Kidney Disease

Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

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Summary

Background

Sodium–glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial.

Methods

EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110.

Findings

Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83–2·41) reduction in eGFR, equivalent to a 6% (5–6) dip in the first 2 months. After this, it halved the chronic slope from –2·75 to –1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42–58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36–136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19–38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001).

Interpretation

Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor.

Discussion

Our analyses showed that, in this cohort of patients with chronic kidney disease at risk of progression, allocation to empagliflozin caused a small dip in kidney function of approximately 2 mL/min per 1·73 m2 (or 6%) and then halved the subsequent rate of long-term loss of kidney function. This overall result complements the 29% (95% CI 19–38) reduction in risk of kidney disease progression when assessed with the categorical composite outcome of end-stage kidney disease, a sustained decrease from baseline in eGFR of at least 40% or to less than 10 mL/min per 1·73 m2, or death from kidney failure. The beneficial effects of empagliflozin on the progression of chronic kidney disease varied by diabetes status and eGFR, but most prominently by albuminuria, where relative benefits might in fact be larger among participants with lower albuminuria. These findings are consistent with observations in other trials of SGLT2 inhibitors in chronic kidney disease, although these trials focused on patients with diabetes, significant levels of albuminuria, or both.

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 The broad range of patients included in the large EMPA-KIDNEY trial has allowed this to be explored in a more diverse population than those included in other large trials of SGLT2 inhibition in chronic kidney disease; in particular, EMPA-KIDNEY included participants with an eGFR of less than 25 mL/min per 1·73 m2 and with a uACR of less than 200 mg/g who were excluded from these previous trials.

The acute dip in eGFR when empagliflozin was initiated in EMPA-KIDNEY was modest (in all participant subgroups; it was on average ❤ mL/min per 1·73 m2 or <10% of baseline eGFR) and was largely reversible when treatment was discontinued. The acute effect was larger among participants with diabetes than in those without (on both absolute and relative scales), which might reflect the greater prevalence and degree of hyperfiltration in this group. The acute effect of SGLT2 inhibition on kidney function was recognised early in the development of this drug class (although not in all studies

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) and is believed to be due to the acute reduction in intraglomerular pressure caused by afferent arteriolar vasoconstriction stimulated by increased sodium delivery to the macula densa.

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 The associated rapid reduction in albuminuria supports this hypothesis,

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 and this reduction in intraglomerular pressure is one of the postulated mechanisms of the beneficial effects of SGLT2 inhibition on kidney function.

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 Our exploratory analyses suggest that the reduction in albuminuria might be the most important measured determinant of the benefits observed in EMPA-KIDNEY, explaining a fifth of the effect on chronic slopes and two-fifths of the effect on the primary composite outcome of kidney disease progression, consistent with analyses from other trials in chronic kidney disease.

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 These analyses need to be interpreted with some caution because they could have been subject to bias due to measurement error and residual mediator–outcome confounding. Whether this association is due to avoidance of direct toxic effects of albumin on tubular function, a reduction in intraglomerular pressure, or another unmeasured correlate of urinary albumin is not clear. However, these analyses also suggest that other mechanisms unrelated to albuminuria, blood pressure, or glycaemic control contribute to the benefit of SGTL2 inhibition on kidney function.

Our analyses focused on chronic slopes. Although effects on total slope correlate strongly with effects on clinical outcomes over short (2–3-year) follow-up periods,

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 the chronic slope is likely to be more informative for longer time periods. When the magnitude of the acute dip correlates with the relative reduction in the chronic slope (which is plausible because they share causal mechanisms, such as reduced intraglomerular pressure), this reduces variation between subgroups in total slope when measured over 2–3 years. However, this would not be the case with longer follow-up (see appendix p 29 for an explanatory example). Clinicians seeking to delay or avoid kidney failure would usually consider such longer time periods for which the chronic slope is most relevant. Furthermore, the limited variation in total slopes between patient subgroups reduces the ability to explore any such differences in treatment effect that might exist between those subgroups. This is shown by the apparent consistency of treatment effect on total slope in EMPA-KIDNEY versus the evidence of effect modification when using chronic slopes.

When comparing chronic slopes, we have reported both the absolute and relative differences but have emphasised the latter. Absolute differences are determined by both the background annual rate of change in eGFR and the relative effect of treatment, so any heterogeneity observed could be due to either of these components. This is demonstrated in the analysis by baseline uACR: the absolute difference in the chronic slope among participants with a uACR of 2000 mg/g or higher was 1·82 mL/min per 1·73 m2 per year, whereas the background chronic slope among participants with a uACR of less than 30 mg/g was 0·88 mL/min per 1·73 m2 per year, so it was impossible for the absolute difference in the latter subgroup to be similar to that observed in the highest uACR subgroup. Indeed, the absolute difference in the chronic slope was positively associated with baseline uACR; however, the relative difference was inversely associated such that participants with the lowest baseline uACR had the largest relative reduction (86% [95% CI 36–136] in those with uACR <30 mg/g vs 29% [19–38] in those with uACR ≥2000 mg/g). There was no strong evidence that this association was importantly modified by the presence or absence of diabetes. Contrary to some international guidelines that only suggest (rather than recommend) using SGLT2 inhibitors in patients without diabetes and without significant albuminuria (uACR <200 mg/g),

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 these analyses suggest that patients with low albuminuria (with or without diabetes) are likely to gain substantial benefit in terms of preservation of kidney function from SGLT2 inhibition, in addition to the other benefits of reductions in risk of acute kidney injury and cardiovascular disease.

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 Given the short follow-up in EMPA-KIDNEY (median 2 years) it would be expected that a treatment that causes a 2 mL/min per 1·73 m2 acute dip in eGFR in the subgroup of patients with uACR <30 mg/g (progressing at only 1 mL/min per 1·73 m2 per year) would not demonstrate definitive benefits on the categorical outcome (by contrast with subgroups with higher uACR progressing faster than 2 mL/min per 1·73 m2 per year). These analyses of the chronic slope suggest that important benefits would likely emerge with longer treatment (see appendix p 29 for an example).

These analyses are limited by the characteristics of patients included in EMPA-KIDNEY.

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 Few patients with type 1 diabetes were included, and patients with autosomal dominant polycystic kidney disease or with a kidney transplant were not eligible for the trial. In a companion paper, we assess whether the effects of allocation empagliflozin vary in different types of kidney disease.

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 The trial deliberately excluded patients at low risk of chronic kidney disease progression (ie, those with an eGFR of ≥45 mL/min per 1·73 m2 and uACR <200 mg/g), but demonstrated that the relative benefit on the chronic slope was inversely proportional to predicted risk of kidney failure. Participants only received study treatment for 2 years on average because the trial was stopped earlier than planned owing to clear evidence of benefit. A further 2 years of off-treatment follow-up is underway to assess the longer-term effects of an average of 2 years of treatment.

In summary, in EMPA-KIDNEY, allocation to empagliflozin compared with placebo caused a modest acute dip in eGFR, and then substantially slowed the longer-term progression of chronic kidney disease. The longer-term benefits varied by diabetes status, eGFR, and most prominently uACR (and related characteristics such as predicted risk of kidney failure). Although the trial stopped early because of clear benefits emerging based on results in patients at highest risk, these analyses show that patients at lower risk such as those with lower levels of albuminuria—many of whom in their lifetime would otherwise develop kidney failure—could benefit in terms of preservation of kidney function, in addition to other proven cardiovascular and mortality benefits.

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 If widely implemented, use of SGLT2 inhibitors could have a substantial effect on the public health impacts of chronic kidney disease.

