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Diabetes: Past and Present

Introduction

Chances are you know someone with diabetes. Perhaps you live with it yourself. Diabetes is an epidemic, affecting nearly 350 million people worldwide—more than the combined populations of Russia, Mexico, and Germany. In the coming decades, the numbers are expected to climb. Yet despite our growing understanding of how to treat the condition, many people do not receive the support they need.

Source: Novo Nordisk.

Over time, diabetes can damage the body’s organ systems. Globally, over half of people with this chronic condition will die of a heart attack or stroke. People with diabetes also experience higher rates of blindness, kidney failure, and painful nerve damage. These symptoms are especially likely to occur in those with advanced diabetes, which affects about a quarter of those living with the condition. As a society, we can do more to ensure that people don’t just live with diabetes, but that they live well.

A History of Diabetes Research and Treatment

Our knowledge of diabetes is thought to extend all the way back to ancient Egypt, when a disorder of frequent urination was described in the Ebers Papyrus of 1550 BC. The word “diabetes,” comes from the Greek, meaning to flow through a system, and first came into medical use in the second century AD. In medieval times, the disease was detected by urine tests and was considered a condition of the kidneys.

It wasn’t until the late 18th century that researchers made the connection between diabetes and the amount of sugar circulating in the blood. Despite this important revelation, there were no good treatments. In fact, the ensuing decades became known as “the starvation era” because people discovered that starvation therapy—which allowed 400 calories per day—eliminated glucose from the urine and increased life expectancy of young diabetic children by one and a half years. But the disease remained, in essence, a death sentence.

The year 1921 was a watershed year in diabetes research and treatment. A pair of Canadians extracted material from the pancreas which they called “isletin,” later known as “insulin.” Insulin is a hormone that allows the body to use sugar (glucose) from foods for energy or for storage. Insulin helps sugar exit the blood and enter the body’s cells.

When the researchers injected insulin into dogs without a pancreas, the dogs lived longer. Bovine insulin was soon given to a human patient: a 14-year-old boy who had been admitted to Toronto General Hospital listless and underweight. After the injection, the boy’s condition quickly improved. Ever since, insulin has been a mainstay of diabetes treatment.

The following decades advanced our understanding of insulin’s precise role in diabetes. In 1979, the terms type 1 and type 2 diabetes were officially adopted at a universal consensus meeting. In type 1 diabetes, the body’s immune system triggers a process that destroys beta cells, the cells that secrete insulin. People with type 1 diabetes either make no insulin at all or they make a very small amount. The condition progresses rapidly. Patients receive insulin therapy at the time of diagnosis in order to avoid serious complications.

The majority of people living with diabetes have type 2. During the early stages of type 2 diabetes, the beta cells initially produce insulin, but the body is not able to use it efficiently. In response, the beta cells produce extra insulin to meet the body’s needs. Over time (typically about a decade after diagnosis), the beta cells become worn down and the body’s ability to produce insulin decreases significantly. Blood sugar levels rise, increasing the risk of complications. At this point, insulin therapy is needed.

Insulin’s discovery allowed people to live longer with diabetes, but many continued to experience long-term complications. Without tools for monitoring daily blood sugar levels, physicians could not determine how much insulin a given patient needed. Eventually, glucose meters became portable, precise, and accurate, allowing people to self-monitor their blood glucose levels between clinic visits.

Risk reduction by lowering HbA1C by one percentage point
Source: UKPDS, Stratton et al. BMJ 2000; vol. 321:405–12; Holman et al. NEJM 2008; 359:1577-1589

Following the improvements in glucometers, the Diabetes Control and Complications Trial Research Group published a seminal paper in 1993 in the New England Journal of Medicine [1]. The paper demonstrated that intensive insulin therapy—designed to keep glucose levels as close to normal as possible—delays the onset and slows the progression of complications in people with type 1 diabetes. Five years later, in 1998, the UK Prospective Diabetes Study Group published an equally significant paper examining type 2 diabetes [2]. Published in the Lancet, the paper reported that intensive blood glucose management substantially decreases the risk of complications in people with type 2 diabetes.

We have come a long way. Yet despite the success of intensive insulin therapy in research studies, in day-to-day clinical reality, most patients who use insulin still have high blood sugar levels (hyperglycemia). Currently, a variety of diabetes interventions are in use, with varying results.

