulin action. Insulin sensitizers; insulin secretagogues, such as the sulfonylureas; alpha-glucosidase inhibitors, and peptide analogues, including insulin-mimetics and amylin analogues, all increase insulin. When these drugs fail, the next step is direct administration of insulin. In essence, these hyperinsulinemic patients are treated with insulin and/or agents that increase the effectiveness of that hormone—an approach that could be compared to treating hyperthyroidism with thyroxine.

The traditional response to this quandary is that T2DM patients develop high levels of insulin resistance and that, accordingly, the drug regimens and the administration of insulin aim to overcome that resistance. This view is challenged by metabolic surgery. Within days after metabolic procedures, when the T2DM clears, the insulin levels return to normal while measures of insulin resistance still may not be back to normal after three months.[10] Based on these data, it is unlikely that the hyperinsulinemia is due to insulin resistance. It is far more likely that the insulin resistance is a self-protective response of the body’s cells, primarily muscle, to too much fuel.

T2DM is not the only disease characterized by high insulin levels. Hyperinsulinemia has also been documented in hypertension, dyslipidemias, nonalcoholic steatohepatitis (NASH), gastroesophageal reflux disease (GERD), polycystic ovary syndrome (PCOS), and severe obesity, all of which resolve following metabolic surgery in parallel to the restoration of normal insulin levels.

Given these observations, the use of insulin and drugs to increase insulin secretion and decrease insulin resistance for T2DM becomes problematic. Is it possible that our current medical measures are actually harming patients? A paper by Currie[11] suggests that might be true. In a retrospective comparison of outcomes between two groups of patients advanced to multioral therapy or multioral therapy plus insulin after failure of metformin, Currie’s data documented that those given insulin had three times higher mortality rates than those who did not get the insulin. Unfortunately, the study is sharply limited because there was no assurance the two groups were equal. A prospective study is badly needed, but, even so, the results are disconcerting.

A recent article by Owens,[12] who argues for earlier initiation of insulin therapy, provides a solid review of the arguments for insulin therapy in T2DM, including the the United Kingdom Prospective Diabetes Study (UKPDS), but a close reading of the publication documents the lack of a robust clinical test insulin therapy.

This is not a call to stop the use of insulin or insulin-enhancing medications for the treatment of T2DM. It is instead intended as a stimulus for a prospective trial of insulin with objective measures of outcome including the complications of T2DM, not just measures of risk.

“Do no harm” is a central credo of medical practice. It’s time that our medical colleagues also produce evidence that the medical treatment, while not as effective as surgical intervention, also does no harm.

References
1.     Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316–323.
2.    Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–1576.
3.    Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577–1585.
4.    Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309(21):2240–2249.
5.    MacDonald KG Jr, Long SD, Swanson MS, et al. The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus. J Gastrointest Surg. 1997;1(3):213–220.
6.    Zhang N, Maffei A, Cerabona T, et al. Reduction in obesity-related comorbidities: is gastric bypass better than sleeve gastrectomy? Surg Endosc. 2013;27(4):1273–1280.
7.    Christou NV, Lieberman M, Sampalis F, Sampalis JS. Bariatric surgery reduces cancer risk in morbidly obese patients. Surg Obes Relat Dis. 2008;4(6):691–695.
8.    American Diabetes Association. http://www.diabetes.org/diabetes-basics/diabetes-statistics/?loc=DropDownDB-stats. Accessed October 1, 2013.
9.    Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y follow-up. Am J Clin Nutr. 1992;55(2 Suppl):582S–585S
10.    Reed MA, Pories WJ, Chapman W, et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab. 2011;96(8):2525–2531.
11.    Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010;375(9713):481–489.
12.    Owens DR.Clinical evidence for the earlier initiation of insulin therapy in type 2 diabetes. Diabetes Technol Ther. 2013;15(9):776–785.

Category: Let's Get Real, Past Articles