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy

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Abstract

BACKGROUND

A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL.

METHODS

In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed.

RESULTS

Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was −2.7±1.8, 0.2±1.7, −1.5±1.8, and −7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group.

CONCLUSIONS

In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo.

Survey reveals why nephrology professionals might not recommend plant-based diets

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Nephrology professionals may not routinely recommend plant-based diets to patients with kidney disease due to concerns over patient acceptance and their ability to follow the diet plan, according to survey results.

The results, presented virtually at the National Kidney Foundation Spring Clinical Meetings, also highlighted a lack of patient knowledge regarding the benefits of such diets.

Plant-based diets

Melanie Betz, MS, RD, CSR, CSG, LDN, chronic kidney disease nutrition and education specialist with University of Chicago Medicine, told Healio Nephrology that she designed the survey to gain a better understanding of how frequently plant-based diets are adopted by this patient population, as well as to explore potential barriers that may limit recommendations.

“I found that [plant-based diets] were being discussed quite a bit in the literature, and in professional communities, but patients seemed to be unaware of them — and even afraid of them — in online CKD groups I help with,” she said.

For the study, Betz and colleagues administered questionnaires to 657 health care professionals, 58% of whom were registered dieticians and 53% of whom worked in dialysis, and 844 patients, 35% of whom had non-dialysis-dependent CKD and 35% of whom had a kidney transplant.

Despite 79% of health care professionals indicating plant-based diets can be an effective lifestyle modification for treating CKD, only 56% reported that they recommend the diets to their patients.

“My research showed that the most common reason [plant-based diets] are not recommended is low perceived patient acceptance and that they are not realistic for patients,” Betz said. “I found this surprising because I had guessed that concerns over electrolyte abnormalities would be a much bigger barrier to recommendation.”

Among patients, most reported that the eating preferences of their families, their personal preference for meat and meal planning were the primary challenges to following a plant-based diet.

Betz contended it is critical not to view incorporating plant-based diets as an “all-or-nothing” approach.

“We need to meet patients where they are and encourage plant-based diets to the extent patients can or are willing to follow them,” she said.

According to Betz, it is not necessary for patients to completely stop eating meat; just one to two “meatless meals” per week could help reduce protein and dietary acid load, thereby slowing CKD progression, she said.

Regarding specific methods to increase adherence to plant-based diets, both professionals and patients ranked counseling sessions with a registered dietician as most beneficial.

“Recommending early dietitian intervention can help patients make these dietary changes,” Betz said. “Dietitians have the time and expertise to help patients learn how to implement plant-based diets.

“I also think it may help to frame nutrition interventions as a way to slow CKD progression, rather than just, ‘this is good for your kidneys.’ Patients are usually very interested in what they can do to prevent dialysis, and plant-based diets can do this.”

Kidney Disease Gene Risk Info Aids Prevention in Primary Care

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Trial showed benefits in hypertensive patients of African descent

A computer rendering of a healthy kidney and a diseased kidney over a DNA helix.

For hypertensive people of African ancestry, knowing their genetic risk for chronic kidney disease modestly helped with their efforts to prevent it, a pilot randomized clinical trial showed.

Three months after being given the news that they carried high-risk variants in the APOL1 gene on chromosome 22, patients had a significantly greater reduction in systolic blood pressure than those told they had low-risk APOL1 genotypes or who weren’t told their genetic risk (mean 6 vs 3 mm Hg in both other groups).

By 12 months, those with information about their high genetic risk were more likely to have gotten urine albumin testing for kidney disease (an increase of 12 vs 6 to 7 percentage points in the other two groups, P=0.01 vs controls), Girish Nadkarni, MD, MPH, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues reported in JAMA Network Open.

The patients with high-risk APOL1 genotypes more often reported improving their dietary and exercise habits (59% vs 37% with low-risk genotypes, P<0.001) and increasing their antihypertensive use (10% vs 5%, P=0.005).

The trial returned the genetic results to both the patients in the intervention group and their primary care physicians, conveyed through trained laypersons and alerts in the electronic health record (EHR), respectively.

Thus, the researchers suggested that their results “may support an approach of broad implementation of genetic medicine in primary care.”

Primary care is where most healthcare happens for patients, and although genetic counselors have typically been on the front lines of genetic testing, they are in short supply compared with the number of people who would need it for common conditions.

High-risk variants of APOL1 are found in one of seven people of African ancestry, for whom they confer a five- to 10-fold increased risk for chronic and end-stage kidney disease from hypertension.

Getting such genetic testing into broad use “will benefit racial and ethnic minority groups that have been traditionally underrepresented in both clinical trials and genetic studies,” Nadkarni’s group noted.

The trial used layperson coordinators, mainly of African ancestry, who had been trained by genetic counselors to convey test results and “to be sensitive to the culture and challenges facing patients.” This approach was viewed “very favorably,” with only 3% of patients saying they wouldn’t choose to get tested again.

“Clinician extenders (nurse practitioners and physician assistants) may be useful for other practices to consider to permanently fill this role for busy clinicians or as a bridge while clinicians learn to incorporate information from a relatively new field into their workflow,” the researchers suggested.

The trial enrolled 2,050 patients of African ancestry with hypertension from 15 academic, community, and safety-net practices in two health systems in New York City. Participants were randomly assigned 7:1 to immediately be given APOL1 allele genotype results or for results to be delayed until after the 12-month visit (controls).

The coordinators collected venous blood samples (or saliva samples, if needed) for genetic testing at baseline and then returned the results in person for high-risk APOL1 genotypes (homozygous or compound heterozygous G1 or G2 alleles) or over the phone for patients who were low-risk, heterozygous G1 or G2 or homozygous wild-type allele carriers.

Participants’ primary care physicians got a one-time EHR alert — with the genotype result, recent blood pressure readings, and links to information — when they saw the patient within the 12-month follow-up period.

Few prior studies testing the impact of disclosing genetic risk for chronic diseases have found it improved outcomes, Nadkarni’s group noted. The benefits in this trial, while modest, “may be due to the use of EHR alerts, which have previously shown efficacy, along with disclosure of genetic results to patients.”

“The magnitude of systolic blood pressure improvement was small, but we did not provide specific BP target recommendations or BP-lowering strategies to clinicians or patients,” they noted. It’s possible that more intense BP-lowering efforts would boost the impact.

There were some downsides to disclosure of high-risk genotypes, with more of these patients upset about their results (8% vs 1%, P<0.001) and worried they would develop kidney problems (27% vs 17%, P<0.001).

“We offered all patients the opportunity to speak to or meet with a genetic counselor at no cost; however, none chose to do so,” the researchers noted.

Limitations included exclusion of patients with pre-existing chronic kidney disease and lack of comprehensive data on lifestyle and dietary intake or medication refill data.

A similarly designed 5,400-patient national trial, GUARDD-US, is underway and expected to reach completion at the end of the year.

What Are My Choices for Metformin Alternatives?

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Metformin alternatives

While you are likely familiar with metformin and insulin as the two well-known medications for treating type 2 diabetes, many other options are available to help you manage your glucose levels. Here is a rundown of some of the other options that may improve your health and diabetes management.

When you are diagnosed with type 2 diabetes, you will likely hear from your healthcare team that the most common initial treatment regimen consists of some combination of metformin and lifestyle changes to your diet and exercise.

For most people, type 2 diabetes is a progressive disease (this means that without proper treatment it can continue to worsen over time). In addition, some people may have more severe and chronic hyperglycemia for a long time prior to being diagnosed with type 2 diabetes. As a result, you might need additional medications the longer you have diabetes to keep your glucose levels in a healthy range.