Current Interventions

Lifestyle Modification: The American Diabetes Association (ADA) recommends adopting a healthy diet and physical exercise as the first line of therapy for type 2 diabetes. Maintaining a stable lower weight is usually helpful, and exercise improves the body’s ability to use insulin. Tobacco cessation is also beneficial; smokers with diabetes experience higher rates of serious complications such as heart disease. These lifestyle modifications can help slow the progression of type 2 diabetes in the decade following diagnosis. However, many people find that their diabetes changes dramatically in the second decade, and lifestyle modifications are no longer sufficient for maintaining healthy blood glucose levels.

Patient Education: The ADA recommends that patient education be provided at the time of diagnosis and as needed thereafter. Patient education programs offer information about nutrition, medication, and complications. They can help patients understand the significance of hemoglobin A1C (HbA1c) levels, which reveal average blood sugar levels over a period of months. The ADA recommends an HbA1c level less than 7%.

In the United Kingdom and Ireland, a collaborative called Dose Adjustment For Normal Eating (DAFNE) provides individuals with type 1 diabetes roughly forty hours of training while they learn to adjust mealtime insulin levels. In 2002, a randomized controlled trial examined the effectiveness of DAFNE. The initial results were promising: HbA1c levels had fallen 1.0% at the end of six months, but the percentage was just 0.5% at 12 months. Four years out of the DAFNE trial, participants’ HbA1c levels were only 0.2% below baseline [3].

The American Association of Diabetes Educators (AADE) recently conducted a systematic review of the literature to assess the effectiveness of a variety of patient education interventions [4]. Examining randomized controlled trials, they found that patient education resulted in a reduction in HbA1c levels by about 0.56%. The most dramatic difference occurred in those individuals starting with the highest HbA1c at baseline.

Oral Antidiabetic Medications: Several classes of medication are available to treat the early stages of type 2 diabetes. The ADA recommends the drug metformin as a first-line medication for treating diabetes. Metformin lowers the liver’s production of glucose and improves its ability to use insulin. Used alone, metformin reduces HbA1c levels by 1-1.5% [5]. It can be combined with other classes of oral medication, such as DPP-4 inhibitors. This class of medication works by blocking the action of DPP-4, an enzyme that destroys the hormone incretin. After meals, incretin helps the body produce more insulin while reducing the amount of glucose produced by the liver. DPP-4 inhibitors reduce HbA1c by 0.5-1% [5].

SGLT-2 inhibitors are another class of oral medication. They work by preventing the kidneys from reabsorbing glucose back into the blood. Instead, excess glucose is eliminated from the body via urine. SGLT-2 inhibitors reduce HbA1c by 0.5-1% [5].

GLP-1 agonists/other injectables: Patients who do not achieve optimal HbA1c levels with oral medications may be prescribed injectable medications that function as hormones. These include GLP-1 agonists, which mimic the hormone incretin. GLP-1 agonists reduce HbA1c by 1.0-1.5% [5]. Amylin agonists resemble the hormone amylin, which slows digestion, which in turn slows the release of glucose into the blood. Amylin agonists decrease HbA1c levels by 0.5-1.0% [5].

diabetes interventions success rates
Source: PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. June 2015.

The U.S. Department of Health & Human Services reports that on average, many of the above medications reduce HbA1c levels by 1%. Two drug combination therapies reduce HbA1c levels an additional 1% when compared with single-drug therapies [6].

People are frequently able to manage the first decade of their diabetes with metformin or a combination of oral antidiabetics. In the second decade, however, these medications become less effective as diabetes advances. At this point, insulin therapy becomes necessary.

Insulin: Diabetes is an insulin deficiency disease, and insulin therapy can be very effective in improving HbA1c levels. Unlike other medications, insulin dosage can be progressively increased if a patient’s HbA1c levels remain high. In fact, when used in adequate doses, insulin can decrease any level of elevated HbA1c to (or close to) the target goal [7].

Most patients have achieved optimal results in clinical trials, with physicians monitoring and adjusting insulin doses frequently. Outside of these trials, however, this high degree of physician oversight is not available. Lack of professional support is a key barrier to improving the effectiveness of insulin therapy.

