(A Short History of Diabetes Research)
It is widely accepted that corporate interests have undue influence in political affairs.
Corporate lobbyists seem to have access to decision makers where ordinary people are shut out.
Politicians routinely move from politics to well paid jobs in the industries they were responsible for in Government.
Political parties receive large, often secret donations from corporate interests – presumably there is a quid pro quo in the way policy is framed.
Vested interests are a powerful driver in the development of policy.
Has the same thing happened in Health?
Health is a large industry with more than $100B spent per year by Government and private payors.
Many senior clinicians receive benefits in the form of research grants or direct funding from Pharmaceutical companies and other interests involved in Health.
There is at least a risk that these payments have and are distorting medical evidence in favour of the treatments being studied.
The History of Research in Diabetes
To illustrate this issue – let us study the history of the treatment in Type 2 Diabetes
With the discovery of Insulin it became possible to treat Type 1 Diabetes. Sufferers of this condition had a grim prognosis before this with a life expectancy of only a few years.
Type 1 Diabetes is characterized by Insulin deficiency. Insulin is a hormone produced by the pancreas which keeps blood sugar within a tight range. Blood sugar is essential to metabolism, particularly for the brain.
Without insulin the blood sugar becomes much higher than normal and the patient may develop a life threatening condition called Diabetic Ketoacidosis.
The DCCT study showed that good control of blood sugar with regular insulin injections extended lifespan to near normal.
Poor control was associated with microvascular (small blood vessel) disease causing blindness and kidney failure, and macrovascular (large blood vessel) disease causing heart attack and stroke.
Type 2 Diabetes (T2DM) is similar to Type 1 in that the patient has high blood sugar and is subject to many of the same complications as Type 1 Diabetes sufferers, ie renal failure, blindness, heart attack and stroke.
However here the similarity ends. Type 2 Diabetes is characterized not by lack of insulin, but high levels of insulin and insulin resistance by fat cells. It is strongly associated with Obesity and the Metabolic Syndrome –
a combination of obesity, hypertension and high Cholesterol.
The findings of the DCCT study in Type 1 Diabetics have been extrapolated to Type 2 Diabetes – ie that tight sugar control prevents death and disability from the complications of Diabetes.
Is this extrapolation valid?
HBA1C as a measure of Blood Glucose
Another piece in this puzzle is the development of the Glycated Haemaglobin (HBA1C) test as a measure of average blood sugar.
Blood sugar can be measured directly but it fluctuates constantly due to fasting, eating and the administration of insulin or other treatments.
HBA1C is a measure of the average blood sugar over the last 6 weeks or so.
It has become a proxy for the effectiveness of Diabetes treatment, so much so that it is now used by Health administrators as a Key Performance Indicator (KPI) to measure the effectiveness of the Health service.
Research in Type 2 Diabetes
In 1962, a US Senator was surprised to discover that the tablets his daughter was taking for Diabetes had no systematic research performed to show whether they had any benefit.
He initiated the first Randomized Controlled Trial (RCT) to study the effectiveness of the treatment (UGDP). This was a revolution at the time in Medical Research – patients are allocated randomly to either treatment or placebo groups. Neither the treating clinician nor the patient know which treatment is being administered. This was a large, carefully conducted trial which ran for some 8 years before it became clear that the treatments were actually harmful. The trial was stopped and shares in the company making the drug plummeted. The researchers endured a storm of criticism and legal action which was successfully defended, but lasted some 10 years.
Understandably, this had a chilling effect on research for a time, but in 1975 a large trial was set up in UK to attempt to answer the question whether tight Diabetic control in Type 2 Diabetes improved outcomes. (UKPDS).
This was a large trial which ran for 10 years. It showed an improvement in mortality in patients receiving treatment for Hypertension. However it did not show a significant improvement in mortality with intensive glucose lowering treatment , though there were improvements in Diabetes related complications. A small subgroup showed significant improvement in mortality – obese patients on Metformin (which causes weight loss).
Several other large trials were conducted (ACCORD, ADVANCE) which also failed to show significant improvement in mortality with intensive Diabetes treatment. In fact the ACCORD trial found increased mortality with tight glucose control.
Several followup studies were conducted some years after the end of these trials. The UKPDS participants appeared to show significant improvement in those receiving intensive treatment, but these findings were not replicated in the other trials.
In spite of these apparently equivocal findings, current guidelines advocate tight control in type 2 Diabetes. HBA1C is regarded as an endpoint in treatment with the accepted target being less than 7.0%
These seminal studies were largely Government funded. However Government has essentially withdrawn from Health Research since and most drug research is now funded by Pharmaceutical companies.
For some 20 or more years after these studies, mortality was effectively ignored as an endpoint and HBA1C became a proxy for outcomes. If a drug lowered HBA1C it was regarded as effective.