Insulin remains the most effective therapy to lower glucose, particularly in comparison to most oral medicines for type 2 (including metformin). Therefore, at the time of diagnosis, if there is evidence of long-standing and persistent hyperglycemia, you may be advised to start insulin, since it is most effective and rapid in its action to lower glucose levels. Once diagnosed, if you are unable to meet your glucose targets (whether that be because your condition has progressed over time, your current medications are not doing enough to lower your glucose, or because you were experiencing significant symptoms), your healthcare team may suggest using insulin.

While these treatments are some of the most well-known, there are many other medications available today for people with type 2. These additional drugs have dramatic effects; many of them can lower your risk for various diabetes-related complications, while still maintaining similar glucose-lowering properties.

“People with diabetes should be aware of their need for different medications based on their risk profiles,” said Dr. Robert Gabbay, chief scientific and medical officer for the American Diabetes Association. “All people with diabetes should also be referred for and receive DSMES, or diabetes self-management education and support, at diagnosis. This gives people the opportunity to engage with a skilled diabetes care and education specialist, ask questions about therapies, and increase awareness.”

As new diabetes drugs continue to receive FDA approval at an unprecedented rate, here is a look at the different types of medications that can improve your health and help you better manage your diabetes. If you are at an increased risk for developing complications, or your glucose levels have not responded well with metformin, talk with your healthcare provider about whether these medications may be a better option.

SGLT-2 inhibitors

SGLT-2 inhibitors are oral medications that can help lower your glucose levels by helping your body remove excess glucose by excreting it in your urine. These drugs can lower A1C levels, and research has shown that they can also slow the progression of kidney disease and protect against heart disease (heart attack, stroke, hospitalization for heart disease and death) and heart failure. However, SGLT-2 inhibitors should not be prescribed to those who have already progressed to stage 4 or end stage kidney disease.

Additionally, unlike other glucose-lowering drugs, SGLT-2s come with a relatively low risk of hypoglycemia. The currently available SGLT-2 inhibitors include Farxiga, Invokana, Jardiance, and Steglatro.

Side effects of taking an SGLT-2 inhibitor may include:

  • More frequent urination
  • Increased risk for urinary tract infections and genital yeast infections
  • Increased risk for kidney damage for those already at advanced stages of kidney disease
  • Increased risk for diabetic ketoacidosis (DKA)
  • Low blood pressure, syncope (loss of consciousness caused by low blood pressure), and dehydration due to volume depletion
  • Invokana, specifically, may increase your risk for amputations, ketoacidosis, and kidney damage beyond that associated with other SGLT-2 drugs.

GLP-1 receptor agonists

GLP-1 receptor agonists are another type of glucose-lowering medication, which can either be taken orally or, more commonly, through a once-daily or once-weekly injection. GLP-1 receptor agonists can lower your A1C levels, and some have been shown to lower your risk for heart and kidney disease as well.

Perhaps most remarkable, however, is that taking a GLP-1 receptor agonist can lead to significant weight loss. If you have struggled with weight management through diet and exercise changes alone, talk with your healthcare provider about starting a GLP-1 receptor agonist. The currently available medications in this class are Adlyxin, Bydureon, Byetta, Ozempic, Rybelsus, Trulicity, and Victoza.

Side effects of taking a GLP-1 receptor agonist may include:

  • Nausea
  • Vomiting and diarrhea (usually decreases over time)
  • Risk for hypoglycemia, if taken in combination with insulin or a sulfonylurea (read below)

DPP-4 inhibitors

DPP-4 inhibitors are a class of drugs that can lower your glucose by inhibiting glucagon release in your body, a hormone that causes your blood sugar to rise. This helps stimulate insulin production and decreases the emptying of your stomach, making you feel more full. Both of these effects help lower glucose levels.  These drugs are taken orally and are often combined with metformin to bolster the glucose-lowering action. When taken with metformin, there is a low risk for low blood sugar with a DPP-4 inhibitor, but taking them with insulin or sulfonylureas can place you at a higher risk.

While they can lower your glucose, DPP-4 inhibitors have not been shown to have the same effects on weight loss and complications as the SGLT-2 and GLP-1 drug classes. Available DPP-4 inhibitors include Januvia, Nesina, Onglyza, and Tradjenta.

Side effects include:

  • Gastrointestinal problems
  • Flu-like symptoms
  • Increased risk for pancreatitis

Sulfonylureas (SFUs)

SFUs are a type of glucose-lowering medications that have been around for many years as a treatment for type 2 diabetes. While SFUs are effective at lowering glucose and are available as less expensive generic brands, they significantly increase your risk for low blood sugar and can cause weight gain. Given that other drug classes can lower your glucose and reduce complications without the added risk for hypoglycemia, you may want to discuss these other options with your healthcare provider.

Side effects include:

  • Higher risk for experiencing hypoglycemia
  • Weight gain
  • Hunger
  • Upset stomach

Thiazolidinediones (TZDs)

TZDs are another glucose lowering medication that work by reducing insulin resistance. Similar to SFUs, TZDs are cheaper and come in generic brands but can place users at a higher risk for negative side effects such as weight gain and an increased risk for heart failure. Discuss these risks with your healthcare provider to find the best option for you.

Side effects include:

  • Weight gain
  • Edema, or fluid buildup, usually in your feet, legs, hands, or arms
  • Increased risk for heart failure or experiencing a bone fracture

Combination Drugs

Combination drugs, as the name suggests, combine two or more drugs, usually from different classes, into a single medication. Combination drugs can increase the effectiveness of each individual medication, reduce overall side effects, or decrease the total number of injections or pills in your daily treatment routine. Some currently available combination drugs include Janumet (Januvia + metformin), Kombiglyze XR (Onglyza + metformin extended release), and Synjardy (Jardiance + metformin).

Of course, these different drugs can also be taken as separate doses at the same time, or in combination with your insulin regimen. Layering multiple therapies can alleviate some negative side effects, help lower your glucose more effectively, and help prevent complications at the same time. Combination therapies allow your healthcare provider to develop a much more personal treatment for you.

Cost and access

Depending on your insurance coverage, drug costs are often a factor in determining which treatment you receive. Given how they minimize side effects and protect against complications, GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors are all ideal options, but they tend to be more expensive and aren’t yet available in generic forms in the US.

SFUs, TZDs, and metformin are available in generic brands and are typically much cheaper – but obviously, as is the case with SFUs and the risk of severe hypoglycemia, there may be reasons why these drugs are not preferred. Regardless, all of these medications can help you lower your glucose, so talk with your provider about which treatment fits your budget and insurance coverage.

The bottom line

While metformin and lifestyle modification remain the first-line therapies for type 2 diabetes, as you can see, there are several other medications that you may be able to try before needing to go on insulin. Depending on your risk for developing complications like heart or kidney disease, it’s often more effective to start using a GLP-1 receptor agonist or an SGLT-2 inhibitor before progressing to insulin injections.

This flowchart from the American Diabetes Association details the process for how your healthcare provider makes decisions on which medications may best for each individual. While the chart may seem complex, it illustrates the many different options that might be available to you depending on cost, risk factors, and overall health goals.

“Ask questions,” said Dr. Gabbay. “Have a frank discussion with your diabetes care provider to understand the available options, why a treatment may or may not be for you, and ask questions to understand the treatments you do receive.”

Talk with your healthcare provider about whether you might benefit from one of these drugs. The path from metformin to insulin is by no means direct, and there may be other options that can help you improve your diabetes management.