A second barrier is the fear of hypoglycemia (low blood sugar levels). If a patient receives too much insulin, blood sugar levels will drop, sometimes quite suddenly. Hypoglycemia is usually mild and can be treated by eating or drinking a small amount of glucose-rich food, but left untreated, hypoglycemia gets worse and can lead to serious side effects.

The complex nature of both diabetes and insulin requirements provides a third barrier to initiation of insulin therapy, especially in a primary care setting. During the first few years of insulin therapy, dosage increases steadily, and many patients need to transition from a simple regimen of once-daily (basal) injections, to a more complex regimen involving a once-daily injection of basal insulin plus three pre-meal (bolus) injections. What’s more, the amount of insulin needed for each injection varies regularly. So despite insulin’s relatively long history and its therapeutic advantages, it has a low success rate. The problem is not insulin—but rather a lack of clinical oversight to assist patients with necessary dose adjustments.

Insulin Pumps: Insulin pumps are wearable electronic devices that provide insulin throughout the day. They release insulin into the body through a small tube that goes directly under the skin. The patch pump—an insulin pump without tubing—is another version. The patch, containing a reservoir of insulin, is worn directly on the body; insulin doses are then wirelessly managed by a separate controller. For the majority of patients, the success rate of pumps is similar to that of injections. Pumps suffer from the same limitations as insulin injections: They require a professional to adjust insulin doses. Since insulin needs are dynamic, often changing week-to-week, many patients fail to maintain good HbA1c without a professional to monitor the patient’s blood glucose levels and adjust insulin accordingly.

Digital Data Delivery Systems: The digital age brought about advances in computing, microelectronics, and communications. These advances have been used to develop new interventions for diabetes. Wireless e-diaries have been created to help patients keep track of their sugar levels and to communicate this data with physicians. While these kinds of advances may improve the convenience and accuracy of treatment, they don’t resolve the need for frequent dose adjustments by a healthcare provider. For optimal results, physicians need to review patients’ data often—and there simply are not enough physicians to accomplish this task. Thus, data delivery systems may not provide benefits above and beyond the current standard of care.

The artificial pancreas attempts to remove the reliance on physicians to adjust insulin doses. Using digital technology, an artificial pancreas would combine continuous blood monitoring with an insulin pump—a combination that would attempt to replicate the function of pancreatic beta cells. Several versions of the artificial pancreas are being tested; however, current models are considered cumbersome and uncomfortable—potentially unfit for widespread use.

Cell Therapy: Cell therapy involves injecting or transplanting intact living cells into a patient in order to replace that patient’s dead or damaged cells. In theory, cell therapy might one day restore beta cell function, allowing the body to once again produce its own dynamic supply of insulin. Major milestones have yet to be reached, however, and cell therapy as a treatment for diabetes remains a long way off.

Summary

People with diabetes are not receiving the help they need. In the United States alone, nearly 8 million patients inject insulin, of whom two thirds are unable to maintain healthy blood glucose levels. This proportion has not changed significantly since the 1990s. Too many people experience complications such as heart and kidney failure while healthcare systems struggle to provide the necessary equipment, funds, and expertise.

The good news is we know what works. Studies indicate that frequent adjustment of insulin dosage allows most people to attain healthy blood sugar levels. The challenge is to develop a scalable way to achieve the positive results that have thus far been realized only in experimental settings. Finding a way forward could improve the lives of millions of people—in our own communities and around the world.

This is what we’re working on at Hygieia. We believe diabetes management should be easier, and that there is a better way to use insulin. That is why we’re here.

References

  1. DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993; 329: 997-986.
  1. UKPDS Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet 1998; 352: 837-853.
  1. Heller et al. Improving management of type 1 diabetes in the UK: the Dose Adjustment For Normal Eating (DAFNE) programme as a research test-bed. A mixed-method analysis of the barriers to and facilitators of successful diabetes self-management, a health economic analysis, a cluster randomised controlled trial of different models of delivery of an educational intervention and the potential of insulin pumps and additional educator input to improve outcomes. Southampton (UK): NIHR Journals Library; 2014 Dec. (Programme Grants for Applied Research, No. 2.5.) Scientific summary.
  1. http://www.endocrinologyadvisor.com/aade-2015/aade-dsme-diabetes-education/article/433887/
  1. PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. June 2015.
  1. Dept of Health & Human Services, Agency for Healthcare Research and Quality.
  1. Nathan et al. Medical Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2009; 32: 193-203.