Type 1 Diabetes: Two Roads Diverged, How Far Have We Come?

Author: Brian Rifkin, MD

Hattiesburg Clinic

Hattiesburg, MS

Care of patients with diabetes has advanced significantly since Banting and Best discovered insulin over a century ago. The prognosis of type 1 diabetes (T1D) went from being a death sentence, with patients experiencing prolonged starvation, to a chronic treatable illness. Like any chronic condition, however, the risks of cumulative organ damage were compounded with the duration of disease, and life expectancies remained low for decades. Over time, the way we think about the pathophysiology of diabetes has changed dramatically. The classification of diabetes as type 1 (younger, thinner, insulin dependent) versus type 2 (older, heavier, non-insulin dependent) was defined in the 1980s by the WHO expert committee of the National Diabetes Data Group. T1D was further characterized by the autoimmune destruction of pancreatic Beta-cells leading to an absolute insulin deficiency, which was in stark contrast to the cellular insulin resistance seen in persons with T2D. The 1980s also saw the introduction of treatments to combat diabetic nephropathy. Medications in the Renin-Angiotensin-Aldosterone inhibitors (RASi) class were shown to be beneficial in treating patients with both T1D and T2D, with decreased cardiovascular and kidney complications. Finally, the DCCT in the 1990s showed the many benefits of intensive glucose control in decreasing the incidence of diabetic retinopathy, neuropathy and nephropathy. Unfortunately for patients with T1D, medication breakthroughs in the treatment of DN over the last decade have not kept pace with those for T2D patients.

People with T2D compose roughly 90% of the world’s patients with diabetes. Not surprisingly, newer therapeutics for preventing diabetic nephropathy (DN) have been aimed almost exclusively at this group. In fact, many of the newer medications (e.g. SGLT2 inhibitors, GLP-1 RA, NS-MRAs), that have shown overwhelming benefits in patients with DN, have excluded persons with T1D from trials. There was, however, at least one trial with sotagliflozin, an SGLT2 inhibitor, in patients with T1D which showed improved glycemic control but also increased risk of diabetic ketoacidosis (DKA), making their use restricted (FDA unapproved) except to the most compliant and knowledgeable patients. A 2024 article looked at the use of GLP1-RAs and SGLT2 inhibitors in T1D using a pooled cross sectional analysis of EHR records that included 257 million US residents. Approximately 945,000 T1D patients were identified with 6.6% being prescribed GLP1-RAs and 2.4% SGLT2 inhibitors in 2023, a significant increase in both from the prior decade. The reasons for the exclusion of T1D patients vary from difficult recruitment (due to many patients being below the age of consent) to the higher risk for life-threatening complications including severe hypoglycemia or DKA. As of now, unfortunately, patients with type 1 diabetes have limited approved medication choices for the prevention of hyperglycemia induced end organ damage.

Diabetes is a major contributor to CKM (Cardiovascular Kidney Metabolic) Syndrome, which is associated with excessive mortality from cardiovascular disease (CVD). Elevated plasma glucose levels, the primary dysfunction in both T1D and T2D, leads to multi-organ damage and failure. Protein glycation, and formation of advanced glycation end products (AGEs), play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, and neuropathy. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. Maintaining euglycemia can mitigate protein glycation and decrease the need to replace, repair or remove dysfunctional proteins and enzymes which contribute to inflammation and tissue damage.

The presence of T1D has been shown to decrease the life expectancy of a patient by 10-12 years on average, however, there does appear to be an improving trend over the last several decades. Newer designer insulins, insulin pumps and continuous glucose sensors (with and without closed loop systems) have significantly improved patient’s chances of maintaining euglycemia, but they are relatively new to the armamentarium and have only been evaluated in observational studies for their impacts on morbidity, hospitalizations and mortality. As technology advances, it is important to continue to evaluate the prognosis for patients with T1D with attention to improving hard endpoints like cardiovascular and kidney outcomes.

Poulsen et al’s publication in KI Reports looked at kidney outcomes of a registry based cohort of T1D and DN in a single center in Copenhagen, Denmark. This was an attempt to update our understanding of the development of CVD, DN and mortality in T1D patients in the recent era (2000-2020). The T1D population was defined by those treated with insulin, and with glutamic acid decarboxylase 65 antibody positivity or C-peptide levels below the reference range. Data for this study was obtained exclusively from electronic health records. The presence of DN was determined by an eGFR calculation by the CKD-EPI 2009 equation plus the presence of significant proteinuria (median 505 mg/24hr, with an interquartile range of 367-857). A subset of patients also underwent mGFR with chromium-51 labeled ethylenediamine tetra acetic acid plasma clearance. 

Endpoints for the study were derived from diagnosis and procedure codes from the National Patient Register. CVD endpoints included diagnoses of stroke, acute MI, ischemic heart disease, heart failure, coronary bypass surgery, or percutaneous coronary interventions. Kidney failure endpoints included diagnoses of dialysis, transplantation, CKD 5 with an eGFR < 15 ml/min/1.73 m2 on two measurements at least 60 days apart. In addition, eGFR trajectories were estimated separately for men and women. Models were also adjusted for albuminuria, HbA1C, hemoglobin, LDL-cholesterol, triglycerides, systolic blood pressure, BMI, exposure to RASi, antihypertensive and lipid lowering medications.