KIDNEY STONES AND DIABETES

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type 1 diabetes and kidney disease

Kidney stones, according to some patients, can rival the pain of childbirth. And for those individuals who have both given birth and had a kidney stone, some will tell you that the kidney stone was worse.

So, what causes kidney stones and how might having diabetes, specifically type 2 diabetes, put individuals at risk for developing these bothersome stones?

To start, kidney stones are, according to the Cleveland Clinic, “hard mass[es] of crystallized minerals that form in the kidneys or urinary tract.”

When one of the half a million people who present themselves annually at emergency rooms across the nation, those individuals are often exhibiting the telltale signs of kidney stones, according to the Mayo Clinic:

  • Severe pain in the side and back, below the ribs
  • Pain that radiates to the lower abdomen and groin
  • Pain that comes in waves and fluctuates in intensity
  • Pain on urination
  • Pink, red, or brown urine
  • Cloudy or foul-smelling urine
  • Nausea and vomiting
  • Persistent need to urinate
  • Fever and chills if an infection is present
  • Urinating small amounts

It is important to note that if you or a loved one are experiencing one of the following signs or symptoms, you should seek medical attention immediately:

  • Pain so severe that you can’t sit still or find a comfortable position
  • Pain accompanied by nausea and vomiting
  • Pain accompanied by fever and chills
  • Blood in your urine
  • Difficulty passing urine

The presence of kidney stones, however, can also be especially vexing for people with type 2 diabetes, whose urine can be more acidic, especially if individuals have consistently high blood sugars. While kidney stones often do not have one easily discernible cause, it is important to understand how those with type 2 diabetes can reduce their risk for kidney stones through hydration, diet, and achieving or maintaining a healthy weight.

Uric acid makes up one type of kidney stone. The substance can be created in the urine when blood sugar is too high, and may lead to these painful stones. In addition to uric acid stones, there are three other types of kidney stones: calcium stones (calcium oxalate or calcium phosphate), struvite stones, and cystine stones.

While it is true that one out of 10 people will have a kidney stone at some point in their lifetime, most notably after the age of 30 years, there are proactive steps individuals can take to reduce their risk of developing a kidney stone. Reducing risk is especially important because once an individual develops a kidney stone, the likelihood of future stones occurring increases.

Who’s at Risk for Developing Kidney Stones?

To understand how to reduce one’s risk for kidney stones, let us first explore some of the basic risk factors for developing one. According to the American Kidney Fund, some behaviors, medical conditions, and genetics may influence the formation of these dreaded stones:

  • Having kidney stones previously and/or having a family history of kidney stones
  • Not drinking enough water on a consistent basis
  • Following a diet high in protein (Hello, keto and low-carb lifestyles!), sodium, and/or sugar
  • Being classified as overweight or obese
  • Having had gastric bypass or another intestinal surgery
  • Having polycystic kidney disease or a related cystic kidney disease
  • Having any condition that causes your urine to contain high levels of calcium, cystine, oxalate, or uric acid (such as type 2 diabetes)
  • Having a condition that causes swelling or irritation in your bowel and joints
  • Taking certain medications or pills, such as water pills (diuretics), calcium-based antacids, or high doses of calcium — such as pre- or post-natal vitamins

Important to note, men are often much more likely to develop kidney stones during their lifetime — 19 percent —  than women, who are about half as likely. White, non-Hispanic men, per the American Kidney Fund, are much more likely to develop kidney stones than people of other ethnicities.

The sobering news for why prevention is paramount? The National Kidney Foundation reports, “Those who have developed one stone are at approximately 50% risk for developing another within 5 to 7 years.”

How Do I Reduce My Risk for Kidney Stones?

There are many lifestyle changes that may delay or even prevent kidney stones and the resulting pain. Some of those changes may even help prevent the development of kidney disease, a common and very dangerous complication of diabetes.

The Mayo Clinic recommends some of the following guidelines for anyone at risk of developing kidney stones:

  1. Stay hydrated throughout the day by drinking plenty of water. For people with a history of kidney stones, doctors recommend passing 2.5 liters of urine a day. If you live in a hot and humid climate and/or exercise a lot, drink even more water.
  2. Choose a diet low in salt and animal protein. This can be tricky for those observing a ketogenic or low-carb diet, especially if you depend on meat to curb cravings. But consider balancing your sodium and red meat intake with lower-carb vegetables whenever possible.
  3. Continue to eat low-fat, calcium-rich foods, but skip the calcium supplement.
  4. As the National Institute of Diabetes and Digestive and Kidney Diseases points out: “Studies have shown that the Dietary Approaches to Stop Hypertension (DASH) diet can reduce the risk of kidney stones.” To learn more about the DASH diet, click here.

Conclusions

While having type 2 diabetes may put certain people at greater risk of developing kidney stones, especially as they age, there are many potential steps one can take to diminish the risk of hurting one’s kidneys further. Diet and water intake can help moderate your risk, as well as maintaining a healthy weight and blood sugar.

References

“6 Easy Ways to Prevent Kidney Stones.” (2019). National Kidney Foundation.

Carbone, A., Al Salhi, Y., Tasca A3, Palleschi, G.., Fuschi, A., De Nunzio, C., Bozzini, G., Mazzaferro, S., & Pastore, AL. (2018). “Obesity and Kidney Stone Disease: A Systematic Review.” Minerva Urol Nefrol. 70(4): 393-400. doi: 10.23736/S0393-2249.18.03113-2.

“Eating, Diet, and Nutrition for Kidney Stones.” (2017). National Institute of Diabetes and Digestive and Kidney Diseases.

“Is there a Connection between Diabetes and Kidney Stones?” (2019). Next Generation of Clinical Research.

“Kidney Stones.” (2019). Mayo Clinic.

“Kidney Stone Risk Factors.” (2019). American Kidney Fund.

Sorensen, M.D. (2014). “Calcium intake and urinary stone disease.” Translational Andrology and Urology, 3(3): 235–240. doi: 10.3978/j.issn.2223-4683.2014.06.05.

Heartburn Pills Linked to Kidney Disease

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Heartburn Pills

Story at-a-glance –

  • Proton pump inhibitors (PPIs) have been linked to an increased risk of chronic kidney disease
  • PPIs have previously been linked to a kidney disorder called acute interstitial nephritis
  • These heartburn drugs may also increase your risk of fractures, serious infections, heart attack and nutrient deficiencies

Heartburn drugs known as proton pump inhibitors (PPIs) are among the most commonly used drugs in the world. About 15 million Americans use PPIs, either in prescription or over-the-counter form. Brand names include Prilosec, Prevacid and Nexium.

The drugs have long been touted as a safe way to relieve heartburn, indigestion and acid reflux. They work by inhibiting the production of acid in your stomach, which helps to relieve symptoms but appears to have a number of unintended consequences as well, including for your kidneys.

PPIs have previously been linked to a kidney disorder called acute interstitial nephritis. Now researchers have linked them to the risk of chronic kidney disease, prompting experts to call for more caution in their use.

Heartburn Drugs May Increase Your Risk of Kidney Disease

Researchers from the Johns Hopkins Bloomberg School of Health analyzed two sets of data representing more than 250,000 people.1

In the first set, the 10-year absolute risk of developing chronic kidney disease was 11.8 percent among those taking PPIs compared to 8.5 percent among those not taking the drugs.

The second analysis found the 10-year absolute risk of chronic kidney disease among those taking PPIs was 15.6 percent compared to 13.9 percent among non-users.2

The study left some unanswered questions, like how long those who developed kidney disease had been taking PPIs. It’s also not known how the drugs may be harming the kidneys.