This produced a whole series of drug classes – some have since been shown to be harmful such as Rosiglitazone and have disappeared.
In recent years new classes such as the Glutides are showing cardiovascular and mortality benefit and these endpoints are again receiving more attention.
Is Obesity the real issue?
The developed world is getting fatter.
In the last generation average weight has increased by some 7kg which is a dramatic increase.
There has also been a dramatic increase in the incidence of Type 2 Diabetes which is strongly associated with Obesity. It now affects 3-5% of the population with a further probable 3% undiagnosed
Obesity shortens lifespan by up to 7 years. But significant weight loss in the obese can return lifespan to near normal. Moreover, a 15kg weight loss completely reverses Diabetes in those who achieve it (DIRECT study)
Yet weight loss and obesity have achieved little attention in the treatment of Diabetes – the focus has been on medication and HBA1C. The standard view is that once established, Diabetes is irreversible and relentless – the best that can be done is to prevent complications by keeping HBA1C low. Again standard recommendations for treatment appear to be at odds with evidence. Only those drugs that help with weight loss (Metformin, Glutides) are now being shown to improve Cardiovascular Mortality and death rates
What about Insulin?
Insulin is still widely recommended as a treatment to lower HBA1C in T2DM when other measures fail.
It promotes the movement of Glucose from the blood into fat cells and its storage as fat. As such it is an anabolic hormone and promotes weight gain while lowering blood Glucose and HBA1C.
But does it make any difference to outcomes?
The original UGDP study recruited patients for treatment with Insulin. The insulin arms were of the study were continued after the oral hypoglycaemics were stopped – there was no improvement in CV outcomes or all cause deaths
A Google search with the question “Does Insulin improve outcomes in Type 2 Diabetes?” yielded a number of results – the top 3 are quoted below
“Mortality and Other Important Diabetes-Related Outcomes With Insulin vs Other Antihyperglycemic Therapies in Type 2 Diabetes”
Craig J. Currie,corresponding author Chris D. Poole, Marc Evans, John R. Peters, and Christopher Ll. Morgan
J Clin Endocrinol Metab. 2013 Feb; 98(2): 668–677.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612791/
The authors conclude that:
“In people with T2DM, exogenous insulin therapy was associated with an increased risk of diabetes-related complications, cancer, and all-cause mortality.”
“Insulin: Potential Negative Consequences of Early Routine Use in Patients With Type 2 Diabetes”
Harold E. Lebovitz, MD, FACE⇓
↵Corresponding author: Harold E. Lebovitz, hlebovitz1@hotmail.com.
Diabetes Care 2011 May; 34(Supplement 2): S225-S230.
https://doi.org/10.2337/dc11-s225
CONCLUSIONS
“Starting insulin therapy early in the course of chronic treatment of patients with type 2 diabetes would imply that there are unique benefits to insulin treatment. As addressed above, there is little evidence to support such a view. Insulin treatment is neither durable in maintaining glycemic control nor is unique in preserving β-cells. Better clinical outcomes than those that occur with other antihyperglycemic regimens have not been shown. The downside of insulin therapy is the need to increase the dose and the regimen complexity with time, the increase in severe hypoglycemia, and the potential increase in mortality as well as the potential increased risk for specific cancers.”
“Insulin Therapy in People With Type 2 Diabetes: Opportunities and Challenges?”
Philip Home1, Matthew Riddle2, William T. Cefalu3⇑, Clifford J. Bailey4, Reinhard G. Bretzel5, Stefano del Prato6, Derek Leroith7,8, Guntram Schernthaner9, Luc van Gaal10 and Itamar Raz11
+Author Affiliations
Corresponding author: William T. Cefalu, william.cefalu@pbrc.edu.
Diabetes Care 2014 Jun; 37(6): 1499-1508.
https://doi.org/10.2337/dc13-2743
This article is less negative than the other two with regard to insulin but identifies subgroups where it is not beneficial
So it appears that research and guidelines/recommendations are in conflict in many cases.
Why is this so?
I would argue that vested interests are corrupting our medical evidence base and have been doing so for many years. Much of the evidence we rely on for our day to day clinical practice is tainted.
We have ignored therapeutic approaches which would improve outcomes (ie weight loss) in favour of medication regimes which target a proxy measure (HBA1C). Moreover treatment which at best has no benefit (Insulin) is still widely recommended.
We need to acknowledge this explicitly and start to consider ways of reversing this trend.
References
Summary of the DCCT/EDIC study
https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/GetPdf.cgi?id=phd000390
UDGP Study
Meinert CL, et al. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes. 1970;19(suppl):789-830.
UKPDS
UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352:837-853.
ADVANCE study
Patel A, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24): 2560— 2572.
ACCORD study
Gerstein HC, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008. 358(24):2545-2559.
The DiRECT Trial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754868/
TjilpiDoc 