During follow-up, 591 patients were identified with new onset DN. The median age of diagnosis of T1D was 23 years, with the median onset of DN of 53 years. Glucose control was suboptimal, however, with a median HbA1C of 73 mmol/mol (8.8%, or average serum glucose of 207 mg/dL). Impressively, 73% of patients received RASi, and 46% were on lipid lowering medications. At baseline, higher age, albuminuria and treatment with antihypertensive medications were associated with lower eGFR levels. Conversely in men, higher hemoglobin levels and HbA1C levels were associated with higher eGFR baselines.  Although no specific explanation was offered by the authors, higher HbA1C levels, and associated hyperglycemia, might be associated with hyperfiltration in the early stages of DN. Similarly, excessive urination from hyperglycemia might lead to hemoconcentration and modest elevations of serum hemoglobin levels. Additionally, in men during a median follow-up of 7 years, higher age, LDL, BMI, treatment with antihypertensives and lipid lowering medications was associated with a lower eGFR. Not surprisingly, those with worse laboratory findings, requiring more medications to achieve specified therapeutic goals, had worse outcomes. A subset of 283 patients underwent mGFR studies. This subpopulation was younger and had earlier onset of DN, with a median age of 50 years. These patients were also more likely to be on RASi, with 83% on treatment at baseline. There was no apparent improvement in mGFR trajectories during the study period. Evaluation of the mGFR trajectories added additional evidence for an unchanged GFR loss trajectory over the last 20 years, despite treatment innovations (Fig 1).

The patients in the registry were followed for 3-12.2 years. Not surprisingly as the number of complications increased, mortality worsened (Fig 3). The crude mortality rate per 100-person years was 2.4 for DN, 7.2 for kidney failure and 18.7 for CVD with kidney failure. The risk of developing kidney failure was increased 71% in T1D with a history of CVD. These diseases share many similar risk factors, and in adults with T2D are often concomitant. Many treatments in patients with T2D and DN are actually aimed at modifying CVD, because patients are seven times more likely to die from CVD than progress to end stage kidney disease (ESKD). In this study the mortality risk for men without prior CVD was 28% after 10 years, but increased to 44% with poor control of risk factors. Men and women with CVD prior to DN had even worse outcomes with a 62% mortality at 10 years. Women did slightly better with a 26% 10-year mortality with controlled risk factors and no CVD. In women with poorly controlled risk factors the 10-year mortality risk increased to 40%, with only a 45% probability of being alive without CVD or kidney failure. 

The risk of developing CVD, kidney disease, and death were high and negatively impacted by male sex, the presence of CVD and poor risk factor control. Previous studies demonstrated the average decline in eGFR was approximately 4 ml/min/1.73 m2 in the preceding two decades (1980-2000). The current study found an average decline of 3 ml/min/1.73 m2 in women and 3.2 ml/min/1.73 m2 in men (2000-2015). The authors note the decline in eGFR was not linear, as seen in untreated T1D, but that several distinct patterns of eGFR loss could be identified. Some patients had rapid decline in the initial 5 years after diagnosis of DN, which may have skewed eGFR trajectories. It is difficult to compare this study to earlier studies that look at CVD and DN endpoints, as the definitions of disease as well duration of follow-up varied between studies. Despite the decreasing incidence of CVD and mortality in individuals with T1D and DN, the rates remain significantly increased compared to the general population. Based on this data, the overall prognosis for patients with T1D does not appear to have improved in the last two decades.

This study had several limitations. First, they did not include patients without albuminuria or with just CKD (eGFR < 60 ml/min/1.73 m2), which makes these observations less likely to be generalizable to all T1D patients. Next, endpoints were based upon diagnosis codes, which can be misleading or erroneous. In addition, no kidney biopsies were performed to confirm DN. It is possible that patients with more accelerated eGFR decline may have had additional kidney pathologies. The authors did not specifically evaluate the outcomes in patients with regression of proteinuria. There may be a subset of patients that are responsive to RAS blockade that have better prognoses. Finally, they did not have data on central or visceral obesity. In addition to poor glycemic control, waist size and visceral fat are directly correlated with CVD mortality, unlike BMI.

Although T1D patients make up a slim minority of patients with diabetes, patients are living longer and experiencing more organ failure complications, just like their T2D counterparts. The recent COVID-19 pandemic showed that in genetically predisposed patients, spikes in the diagnosis of T1D might lead to regional clusters and increased incidence of disease, making the burden on T1D uneven around the globe. T1D typically occurs in younger patients, who have a majority of their life (with diabetes) ahead of them. Major advances in therapeutics for patients with T2D, with improved kidney failure and CVD outcomes, have been fast and furious in the last 10 years. Multiple targets have been identified that now constitute the four pillars of DN care (RASi, SGLT2i, GLP-1 RA, NS-MRA). Unfortunately, patients with T1D have been seemingly left in the dust, unable to partake in many of these treatments. Unsurprisingly, positive outcomes have lagged as a result. There should be a certain urgency to address the needs of T1D patients as vigorously as T2D patients, until such a day as there is a cure.