Many of those taking PPIs had other risk factors for kidney disease as well, including being more likely to use blood pressure medication (high blood pressure is linked to an increased risk of kidney disease).

However, even though the analysis couldn’t prove that PPIs were directly responsible for the increased risk of kidney disease, the finding warrants caution in the drugs’ use, especially given their prevalence.

Adam Schoenfeld, an internal medicine resident at the University of California, San Francisco, said in an accompanying editorial, “mounting evidence demonstrates that PPIs are associated with a number of adverse effects and are overprescribed.”3 He continued in NPR:

“I think it’s a pretty big concern … When they first came out they weren’t associated with side effects, or we didn’t think they were … So we put [people] on this medication thinking: ‘It’s a quick fix and they’re very safe.’ But in actuality they’re associated with a range of side effects.”

PPIs Are Also Linked to Heart Risks

If you take PPIs, you should know that not only might your kidneys be at risk, but your heart may suffer as well.

After reviewing the medical records of nearly 3 million people, researchers from Stanford University in California found people with gastroesophageal reflux disease (GERD) who took PPIs had a 16 percent risk of heart attack.4

A two-fold increased risk of cardiovascular mortality was also noted in PPI users.5 Such risks make sense when you consider that PPIs are known to reduce nitric oxide (NO) in your blood vessel walls.

NO has the effect of relaxing your blood vessels, so by reducing the amount of NO in your blood vessel walls, PPIs may raise your risk of a heart attack.

PPIs May Raise Your Risk of Fractures

In 2010, the U.S. Food and Drug Administration (FDA) mandated a new fracture risk warning be added to the labels of both prescription and OTC PPIs.

The safety announcement was based on a review of several epidemiological studies, which found the drugs were associated with an increased risk of factures of the hip, wrist and spine.6

The greatest risk of increased facture risk was found in people who had taken high doses of the drugs (available only in prescription form) or had taken the prescription drugs for at least one year.

Because of this, in 2011 the FDA recalled the safety warning for OTC PPIs, stating that “an osteoporosis and fracture warning on the over-the-counter (OTC) proton pump inhibitor (PPI) medication “Drug Facts” label is not indicated at this time.”7

Their reasoning was that OTC PPIs “are marketed at low doses and are only intended for a 14-day course of treatment up to three times per year.” Since OTC heartburn drugs are only supposed to be used for short courses of treatment, they believed the fracture risk was low.

In reality, however, many people use OTC heartburn meds for much longer than two weeks at a time, and therefore might be exposed to them long-term. Some people may also take higher doses than are recommended. Even the FDA acknowledged this, stating:

“… [C]onsumers, either on their own, or based on a healthcare professional’s recommendation, may take these products for periods of time that exceed the directions on the OTC label.”

Unfortunately, instead of letting consumers know about the fracture risk (so they could make an informed decision about using the drugs), the FDA left it up to health care professionals to be aware of the fracture risk in patients taking OTC PPIs at high doses or for extended periods.

If there’s no communication between the two parties, the consumer will be left at risk.

PPIs May Rob Your Body of Important Nutrients, Increase Your Risk of Serious Infections

If you suffer from acid reflux, suppressing your stomach acid may seem like a very good idea. Be aware, however, that doing so comes with significant risks. Stomach acid is important for your body to absorb vitamin B12, for instance.

The acid separates the B12 from the protein it’s attached to, which is essential for it to be absorbed by your body. People taking PPIs for more than two years had a 65 percent increased risk of vitamin B12 deficiency.8 This, in turn, can lead to a number of troublesome ailments, including:

  • Anemia
  • Nerve damage
  • Psychiatric problems
  • Dementia

Your magnesium levels are also at risk. In 2011, the FDA warned that PPIs may cause low magnesium levels if taken for longer than one year. Even taking a magnesium supplement was not enough to sufficiently increase levels among about one-quarter of those taking PPIs.9

Early signs of magnesium deficiency include loss of appetite, headache, nausea, fatigue, and weakness. Ongoing magnesium deficiency can lead to muscle cramps, seizures, abnormal heart rhythms, personality changes and more.

Further, PPIs may increase your risk of Clostridium difficile-associated diarrhea, a potentially life-threatening infection, by 65 percent.10 The risk of hospital-acquired pneumonia may also increase with PPI use, an important consideration since PPIs are commonly given to hospital patients.

One study using a microsimulation model found that this practice needs serious review, as new initiation of PPI therapy led to an increase in hospital mortality in about 90 percent of patients.11

Reducing stomach acid also diminishes your primary defense mechanism against food-borne pathogens, thereby potentially increasing your risk of food poisoning.

Heartburn Drugs Only Treat the Symptoms, Not the Cause

In most cases, acid reflux is not due to having too much acid in your stomach; rather, it’s a condition related more commonly to hiatal hernia — a condition in which the acid comes out of your stomach, which is where it’s designed to be confined to. After food passes through your esophagus into your stomach, a muscular valve called the lower esophageal sphincter (LES) closes, preventing food or acid from moving back up.

Gastroesophageal reflux occurs when the LES relaxes inappropriately, allowing acid from your stomach to flow (reflux) backward into your esophagus.

In the early ‘80s, Dr. Barry Marshall, an Australian physician, discovered that an organism called helicobacter pylori(initially called campylobacter) causes a chronic low-level inflammation of your stomach lining, which is largely responsible for producing many of the symptoms of acid reflux.

One of the explanations for why suppressing stomach acid is so ineffective — and there are over 16,000 articles in the medical literature attesting to this — is that when you decrease the amount of acid in your stomach, you suppress your body’s ability to kill the helicobacter bacteria.

So suppressing stomach acid production tends to just worsen and perpetuate the condition. If you’re taking a PPI drug to treat your heartburn, understand that you’re treating a symptom only; you are in no way addressing the underlying cause. And, by doing so, you’re exposing yourself to other potentially more dangerous health problems, courtesy of the drug itself.

That being said, please don’t try to quit PPIs cold turkey, as this can lead to a relapse and severe pain. To minimize this risk, you can gradually decrease the dose you’re taking, and once you get down to the lowest dose of the PPI, you can start substituting with an OTC H2 blocker like Tagamet, Cimetidine, Zantac, or Ranitidine.

Then gradually wean off the H2 blocker over the next several weeks. While weaning yourself off these drugs, start implementing the lifestyle modifications discussed below to help eliminate your heartburn once and for all.

Heartburn May Be Due to Too Little Stomach Acid

If you struggle from heartburn, it may be because you have too little stomach acid. One simple strategy to address this deficiency is to swap out processed table salt for an unprocessed version like Himalayan salt. By consuming enough of the raw material, you will encourage your body to make sufficient amounts of hydrochloric acid (stomach acid) naturally.

Sauerkraut or cabbage juice is among the strongest stimulants for your body to produce stomach acid as well. Another benefit is that it can provide you with valuable bacteria to help balance and nourish your gut. Having a few teaspoons of cabbage juice before eating, or better yet, fermented cabbage juice from sauerkraut, will do wonders to improve your digestion. Fresh raw cabbage juice can also be very useful to heal resistant ulcers.12

Another option is to take a betaine hydrochloric supplement, which is available in health food stores without prescription. You’ll want to take as many as you need to get the slightest burning sensation and then decrease by one capsule. This will help your body to better digest your food and will also help kill the helicobacter and normalize your symptoms.

Now, while hiatal hernia and H.pylori infection are unrelated, many who have a hiatal hernia also have H. pylori and associated symptoms.13 If you have a hiatal hernia, physical therapy on the area may work as well, and many chiropractors are skilled in this adjustment.

Natural Treatment for Heartburn

Ultimately, the answer to heartburn and acid indigestion is to restore your natural gastric balance and function and to do that, you need to address your gut health. The most important step is to eliminate processed foods and sugars as they are a surefire way to exacerbate acid reflux.

They also alter your gut microbiome and promote the growth of pathogenic microbes. So be sure to eat lots of fresh vegetables and other unprocessed organic foods. Food allergies can also be a contributing factor to acid reflux, so eliminate items such as caffeine, alcohol, and nicotine.

Reseeding your gut with beneficial bacteria, either from traditionally fermented foods or a high-quality probiotic supplement is also important, as this will not only help balance your bowel flora, it can also help eliminate helicobacter bacteria naturally. Probiotics and fermented foods, especially fermented vegetables, also aid in proper digestion and assimilation of your food. Other helpful strategies to get your heartburn under control include the following suggestions.14,15,16

Raw, unfiltered apple cider vinegar You can help improve the acid content of your stomach by taking one tablespoon of raw unfiltered apple cider vinegar in a large glass of water.
Baking soda One-half to one full teaspoon of baking soda (sodium bicarbonate) in an eight-ounce glass of water may ease the burn of acid reflux as it helps neutralize stomach acid. I would not recommend this as a regular solution but it can sure help in an emergency when you are in excruciating pain.
Aloe juice The juice of the aloe plant naturally helps reduce inflammation, which may ease symptoms of acid reflux. Drink about 1/2 cup of aloe vera juice before meals. If you want to avoid its laxative effect, look for a brand that has removed the laxative component.
Ginger root Ginger has been found to have a gastroprotective effect by blocking acid and suppressing helicobacter pylori. According to a 2007 study, it’s also far superior to lansoprazole for preventing the formation of ulcers, exhibiting six- to eight-fold greater potency over the drug.17

This is perhaps not all that surprising, considering the fact that ginger root has been traditionally used against gastric disturbances since ancient times. Add two or three slices of fresh ginger root to two cups of hot water. Let steep for about half an hour. Drink about 20 minutes or so before your meal.
Vitamin D Vitamin D is important for addressing any infectious component. Once your vitamin D levels are optimized, you’re also going to optimize your production of about 200 antimicrobial peptides that will help your body eradicate any infection that shouldn’t be there.

As I’ve discussed in many previous articles, you can increase your vitamin D levels through sensible sun exposure, or through the use of a tanning bed. If neither of those are available, you can take an oral vitamin D3 supplement; just remember to also increase your vitamin K2 intake.
Astaxanthin This exceptionally potent antioxidant was found to reduce symptoms of acid reflux in patients when compared to a placebo, particularly in those with pronounced helicobacter pylori infection.18 Best results were obtained at a daily dose of 40 mg.
Slippery elm Slippery elm coats and soothes your mouth, throat, stomach, and intestines, and contains antioxidants that may help address inflammatory bowel conditions. It also stimulates nerve endings in your gastrointestinal tract. This helps increase mucus secretion, which protects your gastrointestinal tract against ulcers and excess acidity.

The University of Maryland Medical Center makes the following adult dosing recommendations:19

  • Tea: Pour 2 cups boiling water over 4 g (roughly 2 tablespoons) of powdered bark, then steep for 3 to 5 minutes. Drink 3 times per day.
  • Tincture: 5 mL, 3 times per day.
  • Capsules: 400 to 500 mg 3 to 4 times daily for 4 to 8 weeks. Take with a full glass of water.
  • Lozenges: follow dosing instructions on label.
Glutamine Research published in 2009 found that gastrointestinal damage caused by H. pylori can be addressed with the amino acid glutamine, found in many foods, including beef, chicken, fish, eggs, dairy products, and some fruits and vegetables.20 L-glutamine, the biologically active isomer of glutamine, is also widely available as a supplement.
Folate or folic acid (vitamin B9) and other B vitamins As reported by clinical nutritionist Byron Richards, research suggests B vitamins can reduce your risk for acid reflux.21 Higher folic acid intake was found to reduce acid reflux by approximately 40 percent.

Low vitamin B2 and B6 levels were also linked to an increased risk for acid reflux. The best way to raise your folate levels is by eating folate-rich whole foods, such a sliver, asparagus, spinach, okra, and beans.
Melatonin, l-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine A dietary supplement containing melatonin, l-tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine, was found to be superior to the drug omeprazole in the treatment of GERD.22

Part of the success is thought to be due to melatonin’s inhibitory activity on nitric oxide biosynthesis, which plays an important role in transient LES relaxation, which, as I mentioned earlier, is part of the real underlying problem of GERD.

Impressively, 100 percent of patients receiving this supplement reported a complete regression of symptoms after 40 days of treatment, compared to just under 66 percent of those taking omeprazole. The authors concluded that “this formulation promotes regression of GERD symptoms with no significant side effects.”

Smoking Gun for Stomach Drugs

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Proton pump inhibitors (PPIs) are among the most widely used medications in the U.S. This class of drug is used to treat chronic heartburn. Although the pain often happens in the lower to mid chest area, it is not related to heart disease or a heart attack.

Heartburn Treatment

Story at-a-glance –

  • Proton pump inhibitors (PPIs), medications used to treat chronic heartburn, can cause more health problems than they fix
  • Research has linked PPIs to kidney disease, dementia, heart attack, overgrowth of bacteria, infections, bone fractures and the fastest growing type of esophageal cancer
  • There are several much safer and natural ways of dealing with your heartburn, including changes to your clothing, weight, foods, finding your triggers and adding acid to your meals

Instead, heartburn pain happens when acid refluxes up your esophagus, burning the tissue. The fluid in your stomach is highly acidic, necessary for digestion of your food, protection against bacteria and absorption of many nutrients.

A variety of different reasons can cause this acidic fluid to pass the lower esophageal sphincter (LES) and burn your esophagus, but most cases of heartburn are due either to a hiatal hernia or Helicobacter pylori (H. pylori) infection.

Occasional heartburn is best treated with simple lifestyle changes, such as drinking a bit of apple cider vinegar in water right before or after your meals. Unfortunately, when you experience chronic pain over many weeks, your physician may prescribe a daily medication. PPIs are one class of those medications.

The top selling PPIs include Nexium, Prilosec and Prevacid, all available both as a prescription and over-the-counter (OTC). However, your doctor’s orders may actually do more harm than good in this instance, as these drugs tend to make your situation worse rather than better.

Smoking Gun Points to PPIs

Your cells use a proton pump to produce acid. PPI medications are designed to inhibit the proton pump and reduce the amount of acid produced. PPIs do not specifically target the cells in your stomach, and stomach acid is usually not the primary trigger behind chronic heartburn.

This class of drug is not specific, and instead will inhibit any cell with a proton pump producing acid, whether those cells are in your stomach or not. Researchers from Stanford University and Houston Methodist Hospital in Texas believe this is the smoking gun behind the variety of dangerous side effects linked to PPIs.1

The production of acid in your cells is associated with a specific cleanup process. The cells use acid to clean out end products and garbage from metabolism and cell function. When the acid is not present, there is a buildup of these toxins in the cells, which may lead to the development of a variety of significant health conditions.2

Excess stomach acid is not often the cause for your heartburn. Quite the opposite is true. Low amounts of stomach acid and the subsequent overgrowth of bacteria changes the digestion of carbohydrates, producing gas. The gas increases the pressure on the LES, releasing acid into the esophagus, creating heartburn.

While you may experience speedy relief of heartburn from immediate acting acid neutralizing medications such as TUMS, long-acting medications such as PPIs may increase your risk of heartburn over time.3

When Acid Levels Change, It Damages Your Body’s Ability to Function Properly

When PPIs were first approved by the U.S. Food and Drug Administration (FDA), they were designed to be taken for no more than six weeks. However, today it is not uncommon to find people who have been taking these drugs for more than 10 years.4 Long-term use has been associated with a number of different problems, including:

✓ Bacterial Overgrowth

Long-term use of PPIs encourages overgrowth of bacteria in your digestive tract.5 Bacterial overgrowth leads to malabsorption of nutrients and has been linked to inflammation of the stomach wall.6
✓ Reduced Absorption of Nutrients

One of the most common causes of impaired function of digestion and the absorption of nutrients is the reduction of stomach acid production.

This occurs in both the elderly and individuals on long-term antacid treatments, such as PPIs.7 Acid breaks down proteins, activates hormones and enzymes and protects your gut against overgrowth of bacteria.

Lack of acid results in iron and mineral deficiencies and incomplete digestion of proteins. This may also lead to a vitamin B12 deficiency.8 PPIs are also linked to a reduced absorption of magnesium. Low magnesium levels may lead to muscle spasms, heart palpitations and convulsions.9
✓ Low Stomach Acid

PPIs reduce the amount of stomach acid. Symptoms include heartburn, indigestion, bloating, diarrhea, burping, burning and flatulence.10
✓ Decreased Resistance to Infection

Your mouth, esophagus and intestines are home to a healthy growth of bacteria, but your stomach is relatively sterile. Stomach acid kills most of the bacteria coming from your food or liquids, protecting your stomach and your intestinal tract from abnormal bacterial growth.11

At the same time, the acid prevents the bacteria growing in your intestines from moving into your stomach or esophagus.

Reducing stomach acid changes the pH of your stomach and allows external bacteria to grow. PPIs may reduce acid between 90 and 95 percent, increasing your risk of salmonella, c. difficile, giardia and listeria infections.12,13

Other studies have linked the use of acid-reducing drugs to the development of pneumonia, tuberculosis (TB) and typhoid.14,15,16

The distortion of the gut microbiome affects your immune system and may increase your overall risk of infection. In vitro studies, those done on cells in test tubes, have found PPIs damage the function of white blood cells, responsible for fighting infection.17
✓ Increased Risk of Bone Fractures

Lowering stomach acid production may also reduce the amount of calcium absorption, which in turn may lead to osteoporosis.

Researchers have linked long-term, dose-dependent use of PPIs with increased risk of hip fracture. The longer you take the medication and the more you take, the higher your risk of fracture.18

Antacids and Aspirin

In addition to the side effects listed above, researchers are discovering other health conditions associated with the use of PPIs and other acid reducing drugs.

Even while on PPI medication, you may experience occasional heartburn. Immediate acting antacids used to neutralize the acid in your esophagus may offer relief. Just be aware that this is really only adding insult to injury.

What’s worse, some antacids also contain aspirin, which may heighten your risk of adverse effects. In 2009, the FDA issued a warning about severe bleeding associated with the use of aspirin.

Since that time, the FDA has recorded eight cases of severe bleeding resulting from using over-the-counter antacids to neutralize heartburn.19 In some of those cases, the individual required a blood transfusion to stabilize their condition.

In a statement, Dr. Karen Murry Mahoney, deputy director of the division of nonprescription drug products, said:

“Take a close look at the Drug Facts label, and if the product has aspirin, consider choosing something else for your stomach symptoms.

Unless people read the Drug Facts label when they’re looking for stomach symptom relief, they might not even think about the possibility that a stomach medicine could contain aspirin.”20

What Barrett’s Esophagus Means to You

Long-term gastric reflux and heartburn may lead to Barrett’s Esophagus. This is a change in the cellular structure of the lining of your esophagus in response to chronic exposure to acid. Risk factors for Barrett’s Esophagus include:

✓ Males ✓ Older age ✓ Tobacco use
✓ Obesity ✓ Alcohol use ✓ Caucasian or African-American

The risk of developing cancer of the esophagus is significantly higher when you have Barrett’s Esophagus. In past years, the more common form of skin cancer has been squamous cell carcinoma. However, researchers have now discovered if you have taken PPIs for an extended period of time and have developed Barrett’s Esophagus, you have an increased risk of a more aggressive form called adenocarcinoma.

As recently as 1975, 75 percent of the esophageal cancers diagnosed were squamous cell carcinomas. More amenable to treatment and less aggressive then adenocarcinoma, the numbers have radically shifted in the past 30 years.21 The rate of squamous cell carcinoma has declined slightly, but the number of diagnosed adenocarcinoma of the esophagus has risen dramatically.

In 1975, 4 people per million were diagnosed with adenocarcinoma, and in 2001 it rose to 23 people per million, making it the fastest growing cancer in the U.S. according to the National Cancer Institute (NCI).22

Adenocarcinoma is now diagnosed in 80 percent of all esophageal cancers.23 Researchers theorized PPIs would protect people with Barrett’s Esophagus from adenocarcinoma, but found the reverse to be true. Not only did PPIs not protect the esophagus, but instead there was a dramatic increase in the risk of this deadly cancer, discovered in two separate studies.24,25

PPIs May Raise Your Risk for Dementia, Kidney Disease and Heart Attacks

PPIs affect all cells in your body, which may explain why they have been linked to such deadly conditions as kidney disease, heart attacks and dementia. In the past, PPIs were linked to acute interstitial nephritis, an inflammatory process in the kidneys. In a recent study of over 10,000 participants, researchers found another link to chronic kidney disease.26

The team found that those using PPIs to treat heartburn were more likely than other individuals on different heartburn medications to suffer chronic kidney disease or kidney failure over a five-year period.27

Dr. Ziyad Al-Aly, one of the researchers and a kidney specialist with the Veterans Affairs St. Louis Health Care System, said the findings illuminated a significant point: “I think people see these medications at the drug store and assume they’re completely safe. But there’s growing evidence they’re not as safe as we’ve thought.”28

PPIs have also been linked to dementia in people over age 75. In a study evaluating over 73,000 people over age 75 without any signs of dementia at the outset of the study, researchers made a startling connection. Of the individuals who developed dementia in the following seven years, those who regularly used PPIs had a significantly higher risk of the condition.29

A large data-mining study performed by researchers from Stanford University discovered PPIs were also associated with an increased risk of heart attack, while other long-term heartburn medications were not.30

What Can You Do to Prevent or Treat Heartburn?

In many cases, the root cause of heartburn is not linked to an overproduction of acid, but rather an underproduction. So before risking your health by using heartburn medications like antacids and PPIs, try these natural options:

✓ Address Your Diet

The answer to heartburn and acid indigestion is to restore your natural gastric balance and function. To do that, eat lots of vegetables and other high-quality, ideally organic, unprocessed foods, and make sure you’re getting enough beneficial bacteria from your diet by regularly consuming fermented foods. This will help balance your bowel flora, which can help eliminate H. pylori bacteria — which is a very common cause of heartburn — naturally.
✓ Add Acid

It might seem counterintuitive to add acid to an acidic environment, but as you’ve already discovered, many cases of heartburn are triggered by low acid production. One strategy is to take 3 teaspoons of raw, unfiltered apple cider vinegar in 6 to 8 ounces of fresh water before each meal.31 For a list of other alternatives that can help promote acid production, please see my previous article, “15 Natural Remedies for the Treatment of Acid Reflux.”
✓ Work With Gravity

Heartburn tends to be worse at night, and/or after you lie down. Rather than lying down right after a meal, stay seated or standing for at least three hours, as food pressing on your LES will increase your risk of heartburn. Elevate the head of your bed using blocks sold for that purpose so your bed doesn’t slip and cause injury.32

Avoid stacking pillows to elevate your head, as this can increase pressure on your LES. High pillows also cause poor alignment of your neck and spine, increasing your risk for neck pain.
✓ Ginger Root Tea

Ginger root has been traditionally used against gastric disturbances since ancient times. Its gastroprotective effect comes from blocking acid and suppressing H. pylori. To make your own tea, simmer three slices of raw ginger root in 2 cups of water for about 30 minutes. Drinking it 20 minutes before your meal can help prevent heartburn from developing.
✓ Avoid Tight-Fitting Clothing

Tight clothing increases the pressure on your LES and increases the risk of an acid leak into your esophagus.
✓ Maintain a Healthy Weight

Excess weight around your middle places excess pressure on your LES. Even losing 15 pounds can make a positive difference in your symptoms.
✓ Avoid Triggers

Track the foods that increase your risk of heartburn. It might take some time, but it is well worth the effort.
✓ Organic Coconut Oil

Coconut oil is a natural antibacterial, helping to reduce any overgrowth of bacteria in your stomach. It also helps to soothe your esophagus on the way down, and is a very healthy fat that is good for your overall health. Start with 1 teaspoon to see how your body responds. Common side effects are headache and slight nausea. Gradually work up to 3 tablespoons a day. You could also try adding 1 tablespoon to a cup of tea or coffee.

Mild Kidney Disease Tied to Adverse Pregnancy Outcomes

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Across all stages of kidney disease, the risk for adverse pregnancy outcomes increases, according to a prospective observational study published online March 12 in the Journal of the American Society of Nephrology. Yet the data also indicate that good maternal–fetal outcomes are possible even in the presence of advanced disease.

These findings may be useful for counseling and monitoring affected women during pregnancy, note researchers led by nephrologist Giorgina Piccoli, MD, from San Luigi University Hospital, University of Turin, Italy.
The Torino-Cagliari Observational Study (TOCOS) compared pregnancy outcomes in 504 women with chronic kidney disease (CKD) with those in 836 well-matched low-risk women. The mean age of mothers with CKD in Turin and Cagliari was 31.9 years, and the mean age of the controls in both centers was 29.9 years. The majority of participants were white, and more than half of patients and control participants were nulliparous (56.2% and 58.1%, respectively).

Baseline assessments included hypertension, proteinuria (>1 g/day), systemic disease, and CKD stage at referral. The researchers followed the women, noting adverse outcomes including caesarean section, preterm delivery (<37 weeks), early preterm delivery (<34 weeks), small size for gestational age (SGA), neonatal intensive care unit (NICU) use, new onset of maternal hypertension, new onset or doubling of proteinuria, and CKD stage shift. In addition, they assessed the pregnancies for general combined outcome (preterm delivery, NICU, SGA) and severe combined outcome (early preterm delivery, NICU, SGA).

The risk for adverse outcomes increased in stepwise fashion across all disease stages. For stage 1 vs stages 4 to 5, the general combined outcome was 34.1% vs 90.0%; the severe combined outcome was 21.4% vs 80.0% (P < .001).

In stage 1 CKD, preterm delivery was associated with baseline hypertension, systemic disease, and proteinuria. However, even after adjusting for these classic risks, stage 1 CKD remained associated with adverse pregnancy outcomes even in women without baseline hypertension, proteinuria, or systemic disease (odds ratio, 1.88; 95% confidence interval, 1.27 – 2.79) compared with women in control group.

In terms of specific maternal–fetal outcomes, in women with stage 1 CKD, the rate of caesarean section was 48.4% vs 70.1% for stage 2, 78.4% for stage 3, and 70.0% for stages 4 to 5 (P < .001). Preterm delivery rate was 23.5% for stage 1 vs 50.6% for stage 2, 78.4% for stage 3, and 88.9% for stages 4 to 5 (P < .001). NICU rates by stage were 10.3%, 27.6%, 44.4%, and 70.0% (P < .001). SGA (<10%) by stage was 13.3%, 17.9%, 18.9%, and 50.0% (P = .023). General combined outcome ranged from 34.1% to 90.0% (P < .001), and severe combined outcome from 21.4% 80.0% (P < .001).
New-onset maternal hypertension ranged from 7.9% in stage 1 to 50.0% in stages 4 to 5 (P < .001). New-onset or doubling of proteinuria was 20.5% in stage 1 and 70.0% in stages 4 to 5 (P < .001).

The risk for intrauterine death did not differ between patients and controls.

“Renal function matters, and its effect is likely to be continuous: considering only the cases with a live-born baby, our data confirm a stepwise increase in pregnancy-related risks from stage 1 to stage 4-5,” the authors write. “Interestingly, there is a significant increase in risk from stage 1 to stage 2 CKD, which represents a sort of ‘gray’ area with regard to kidney function.”

The authors also note that the TOCOS data contrast with the data from a 2009 population-based study that found no additional risk with a mild reduction in glomerular filtration rate, thus suggesting that the clinical definition of CKD is more complex than the mere evaluation of glomerular filtration rate.

They recommend that clinicians take special care when treating pregnant women with CKD, even in the absence of known risk factors.

Commenting in an American Society of Nephrology press release, lead author Dr Piccoli said, “The findings indicate that any kidney disease — even the least severe, such as a kidney scar [from] a previous episode of kidney infection, with normal kidney function — has to be regarded as relevant in pregnancy, and all patients should undergo a particularly careful follow-up.” She added that “a good outcome was possible in patients with advanced CKD, who are often discouraged to pursue pregnancy.”

Is ESRD Finally on the Decline?

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USRDS data show a decline in ESRD incidence for the third year in a row.

  • Medpage Today

New cases of end-stage renal disease in the U.S. have declined for the third year in a row, potentially signaling a downward trend, researchers reported.

There were 114,813 new ESRD patients in 2012 — a 3.7% drop from 2011, according to an analysis of data from the United States Renal and Dialysis System (USRDS).

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“Early trends indicate that the ESRD incidence rate may have begun to decrease after having plateaued for many years,” researchers wrote in the report, which was published online.

Rajiv Saran, MD, of the University of Michigan, and director of the USRDS coordinating center, said that while it’s “too soon to declare victory on the war against the rising tide of kidney failure,” their report “provides some good news about kidney disease in the U.S.”

“We will follow these trends closely to see whether they are sustained over the coming years, study what factors may be responsible for bringing about this positive change, and explore how it may be even further accelerated,” he added.

Saran told MedPage Today that some factors that could account for the decline could include earlier detection of chronic kidney disease, better CKD guidelines such as KDOQI, more appropriate referrals to kidney specialists “perhaps as a result of more frequent eGFR reporting by laboratories,” better detection and care of upstream CKD risk factors such as diabetes and hypertension, and better CKD care in general that results in slower disease progression.

Despite the decrease in incidence, 636,905 patients were still being treated for ESRD in 2012 — a 1.3% increase from the prior year.

But the rate of growth of the prevalent ESRD population is slowing, researchers said, with the percentage increases in 2011 and 2012 being the lowest recorded in the last 3 decades.

About 450,000 ESRD patients were being treated with dialysis, while 186,303 had a functioning kidney transplant. There were 17,330 transplants in 2012, including 5,617 from living donors.

And 28,867 patients were added to transplant waiting lists, including both the kidney and kidney/pancreas lists. Nearly 82,000 patients were on the transplant list at the end of 2011, the researchers said.